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Stem Cells International
Volume 2019, Article ID 5171032, 15 pages
https://doi.org/10.1155/2019/5171032
Review Article

Recent Updates on Induced Pluripotent Stem Cells in Hematological Disorders

Siriraj Center for Regenerative Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand

Correspondence should be addressed to Methichit Wattanapanitch; ht.ca.lodiham@taw.tihcihtem

Received 2 November 2018; Accepted 31 March 2019; Published 2 May 2019

Academic Editor: Holm Zaehres

Copyright © 2019 Methichit Wattanapanitch. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Over the past decade, enormous progress has been made in the field of induced pluripotent stem cells (iPSCs). Patients’ somatic cells such as skin fibroblasts or blood cells can be used to generate disease-specific pluripotent stem cells, which have unlimited proliferation and can differentiate into all cell types of the body. Human iPSCs offer great promises and opportunities for treatments of degenerative diseases and studying disease pathology and drug screening. So far, many iPSC-derived disease models have led to the discovery of novel pathological mechanisms as well as new drugs in the pipeline that have been tested in the iPSC-derived cells for efficacy and potential toxicities. Furthermore, recent advances in genome editing technology in combination with the iPSC technology have provided a versatile platform for studying stem cell biology and regenerative medicine. In this review, an overview of iPSCs, patient-specific iPSCs for disease modeling and drug screening, applications of iPSCs and genome editing technology in hematological disorders, remaining challenges, and future perspectives of iPSCs in hematological diseases will be discussed.

1. Introduction

Pluripotent stem cells (PSCs) including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have unlimited self-renewal and proliferation properties as well as an ability to differentiate into mature cell types of all three embryonic germ layers [1, 2]. PSCs offer great potentials to generate clinically relevant number of cells and could provide an alternative source of cells for regenerative medicine [3, 4]. Currently, patient-specific iPSCs can be achieved by reprogramming of adult somatic cells by ectopic expression of pluripotency-associated transcription factors including OCT4, SOX2, KLF4, and c-MYC [2]. The reprogrammed iPSCs have similar characteristics as human ESCs (hESCs) in terms of their self-renewal and differentiation potentials. These patient-specific iPSCs can bypass previous limitations including immunological rejection and ethical barriers that impede the use of hESCs. In addition, they would allow better understanding of mechanisms underlying several human genetic, malignant, and nonmalignant diseases. Recently, genome editing technologies have been applied to correct the mutation of disease-specific iPSCs to create gene-corrected iPSCs, which can be used for autologous cell-based therapy. This review is aimed at providing an update on cellular reprogramming in basic research and potential applications in hematological disorders.

2. Generation of Patient-Specific iPSCs

Reprogramming process involves ectopic expression of pluripotency-associated genes including OCT3/4, SOX2, KLF4, and c-MYC into somatic cells. Initially, Takahashi and colleagues performed reprogramming in mouse and human fibroblasts using retroviral transduction as a delivery method [2, 5]. One of Yamanaka’s factor, c-MYC, is a protooncogene which confers a risk of tumor formation once it gets reactivated. Yu and colleagues reported the use of NANOG and LIN28 to replace KLF4 and c-MYC for reprogramming human fibroblasts, thus providing a safer alternative for clinical applications [6]. The retroviral and lentiviral systems can result in genomic integration of transgenes, therefore increasing the risk of insertional mutagenesis. The lentiviral method has advantages over the retroviral method since it can infect both dividing and nondividing cells giving higher reprogramming efficiency and providing an opportunity for transgene excision via Cre-loxP recombination [7, 8]. Previous studies demonstrated that the transcriptomic profiles of human iPSCs generated by nonintegrating methods are more closely similar to those of the hESCs or the fully reprogrammed cells than those of the iPSCs generated from integrating methods [9]. To facilitate future clinical applications, nonintegrating delivery methods such as adenovirus [10, 11], episomal plasmids (Epi) [12], minicircle DNA vectors [13], piggyBac transposons [14], proteins [15], synthetic mRNAs [16, 17], Sendai virus (SeV) [18, 19], and microRNA mimics [20, 21] have been developed. Each reprogramming strategy has its advantages and disadvantages [22, 23]. Factors determining which reprogramming method is suitable to use are the number and type of starting cells, the reprogramming efficiency, footprint, and long-term translational goals [23]. Reprogramming efficiencies of the nonintegrating methods such as adenoviral vectors (0.0002% [10]), minicircle DNA vectors (0.005% [13]), and proteins (0.001% [15]) are very low. It is also labor intensive and technically challenging to synthesize large amounts of proteins for reprogramming. Of these nonintegrating methods, Epi, mRNA, and SeV are more commonly used and were evaluated systematically by Schlaeger et al. [22]. The efficiency of the mRNA-based reprogramming was the highest (2.1%), followed by SeV (0.077%) and Epi (0.013%) as compared to the lentiviral reprogramming (Lenti) (0.27%). However, the mRNA-based method is not so reliable, as the success rate was significantly lower than other methods (mRNA 27%, SeV 94%, Epi 93%, and Lenti 100%). In terms of workload, the SeV method required the least hands-on time until the colonies were ready for picking whereas the mRNA method required the most hands-on time due to the need for daily transfection for 7 days [16, 17]. Importantly, the mRNA method failed to reprogram hematopoietic cells. Therefore, the SeV, Epi, or Lenti reprogramming must be used for specific hematological diseases that require blood cells for reprogramming. For clinical translation, Epi reprogramming is the most cost-effective and well-suited because the process can be made compliant with current good manufacturing practice (cGMP) [22]. Recently, the CTS CytoTune-iPS 2.1 SeV reprogramming suitable for clinical and translational research is commercially available. However, the clinical-grade kit is very expensive; therefore, the method is not widely used in clinical trials. In 2014, the first clinical trial to treat a patient with neovascular age-related macular degeneration (AMD) used autologous iPSCs generated using nonintegrating Epi vectors, which were proven to be safe for the patient [24].

Generation of patient-specific iPSCs requires somatic cells such as fibroblasts [25] or peripheral blood mononuclear cells [26, 27], as starting materials. There have been reports of other somatic cell types used for the derivation of iPSCs including umbilical cord blood [28, 29], bone marrow [30], amniotic fluid or chorionic villus sample-derived cells from prenatal diagnosis [31], stomach and liver cells [32], neural stem cells [33, 34], and endothelial cells [35]. In order to obtain these cells, invasive procedures performed by medical professionals are required. Recently, easily accessible and noninvasive cell sources including keratinocytes from plucked hair [3638] and exfoliated renal epithelial cells from urine samples [3941] were isolated for iPSC reprogramming, thus allowing simple and noninvasive sample acquisition. These approaches offer advantages especially when subjects are infants or individuals with bleeding disorders. Reprogramming efficiency of each somatic cell type usually varies depending on the endogenous factors that they express, e.g., neural stem cells which endogenously express Sox2 require only Oct4 and/or Klf4 during the reprogramming process [34, 42]. The differentiation stages of somatic cells also determine the reprogramming efficiency, e.g., hematopoietic stem cells or progenitor cells can be reprogrammed with higher efficiency than terminally differentiated B cells or T cells [43]. Despite various cell types used, fibroblasts and peripheral blood mononuclear cells remain the gold standard because of their ease of isolation and reprogramming. A recent study revealed that aberrant hypermethylation in undifferentiated iPSCs acquired during reprogramming process was found to be a crucial factor that affected hematopoietic differentiation capacity, irrespective of the starting cell type. However, iPSCs derived from blood cells were unlikely to acquire aberrant DNA methylations, and these cells had higher hematopoietic differentiation capacity when compared with iPSCs from other parental tissues. In addition, the reprogramming methods were associated with aberrant DNA methylation and maturation capacity; the Epi and SeV methods gave rise to iPSCs with various aberrant DNA methylation levels and hematopoietic differentiation capacity whereas the retroviral reprogramming gave rise to iPSCs with high aberrant DNA methylation and attenuated differentiation capacity [44]. Therefore, it is crucial to identify the starting cell types and reprogramming methods to generate iPSC lines that are suitable for specific applications.

3. iPSCs as Disease Models for Hematological Disorders

Conventionally, transgenic animal models have been used to elucidate disease pathophysiology. However, many of these models do not completely recapitulate disease phenotypes due to fundamental differences between species. In order to study hematological diseases, which affect hematopoietic stem/progenitor cells (HSPCs) in the bone marrow, these cells have to be expanded ex vivo. However, during the past two decades, there had been no robust method for maintaining these HSPCs ex vivo in their multipotent stage [45, 46]. This becomes an important issue especially for diseases affecting mainly the bone marrow such as idiopathic myelofibrosis or aplastic anemia where the tissue samples are really scarce. Therefore, most studies have relied on the use of peripheral blood cells, which have a limited lifespan in culture, for studying disease pathology. The lack of protocol to maintain and amplify these primary cells also hinders genetic modifications, which are important tools to study candidate gene function [45, 47].

The advent of iPSC technology has transformed the way we study disease mechanisms by providing more opportunities to generate numerous disease models from patients. Disease-specific iPSCs and their derivatives represent an early stage of disease thus providing very useful information for elucidating pathological events during disease initiation and progression otherwise undetectable in primary cells. For generation of blood disease models, selection of starting somatic cells that carry genetic or acquired mutations is essential. For genetic blood disorders such as sickle cell disease, thalassemia, and X-linked chronic granulomatous disease, disease-specific iPSCs can be generated from both skin biopsy (fibroblasts) and blood. However, for acquired blood diseases such as aplastic anemia, leukemia, myelodysplastic syndrome, myeloproliferative neoplasms, and paroxysmal nocturnal hemoglobinuria, where only certain hematopoietic (stem/progenitor) cells are affected, disease-specific iPSCs can be generated from the abnormal or malignant hematopoietic clones. Typically, samples are taken from the bone marrow or peripheral blood mononuclear cells, which are very heterogeneous and contain a mixture of normal cells and premalignant and malignant clones. These clonal subpopulations can vary among samples depending on the disease progression, remission, administered therapies, or in vitro culture. Therefore, characterization of cells by next-generation sequencing is necessary to select the suitable starting cells for reprogramming [48]. In contrast, iPSCs derived from fibroblasts of patients with these acquired diseases do not carry the genetic mutations; therefore, they can serve as germ line controls or can be used for production of disease-free HSPCs for autologous transplantation or generation of immune cells for adoptive immunotherapy [45, 49]. Table 1 summarizes the work on disease-specific iPSCs from patients with genetic and acquired diseases for modeling.

Table 1: iPSCs as disease models and applications of gene therapy or genome editing for hematological disorders.

4. iPSCs for Drug Screening and Toxicity Testing

A large number of drugs in the market have been developed through cell line-based compound screening and animal testing. However, drug responses tested in animals cannot always be used to predict safety and efficacy in humans. Many drugs failed to enter the market due to unanticipated adverse effects mainly cardiotoxicity and hepatotoxicity in late-stage trials [50]. Advances in iPSC technology allow generation of unlimited supplies of disease-specific iPSCs from heterogeneous backgrounds such as gender and ethnicity. These cells can be differentiated into disease-relevant cell types that demonstrate the disease phenotype similar to primary cells that are hard to access and have limited proliferation. A large panel of disease-specific iPSCs and their derivatives enable high-throughput screening assay against the library of hundreds of thousand compounds. This approach could facilitate the development of novel therapeutics (Figure 1). In addition to efficacy testing in disease-relevant cell types, other cell types such as cardiomyocytes [51, 52] and hepatocytes [53] can be derived from patient’s iPSCs. This is very beneficial for evaluating potential drug toxicities at early stages of drug development and could minimize the use of animals during drug testing as well as saving considerable time and costs [54]. These iPSC-based phenotypic assays together with high content screening platform represent a new paradigm for drug discovery. To date, most studies using disease-specific iPSCs for drug screening have been successfully carried out in neuronal diseases such as Alzheimer’s disease [55], amyotrophic lateral sclerosis [56], motor neuron disease [57], spinal muscular atrophy [58], familial dysautonomia [59], Rett syndrome [60], and Parkinson’s disease [61] as well as in metabolic liver diseases such as hypercholesterolemia [62].

Figure 1: Applications of iPSCs for disease modeling and autologous cell-based therapy. Disease-specific iPSCs can be generated from patients with inherited blood diseases. A panel of disease-specific iPSCs and their derivatives enable high-throughput screening assay against the library of hundreds of thousand compounds. This approach represents a powerful tool for elucidating disease mechanisms and developing new drugs. Alternatively, the genome editing technology can be employed to correct genetic mutations followed by directed differentiation; the gene-corrected iPSC-derived hematopoietic stem cells (HSCs) or other mature blood cells can be transplanted or transfused to the same patient.

For hematological diseases, JAK kinase inhibitors have been examined in hematopoietic cells differentiated from polycythemia vera- (PV-) derived iPSCs [63]. In this study, peripheral blood mononuclear cells of multiple patients with JAK2-V617F mutations were reprogrammed into iPSCs. A panel of iPSCs with different JAK2 allele compositions including homozygous, heterozygous, and wild type was differentiated into erythroid cells. Samples derived from homozygous and heterozygous JAK2-V617F iPSCs underwent enhanced erythropoiesis when compared to the wild-type iPSCs. Once the HSPCs were treated with JAK inhibitors INCB018424 (approved drug), TG101348 (in clinical trial), or CYT387 (in clinical trial), erythroid proliferation was inhibited in a dose-dependent manner. Both INCB018424 and TG101348 were able to block cell proliferation completely at nM whereas CYT387 showed less activity. These data were in accordance with the clinical trial results that the anemia conditions were observed in patients treated with INCB018424 or TG101348. In contrast, the anemia conditions were improved in some myelofibrosis patients treated with CYT387. Furthermore, JAK2-V617F iPSC-derived CD34+ progenitors were more resistant to JAK inhibitors whereas the derived erythroblasts were sensitive, thus underlying the ineffectiveness of the JAK inhibitors in destroying the diseased clones. More recently, Diamond-Blackfan anemia- (DBA-) iPSCs were generated to model defect in erythropoiesis and screen for novel therapeutics. HSPCs derived from DBA-iPSCs were chemically screened in comparison to the control iPSCs. Treatment with a small molecule inducer of autophagy, SMER28, resulted in enhanced erythropoiesis through the autophagy factor ATG5 and upregulation of globin gene expression in DBA-iPSC-derived erythroid cells [64].

Patient-specific iPSCs were used for modeling myeloid malignancy, which is a disease spectrum ranging from clonal hematopoiesis to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Derivation of iPSCs from the bone marrow or peripheral blood mononuclear cells of patients with different disease stages gave rise to a panel of iPSC lines. A thorough genetic analysis showed that there were normal iPS clones as well as subclones with a variety of genetic mutations and chromosomal abnormalities associated with myeloid neoplasms. Upon hematopoietic differentiation, the high-risk MDS iPSCs had impaired differentiation and reduced clonogenicity affecting erythroid and multilineage progenitors as compared to the low-risk MDS iPSCs, preleukemic or normal iPSCs recapitulating features of disease progression. The disease stage-specific iPSCs were used to study the effects of therapeutic intervention such as the hypomethylating agent, 5-azacytidine (5-AzaC), which is the first-line therapy in MDS, and rigosertib, a small molecule inhibitor of RAS signaling pathways currently in clinical trials for the treatment of high-risk MDS. Treatment with 5-AzaC or rigosertib in HSPCs derived from different disease stage-specific iPSCs resulted in different therapeutic effects [65]. These studies demonstrated the usefulness of disease-specific iPSCs as a powerful tool for elucidating potential drug mechanisms and developing novel therapeutics.

5. iPSCs as an Alternative Source for Autologous Cell-Based Therapy

Hematopoietic stem cell transplantation (HSCT) has been used as a standard of care for the treatment of genetic, malignant, and nonmalignant hematological diseases such as multiple myeloma, lymphoma, aplastic anemia, myeloproliferative disorders, myelodysplastic syndromes, thalassemia, Wiskott-Aldrich syndrome (WAS), sickle cell anemia (SCD), severe combined immunodeficiency (SCID), and autoimmune disorders [98]. HSCs are multipotent stem cells, which are able to self-renew and give rise to all the blood progenitors and mature blood cells. HSCs can be directly obtained from the bone marrow of adults, mobilized peripheral blood and cord blood during normal delivery. Since the bone marrow biopsy is invasive, the granulocyte colony-stimulating factor- (GCSF-) mobilized peripheral blood is more commonly used for most autologous and allogeneic transplantation. However, if the suitable donors with HLA matches are not found, HSCs from cryopreserved cord blood can also be used as an alternative source because they are readily available and cord blood transplantation requires less stringent HLA matching than bone marrow or peripheral blood [99, 100]. Nevertheless, the major limitation of cord blood HSCs is the low number of HSCs in the stored units. Therefore, infusion of two partially HLA-matched cord blood units is required for transplantation into an adult patient [101104].

Despite the success in the HSCT, many patients who received allogeneic HSCT have suffered from major complications such as acute and chronic graft-versus-host diseases (GVHD), which can lead to significant morbidity and mortality [105]. In contrast, autologous HSCT has lower mortality rate as compared to allogeneic HSCT (less than 2% vs. 10%, respectively) [98] and fewer highly morbid immune responses from delayed engraftment. Therefore, autologous HSCs are a good candidate. However, for genetic blood diseases, genetic correction in patient’s HSCs is necessary prior to autologous transplantation. At the moment, the main hurdles impeding the wider clinical applications are the challenge of HSPC expansion in culture [46, 105]. These limitations necessitate an unlimited renewable source of surrogate cells for transplantation. iPSCs provide an inexhaustible source of autologous cells that are amenable for genetic correction and can be subsequently directed to differentiate to HSPCs. For certain acquired blood diseases such as paroxysmal nocturnal hemoglobinuria (PNH) [106] or acute myeloid leukemia (AML) [107], iPSCs derived from mutation-free somatic cell sources such as fibroblasts can be used to generate disease-free iPSCs and healthy HSPCs for autologous transplantation. In contrast, iPSCs from genetic blood diseases require gene therapy or correction before differentiation into HSPCs.

In 2007, Hanna and colleagues demonstrated the first proof of principle for the treatment of sickle cell anemia by combining autologous iPSCs from humanized sickle cell anemia mouse model with gene therapy to correct sickle cell mutation in iPSCs. The corrected iPSCs were then differentiated into HSPCs and transplanted into the irradiated mouse with sickle cell anemia to improve all hematological and systemic parameters of sickle cell anemia [108]. Early studies using patient-specific iPSCs as a potential source for autologous cell-based therapy relied on the use of low-efficiency homologous recombination [109] or lentiviral gene therapy [110, 111]. A drawback of the lentiviral gene therapy system is random integration of a functional gene into the genome, which can result in undesired mutations. Over the past few years, the emergence of genome editing technology such as zinc-finger nucleases (ZFNs), transcriptional activator-like effector nucleases (TALENs), or clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 has opened up the opportunity to correct genetic mutation in iPSCs. This technology relies on artificial endonuclease enzymes that specifically target the DNA sequence and create DNA double-strand breaks (DSBs). The DSBs can then be repaired by an error-prone process called nonhomologous end-joining (NHEJ) in the absence of DNA template, which leads to insertions or deletions (indels). Alternatively, the target sequence can be repaired by introducing a homologous repair template via homology-directed repair (HDR). ZFNs and TALENs are based on DNA-binding proteins and therefore involve protein design and synthesis, which are difficult and labor intensive. On the other hand, CRISPR/Cas9 system, which relies on short guide RNAs (gRNA) to drive RNA-binding Cas9 nuclease to precisely target DSB, has been reported to be much more efficient and easier to design, making rapid adoption by laboratories around the world [112, 113]. Recent studies demonstrated the use of genome editing tools and iPSC technology for targeting monogenic blood diseases. Table 1 summarizes the studies using disease-specific iPSCs and the genome editing technology to correct genetic mutations of blood diseases followed by directed differentiation of the gene-corrected iPSCs into HSPCs or relevant blood cell types. In most studies, the gene-corrected iPSCs and their derivatives showed restoration of gene and protein expressions. These approaches therefore offer promises for autologous cell-based therapy (Figure 1).

In order to apply iPSCs for blood disease modeling and cell-based therapy, generation of the most desired cell types including HSPCs and their progenies is required. These cells must be efficiently generated and expanded to clinical scale. To date, the biggest challenge that hampers clinical use of iPSC-derived HSPCs is to generate functional HSPCs that are expandable, transplantable, and engraftable. Over the last decade, various hematopoietic induction protocols including stromal cell- (feeder-) based [114, 115], embryoid body- (EB-) based [116118], and chemically defined protocols [119, 120] have been reported with varying efficiencies. However, these protocols produced short-lived progenitors, which recapitulate primitive hematopoiesis that occurs in the extraembryonic yolk sac. These progenitor cells can only give rise to myeloid cells and nucleated erythrocytes not the lymphoid lineage and lack repopulating and engraftment potentials [121]. Later, stage-specific induction protocols recapitulating hematopoietic ontogeny have been introduced. These protocols rely on the use of cytokines and morphogens such as bone morphogenetic protein 4 (BMP4) to promote mesoderm specification (KDR+/CD235a-) and the GSK-3β inhibitor (CHIR99021, a Wnt agonist) or TGFβ inhibitor (SB-431542) during the same timeframe to promote definitive hemogenic endothelium (HE, CD34+/CD43-/CD73-/CD184-) while inhibiting primitive hematopoiesis. Addition of vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), and hematopoietic cytokines further specifies the HE cells toward HSPCs, CD34+/CD43+, through the process known as endothelial-to-hematopoietic transition (EHT) [122126]. Most of the stepwise protocols give rise to larger numbers of CD34+/CD43+ HSPCs as compared to the OP9 coculture system. However, there has been no report on the engraftment potential of iPSC-derived HSPCs from these stepwise differentiation protocols. In contrast, using in vivo differentiation approach via teratoma formation, HSPCs with engraftable potential and multilineage reconstitution were generated [127, 128]. However, such process is variable and these cells are not applicable for future clinical setting.

More attempts have been made to identify the combination of transcription factors that can reprogram the somatic cells to HSC-like cells, the so-called induced HSCs (iHSCs). These approaches involve respecification of somatic cells to functional HSPCs. Daley’s group respecified iPSC-derived CD34+/CD45+ myeloid progenitors by ectopic expression of the five transcription factors, HOXA9, ERG, RORA, SOX4, and MYB, toward multilineage progenitors that can be expanded in vitro and engrafted in vivo. These five factors promoted only short-term engraftment of erythroid and myeloid cells. The erythroid precursors were matured, underwent enucleation, and expressed adult hemoglobin [129]. In another report, they generated HSPCs from iPSC-derived HE using a combination of seven transcription factors, ERG, HOXA5, HOXA9, HOXA10, LCOR, RUNX1, and SPI1. These factors supported multilineage/long-term engraftment and reconstitution of HE undergoing endothelial-to-mesenchymal transition (EHT) upon transplantation into primary and secondary sublethally irradiated NSG mice [130]. More recently, using only a single factor, MLL-AF4, iPSC-derived blood cells can be respecified toward long-term engraftable iHSPCs with reconstitution potential toward both myeloid and lymphoid lineages. However, these cells are prone to leukemic transformation during the long-term engraftment period suggesting that the cells are genomically unstable. Interestingly, the genetic aberrations were not found in the in vitro-derived iHSPCs [131]. This finding necessitates further investigations into cellular identity of the iHSPCs and underlying mechanism of leukemic transformation upon transplantation. Therefore, more precise knowledge of supportive cues and transcription factors involved during adult-type definitive hematopoiesis is necessary for generation of safe and functional HSPCs from iPSCs [121, 132].

Apart from efforts to generate HSPCs, differentiation protocols to various blood cell types such as red blood cells (RBCs) [133135], platelets [136139], T lymphocytes [140145], and natural killer (NK) cells [146148] have also been reported. Since RBCs and platelets lack nucleus, they have lower risks of tumorigenesis. Production of universal donor RBCs and platelets generated from iPSCs of blood group O Rh- donors represents an inexhaustible supply for transfusion medicine. However, clinical applications of iPSC-derived RBCs are hindered by terminal maturation of iPSC-derived RBCs, which do not enucleate efficiently and still express mainly embryonic and fetal hemoglobin [134, 135, 149]. Similarly, the major limitation of generation of universal platelets has been inefficient maturation of iPSC-derived megakaryocytes to platelets, which makes the large-scale manufacturing procedure challenging [150]. The forward programming strategy in PSCs by exogenous expression of three transcription factors, GATA1, FLI1, and TAL1, efficiently enhanced production of megakaryocytes allowing the release of functional platelets to large quantities suitable for clinical applications [138]. More recently, turbulence-controllable bioreactors were applied to enhance shedding of platelets and allowed scale up of platelet production to clinically relevant numbers [139]. Generation of cytotoxic T lymphocytes (CTLs) and NK cells from iPSCs has been shown to provide a large supply of rejuvenated cells for adoptive immunotherapy. To date, there have been a number of reports generating iPSC-derived antigen-specific CTLs for the treatment of cancers or infectious diseases including melanoma [144], acute myeloid leukemia [141], hepatocellular carcinoma [145], and EBV [141] and HIV [142] infection. The obtained CTLs had higher proliferation and longer telomere as compared to the original T cells and expressed central memory T cell markers (CCR7, CD27, and CD28), not the exhaustion marker (PD-1) [142]. Recently, chimeric antigen receptor (CAR) technology has been applied for engineering iPSCs to generate CAR-T cells [143] and CAR-NK cells [148] with increased specificity and cytotoxicity for adoptive immunotherapy. Currently, protocols for directed differentiation of iPSCs to functional T or NK cells have relied on the use of mouse stromal cells such as OP9 cells or OP9 cells expressing Notch ligand Delta-like-1 or 4 (OP9-DL1 or DL4) [147, 151, 152]. For clinical application, it is necessary to avoid the use of serum and animal cells for coculturing. To overcome this issue, attempts have been made to replace serum and stromal cells with a fully defined engineered thymus-like niche consisting of recombinant vascular cell adhesion molecule 1 (VCAM-1) and DLL4 for T cell differentiation. This system enabled generation of CD7+ progenitor T cells (proT cells) from cord blood CD34+ HSPCs [153]. Although the in vitro maturation of proT cells to functional T cells has not been demonstrated, this approach provides an important step toward fully defined and xeno-free differentiation platform that can be applied for future therapeutic uses. Similar to in vitro generation of HSPCs, the production of functional hematopoietic cells is still a very inefficient process especially in terms of differentiation efficiency and ex vivo expansion to clinical scale. To overcome these limitations, more detailed knowledge about embryonic and fetal hematopoiesis during human development is necessary.

6. Challenges and Future Perspectives of iPSC Applications

Since the discovery of iPSCs, several progresses have been made to bring iPSCs into clinics. However, there are still important challenges and issues that have to be addressed including the development of safe and clinically relevant iPSCs and generation of functional HSCs and their progenies. For clinical applications, culture and isolation of somatic cells as well as reprogramming process must be xeno-free and clinical grade and performed under good manufacturing practice (GMP) standards. Methods for generation of iPSCs must be integration-free in order to avoid the risks of insertional mutagenesis and transgene reactivation, which can result in tumor formation. In addition, long-term maintenance of iPSC culture can result in the acquisition of chromosomal abnormalities and changes in copy number variants. Standard karyotyping analysis is unable to detect such small chromosomal aberration; therefore, routine examination such as whole genome screening using comparative genomic hybridization is required. After differentiation into specific cell types, DNA methylation and gene/protein expression profiles as well as functional assay of the iPSC-derived cells should be validated and compared with those of the original tissue. Furthermore, tumorigenic potential of residual pluripotent cells in the differentiated cells should be validated in animals before transplantation into the patient [24, 154]. Elimination of these unwanted pluripotent cells is crucial prior to use in the clinical setting. Approaches including positive selection of differentiated cells using specific surface markers [155], selective elimination of residual undifferentiated cells using compounds [156159] or selective media [160, 161], and engineered safety switches such as inducible suicide genes in undifferentiated cells [162, 163], suicide-inducing virus-like particles [164], lectin-toxin fusion protein [165], or microRNA-302 switch [166] could be performed to minimize the risk of tumor formation. More detailed approaches have been extensively reviewed in Jeong et al. [167].

Application of iPSCs in autologous cell-based therapy represents an ideal approach for regenerative medicine since patients do not require long-term immunosuppressive drugs. The first clinical trial using autologous iPSC-derived retinal pigmented epithelial cells for the treatment of macular degeneration has proven to be safe. The patient has no adverse effect after the treatment. However, for more common diseases, autologous therapy may not be practical due to the high cost and the long period of time spent in the manufacturing process: generation, characterization, differentiation into relevant cell types, scale up, and careful validation. Recently, advances in iPSC therapy are moving toward allogeneic approaches in order to bring down the manufacturing cost and reduce the production time. Broad applicability of iPSCs can be achieved by establishment of clinical grade iPSC banking from selected HLA homozygous donors with blood group O to cover the majority of potential recipients [168, 169]. Practically, this approach will be very challenging and requires extensive efforts to establish such iPSC bank especially in populations with more diverse genetic backgrounds. Therefore, the most viable approach is to have a universal iPSC line, which is prepared in advance and can be given to patients on demand regardless of their HLA haplotypes. Several groups generated HLA-engineered stem cells that are invisible to both humoral and cellular alloimmune responses by employing a short-hairpin mRNA (shRNA) to knockdown [137, 170] or genome editing technology to knockout the β2-microglobulin (B2M) gene [136, 171, 172], which is responsible for the HLA class I light chain as well as the CIITA gene, which is a master regulator of HLA class II molecule [173, 174]. These HLA-edited cells are susceptible to lysis by recipient’s NK cells due to missing self-response. Forced expression of less polymorphic HLA-E molecule in HLA-engineered iPSCs has been shown to prevent NK cell lysis [175]. More recently, ectopic expression of CD47 in mouse and human B2M-/- and CIITA-/- iPSCs rendered the cells hypoimmunogenic to T cells and all innate immune responses. Upon transplantation of the engineered hiPSCs and their differentiated derivatives into allogeneic humanized mouse model, the recipients did not elicit any cellular or humoral immune response. The grafts showed long-term survival (50 days) [173]. However, the complete escape of immune surveillance raises some safety concerns regarding the risks of tumor formation and viral infection [172, 173]. Strategy such as targeted disruption of HLA-A/B genes and retaining HLA-C gene in iPSCs can suppress T and NK cell activity while preserving antigen presentation to a certain extent [176]. Alternatively, inducible kill switches can be incorporated into the HLA-engineered cells. Altogether, further refinement of these approaches will increase donor compatibility, reduce the use of immunosuppressive drugs, and ultimately provide a universal source of cells for regenerative medicine.

7. Conclusions

The iPSC technology provides PSCs that can be differentiated to any mature cell types, which are genetically and phenotypically identical to the patients. Generation of hematological disease-specific iPSCs helps increase our understanding of disease mechanism and progression. Together with recent advances in high-throughput screening and genome editing technologies, these patient-specific iPSCs provide a powerful tool to complement in vivo animal models for drug screening, toxicity testing, and development of personalized medicine. Although there are challenges regarding the efficiency of generation of HSPCs and their mature functional blood cells, scale-up process, and validation of clinical-grade cells as well as the concern about immunogenicity to overcome, iPSCs still serve as an ideal source and offer great opportunities for future regenerative medicine.

Conflicts of Interest

The author declares that there is no conflict of interest regarding the publication of this paper.

Acknowledgments

The author thanks Kovit Pattanapanyasat and Chinnavuth Vatanashevanopakorn for comments on the manuscript and Ratchapong Netsrithong for the illustration. This work was supported by the Thailand Research Fund (grant nos. RSA6280090, DPG5980001, and IRG5980006) and the Siriraj Research Fund, grant number (IO) R016234002, Faculty of Medicine Siriraj Hospital, Mahidol University. The author is supported by the Chalermphrakiat Grant, Faculty of Medicine Siriraj Hospital, Mahidol University.

References

  1. J. A. Thomson, J. Itskovitz-Eldor, S. S. Shapiro et al., “Embryonic stem cell lines derived from human blastocysts,” Science, vol. 282, no. 5391, pp. 1145–1147, 1998. View at Publisher · View at Google Scholar · View at Scopus
  2. K. Takahashi and S. Yamanaka, “Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors,” Cell, vol. 126, no. 4, pp. 663–676, 2006. View at Publisher · View at Google Scholar · View at Scopus
  3. A. Biswas and R. Hutchins, “Embryonic stem cells,” Stem Cells and Development, vol. 16, no. 2, pp. 213–222, 2007. View at Publisher · View at Google Scholar · View at Scopus
  4. C. E. Murry and G. Keller, “Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development,” Cell, vol. 132, no. 4, pp. 661–680, 2008. View at Publisher · View at Google Scholar · View at Scopus
  5. K. Takahashi, K. Tanabe, M. Ohnuki et al., “Induction of pluripotent stem cells from adult human fibroblasts by defined factors,” Cell, vol. 131, no. 5, pp. 861–872, 2007. View at Publisher · View at Google Scholar · View at Scopus
  6. J. Yu, M. A. Vodyanik, K. Smuga-Otto et al., “Induced pluripotent stem cell lines derived from human somatic cells,” Science, vol. 318, no. 5858, pp. 1917–1920, 2007. View at Publisher · View at Google Scholar · View at Scopus
  7. C. W. Chang, Y. S. Lai, K. M. Pawlik et al., “Polycistronic lentiviral vector for “hit and run” reprogramming of adult skin fibroblasts to induced pluripotent stem cells,” Stem Cells, vol. 27, no. 5, pp. 1042–1049, 2009. View at Publisher · View at Google Scholar · View at Scopus
  8. C. A. Sommer, M. Stadtfeld, G. J. Murphy, K. Hochedlinger, D. N. Kotton, and G. Mostoslavsky, “Induced pluripotent stem cell generation using a single lentiviral stem cell cassette,” Stem Cells, vol. 27, no. 3, pp. 543–549, 2009. View at Publisher · View at Google Scholar · View at Scopus
  9. Y. Liu, D. Cheng, Z. Li, X. Gao, and H. Wang, “The gene expression profiles of induced pluripotent stem cells (iPSCs) generated by a non-integrating method are more similar to embryonic stem cells than those of iPSCs generated by an integrating method,” Genetics and Molecular Biology, vol. 35, no. 3, pp. 693–700, 2012. View at Publisher · View at Google Scholar · View at Scopus
  10. M. Stadtfeld, M. Nagaya, J. Utikal, G. Weir, and K. Hochedlinger, “Induced pluripotent stem cells generated without viral integration,” Science, vol. 322, no. 5903, pp. 945–949, 2008. View at Publisher · View at Google Scholar · View at Scopus
  11. W. Zhou and C. R. Freed, “Adenoviral gene delivery can reprogram human fibroblasts to induced pluripotent stem cells,” Stem Cells, vol. 27, no. 11, pp. 2667–2674, 2009. View at Publisher · View at Google Scholar · View at Scopus
  12. K. Okita, M. Nakagawa, H. Hyenjong, T. Ichisaka, and S. Yamanaka, “Generation of mouse induced pluripotent stem cells without viral vectors,” Science, vol. 322, no. 5903, pp. 949–953, 2008. View at Publisher · View at Google Scholar · View at Scopus
  13. K. H. Narsinh, F. Jia, R. C. Robbins, M. A. Kay, M. T. Longaker, and J. C. Wu, “Generation of adult human induced pluripotent stem cells using nonviral minicircle DNA vectors,” Nature Protocols, vol. 6, no. 1, pp. 78–88, 2011. View at Publisher · View at Google Scholar · View at Scopus
  14. K. Yusa, R. Rad, J. Takeda, and A. Bradley, “Generation of transgene-free induced pluripotent mouse stem cells by the piggyBac transposon,” Nature Methods, vol. 6, no. 5, pp. 363–369, 2009. View at Publisher · View at Google Scholar · View at Scopus
  15. H. Zhou, S. Wu, J. Y. Joo et al., “Generation of induced pluripotent stem cells using recombinant proteins,” Cell Stem Cell, vol. 4, no. 5, pp. 381–384, 2009. View at Publisher · View at Google Scholar · View at Scopus
  16. L. Warren, P. D. Manos, T. Ahfeldt et al., “Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA,” Cell Stem Cell, vol. 7, no. 5, pp. 618–630, 2010. View at Publisher · View at Google Scholar · View at Scopus
  17. J. R. Plews, J. Li, M. Jones et al., “Activation of pluripotency genes in human fibroblast cells by a novel mRNA based approach,” PLoS One, vol. 5, no. 12, article e14397, 2010. View at Publisher · View at Google Scholar · View at Scopus
  18. N. Fusaki, H. Ban, A. Nishiyama, K. Saeki, and M. Hasegawa, “Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome,” Proceedings of the Japan Academy. Series B, Physical and Biological Sciences, vol. 85, no. 8, pp. 348–362, 2009. View at Publisher · View at Google Scholar · View at Scopus
  19. H. Ban, N. Nishishita, N. Fusaki et al., “Efficient generation of transgene-free human induced pluripotent stem cells (iPSCs) by temperature-sensitive Sendai virus vectors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 34, pp. 14234–14239, 2011. View at Publisher · View at Google Scholar · View at Scopus
  20. Y. D. Sohn, I. Somasuntharam, P. L. Che et al., “Induction of pluripotency in bone marrow mononuclear cells via polyketal nanoparticle-mediated delivery of mature microRNAs,” Biomaterials, vol. 34, no. 17, pp. 4235–4241, 2013. View at Publisher · View at Google Scholar · View at Scopus
  21. N. Miyoshi, H. Ishii, H. Nagano et al., “Reprogramming of mouse and human cells to pluripotency using mature microRNAs,” Cell Stem Cell, vol. 8, no. 6, pp. 633–638, 2011. View at Publisher · View at Google Scholar · View at Scopus
  22. T. M. Schlaeger, L. Daheron, T. R. Brickler et al., “A comparison of non-integrating reprogramming methods,” Nature Biotechnology, vol. 33, no. 1, pp. 58–63, 2015. View at Publisher · View at Google Scholar · View at Scopus
  23. N. Malik and M. S. Rao, “A review of the methods for human iPSC derivation,” Methods in Molecular Biology, vol. 997, pp. 23–33, 2013. View at Publisher · View at Google Scholar · View at Scopus
  24. M. Mandai, A. Watanabe, Y. Kurimoto et al., “Autologous induced stem-cell–derived retinal cells for macular degeneration,” The New England Journal of Medicine, vol. 376, no. 11, pp. 1038–1046, 2017. View at Publisher · View at Google Scholar · View at Scopus
  25. K. Takahashi, K. Okita, M. Nakagawa, and S. Yamanaka, “Induction of pluripotent stem cells from fibroblast cultures,” Nature Protocols, vol. 2, no. 12, pp. 3081–3089, 2007. View at Publisher · View at Google Scholar · View at Scopus
  26. M. E. Brown, E. Rondon, D. Rajesh et al., “Derivation of induced pluripotent stem cells from human peripheral blood T lymphocytes,” PLoS One, vol. 5, no. 6, article e11373, 2010. View at Publisher · View at Google Scholar · View at Scopus
  27. Y. H. Loh, S. Agarwal, I. H. Park et al., “Generation of induced pluripotent stem cells from human blood,” Blood, vol. 113, no. 22, pp. 5476–5479, 2009. View at Publisher · View at Google Scholar · View at Scopus
  28. A. Giorgetti, N. Montserrat, I. Rodriguez-Piza, C. Azqueta, A. Veiga, and J. C. Izpisúa Belmonte, “Generation of induced pluripotent stem cells from human cord blood cells with only two factors: Oct4 and Sox2,” Nature Protocols, vol. 5, no. 4, pp. 811–820, 2010. View at Publisher · View at Google Scholar · View at Scopus
  29. A. Haase, R. Olmer, K. Schwanke et al., “Generation of induced pluripotent stem cells from human cord blood,” Cell Stem Cell, vol. 5, no. 4, pp. 434–441, 2009. View at Publisher · View at Google Scholar · View at Scopus
  30. A. Kunisato, M. Wakatsuki, Y. Kodama, H. Shinba, I. Ishida, and K. Nagao, “Generation of induced pluripotent stem cells by efficient reprogramming of adult bone marrow cells,” Stem Cells and Development, vol. 19, no. 2, pp. 229–238, 2010. View at Publisher · View at Google Scholar · View at Scopus
  31. L. Ye, J. C. Chang, C. Lin, X. Sun, J. Yu, and Y. W. Kan, “Induced pluripotent stem cells offer new approach to therapy in thalassemia and sickle cell anemia and option in prenatal diagnosis in genetic diseases,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 24, pp. 9826–9830, 2009. View at Publisher · View at Google Scholar · View at Scopus
  32. T. Aoi, K. Yae, M. Nakagawa et al., “Generation of pluripotent stem cells from adult mouse liver and stomach cells,” Science, vol. 321, no. 5889, pp. 699–702, 2008. View at Publisher · View at Google Scholar · View at Scopus
  33. B. Di Stefano, A. Prigione, and V. Broccoli, “Efficient genetic reprogramming of unmodified somatic neural progenitors uncovers the essential requirement of Oct4 and Klf4,” Stem Cells and Development, vol. 18, no. 5, pp. 707–716, 2009. View at Publisher · View at Google Scholar · View at Scopus
  34. S. Eminli, J. Utikal, K. Arnold, R. Jaenisch, and K. Hochedlinger, “Reprogramming of neural progenitor cells into induced pluripotent stem cells in the absence of exogenous Sox2 expression,” Stem Cells, vol. 26, no. 10, pp. 2467–2474, 2008. View at Publisher · View at Google Scholar · View at Scopus
  35. P. J. Ho, M. L. Yen, J. D. Lin et al., “Endogenous KLF4 expression in human fetal endothelial cells allows for reprogramming to pluripotency with just OCT3/4 and SOX2-brief report,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 30, no. 10, pp. 1905–1907, 2010. View at Publisher · View at Google Scholar · View at Scopus
  36. I. Petit, R. NS Kesner, O. Karry et al., “Induced pluripotent stem cells from hair follicles as a cellular model for neurodevelopmental disorders,” Stem Cell Research, vol. 8, no. 1, pp. 134–140, 2012. View at Publisher · View at Google Scholar · View at Scopus
  37. Y. Piao, S. S. Hung, S. Y. Lim, R. C. Wong, and M. S. Ko, “Efficient generation of integration-free human induced pluripotent stem cells from keratinocytes by simple transfection of episomal vectors,” Stem Cells Translational Medicine, vol. 3, no. 7, pp. 787–791, 2014. View at Publisher · View at Google Scholar · View at Scopus
  38. B. Boonkaew, L. Tapeng, R. Netsrithong, C. Vatanashevanopakorn, K. Pattanapanyasat, and M. Wattanapanitch, “Induced pluripotent stem cell line MUSIi006-a derived from hair follicle keratinocytes as a non-invasive somatic cell source,” Stem Cell Research, vol. 31, pp. 79–82, 2018. View at Publisher · View at Google Scholar · View at Scopus
  39. C. Steichen, K. Si-Tayeb, F. Wulkan et al., “Human induced pluripotent stem (hiPS) cells from urine samples: a non‐integrative and feeder‐free reprogramming strategy,” Current Protocols in Human Genetics, vol. 92, pp. 21.7.1–21.7.22, 2017. View at Publisher · View at Google Scholar · View at Scopus
  40. Y. Xue, X. Cai, L. Wang et al., “Generating a non-integrating human induced pluripotent stem cell bank from urine-derived cells,” PLoS One, vol. 8, no. 8, article e70573, 2013. View at Publisher · View at Google Scholar · View at Scopus
  41. B. Boonkaew, W. Thummavichit, R. Netsrithong, C. Vatanashevanopakorn, K. Pattanapanyasat, and M. Wattanapanitch, “Establishment of an integration-free induced pluripotent stem cell line (MUSIi005-A) from exfoliated renal epithelial cells,” Stem Cell Research, vol. 30, pp. 34–37, 2018. View at Publisher · View at Google Scholar · View at Scopus
  42. J. B. Kim, B. Greber, M. J. Arauzo-Bravo et al., “Direct reprogramming of human neural stem cells by OCT4,” Nature, vol. 461, no. 7264, pp. 649–653, 2009. View at Publisher · View at Google Scholar · View at Scopus
  43. S. Eminli, A. Foudi, M. Stadtfeld et al., “Differentiation stage determines potential of hematopoietic cells for reprogramming into induced pluripotent stem cells,” Nature Genetics, vol. 41, no. 9, pp. 968–976, 2009. View at Publisher · View at Google Scholar · View at Scopus
  44. M. Nishizawa, K. Chonabayashi, M. Nomura et al., “Epigenetic variation between human induced pluripotent stem cell lines is an indicator of differentiation capacity,” Cell Stem Cell, vol. 19, no. 3, pp. 341–354, 2016. View at Publisher · View at Google Scholar · View at Scopus
  45. Z. Ye, B. K. Chou, and L. Cheng, “Promise and challenges of human iPSC-based hematologic disease modeling and treatment,” International Journal of Hematology, vol. 95, no. 6, pp. 601–609, 2012. View at Publisher · View at Google Scholar · View at Scopus
  46. E. P. Papapetrou, “Gene and cell therapy for β-thalassemia and sickle cell disease with induced pluripotent stem cells (iPSCs): the next frontier,” in Gene and Cell Therapies for Beta-Globinopathies, P. Malik and J. Tisdale, Eds., Advances in Experimental Medicine and Biology, pp. 219–240, Springer, New York, NY, USA, 2017. View at Publisher · View at Google Scholar · View at Scopus
  47. D. Focosi, G. Amabile, A. Di Ruscio, P. Quaranta, D. G. Tenen, and M. Pistello, “Induced pluripotent stem cells in hematology: current and future applications,” Blood Cancer Journal, vol. 4, no. 5, article e211, 2014. View at Publisher · View at Google Scholar · View at Scopus
  48. E. P. Papapetrou, “Modeling myeloid malignancies with patient-derived iPSCs,” Experimental Hematology, vol. 71, pp. 77–84, 2019. View at Publisher · View at Google Scholar
  49. I. I. Slukvin, “Hematopoietic specification from human pluripotent stem cells: current advances and challenges toward de novo generation of hematopoietic stem cells,” Blood, vol. 122, no. 25, pp. 4035–4046, 2013. View at Publisher · View at Google Scholar · View at Scopus
  50. Y. Shi, H. Inoue, J. C. Wu, and S. Yamanaka, “Induced pluripotent stem cell technology: a decade of progress,” Nature Reviews. Drug Discovery, vol. 16, no. 2, pp. 115–130, 2017. View at Publisher · View at Google Scholar · View at Scopus
  51. A. Mathur, P. Loskill, K. Shao et al., “Human iPSC-based cardiac microphysiological system for drug screening applications,” Scientific Reports, vol. 5, no. 1, p. 8883, 2015. View at Publisher · View at Google Scholar · View at Scopus
  52. A. Sharma, W. L. McKeithan, R. Serrano et al., “Use of human induced pluripotent stem cell–derived cardiomyocytes to assess drug cardiotoxicity,” Nature Protocols, vol. 13, no. 12, pp. 3018–3041, 2018. View at Publisher · View at Google Scholar
  53. O. Sirenko, M. K. Hancock, J. Hesley et al., “Phenotypic characterization of toxic compound effects on liver spheroids derived from iPSC using confocal imaging and three-dimensional image analysis,” Assay and Drug Development Technologies, vol. 14, no. 7, pp. 381–394, 2016. View at Publisher · View at Google Scholar · View at Scopus
  54. M. Grskovic, A. Javaherian, B. Strulovici, and G. Q. Daley, “Induced pluripotent stem cells — opportunities for disease modelling and drug discovery,” Nature Reviews. Drug Discovery, vol. 10, pp. 915–929, 2011. View at Publisher · View at Google Scholar · View at Scopus
  55. J. Bright, S. Hussain, V. Dang et al., “Human secreted tau increases amyloid-beta production,” Neurobiology of Aging, vol. 36, no. 2, pp. 693–709, 2015. View at Publisher · View at Google Scholar · View at Scopus
  56. M. F. Burkhardt, F. J. Martinez, S. Wright et al., “A cellular model for sporadic ALS using patient-derived induced pluripotent stem cells,” Molecular and Cellular Neurosciences, vol. 56, pp. 355–364, 2013. View at Publisher · View at Google Scholar · View at Scopus
  57. S. Hoing, Y. Rudhard, P. Reinhardt et al., “Discovery of inhibitors of microglial neurotoxicity acting through multiple mechanisms using a stem-cell-based phenotypic assay,” Cell Stem Cell, vol. 11, no. 5, pp. 620–632, 2012. View at Publisher · View at Google Scholar · View at Scopus
  58. A. D. Ebert, J. Yu, F. F. Rose Jr. et al., “Induced pluripotent stem cells from a spinal muscular atrophy patient,” Nature, vol. 457, no. 7227, pp. 277–280, 2009. View at Publisher · View at Google Scholar · View at Scopus
  59. Y. Jiang, S. A. Cowley, U. Siler et al., “Derivation and functional analysis of patient-specific induced pluripotent stem cells as an in vitro model of chronic granulomatous disease,” Stem Cells, vol. 30, no. 4, pp. 599–611, 2012. View at Publisher · View at Google Scholar · View at Scopus
  60. M. C. Marchetto, C. Carromeu, A. Acab et al., “A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells,” Cell, vol. 143, no. 4, pp. 527–539, 2010. View at Publisher · View at Google Scholar · View at Scopus
  61. O. Cooper, H. Seo, S. Andrabi et al., “Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson’s disease,” Science Translational Medicine, vol. 4, no. 141, article 141ra90, 2012. View at Publisher · View at Google Scholar · View at Scopus
  62. M. A. Cayo, S. K. Mallanna, F. Di Furio et al., “A drug screen using human iPSC-derived hepatocyte-like cells reveals cardiac glycosides as a potential treatment for hypercholesterolemia,” Cell Stem Cell, vol. 20, no. 4, pp. 478–489.e5, 2017. View at Publisher · View at Google Scholar · View at Scopus
  63. Z. Ye, C. F. Liu, L. Lanikova et al., “Differential sensitivity to JAK inhibitory drugs by isogenic human erythroblasts and hematopoietic progenitors generated from patient-specific induced pluripotent stem cells,” Stem Cells, vol. 32, no. 1, pp. 269–278, 2014. View at Publisher · View at Google Scholar · View at Scopus
  64. S. Doulatov, L. T. Vo, E. R. Macari et al., “Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors,” Science Translational Medicine, vol. 9, no. 376, article eaah5645, 2017. View at Publisher · View at Google Scholar · View at Scopus
  65. A. G. Kotini, C. J. Chang, A. Chow et al., “Stage-specific human induced pluripotent stem cells map the progression of myeloid transformation to transplantable leukemia,” Cell Stem Cell, vol. 20, no. 3, pp. 315–328.e7, 2017. View at Publisher · View at Google Scholar · View at Scopus
  66. M. P. Chao, A. J. Gentles, S. Chatterjee et al., “Human AML-iPSCs reacquire leukemic properties after differentiation and model clonal variation of disease,” Cell Stem Cell, vol. 20, no. 3, pp. 329–344.e7, 2017. View at Publisher · View at Google Scholar · View at Scopus
  67. J. Zou, C. L. Sweeney, B. K. Chou et al., “Oxidase-deficient neutrophils from X-linked chronic granulomatous disease iPS cells: functional correction by zinc finger nuclease-mediated safe harbor targeting,” Blood, vol. 117, no. 21, pp. 5561–5572, 2011. View at Publisher · View at Google Scholar · View at Scopus
  68. K. Kumano, S. Arai, M. Hosoi et al., “Generation of induced pluripotent stem cells from primary chronic myelogenous leukemia patient samples,” Blood, vol. 119, no. 26, pp. 6234–6242, 2012. View at Publisher · View at Google Scholar · View at Scopus
  69. G. Amabile, A. Di Ruscio, F. Muller et al., “Dissecting the role of aberrant DNA methylation in human leukaemia,” Nature Communications, vol. 6, no. 1, p. 7091, 2015. View at Publisher · View at Google Scholar · View at Scopus
  70. A. Bedel, J. M. Pasquet, E. Lippert et al., “Variable behavior of iPSCs derived from CML patients for response to TKI and hematopoietic differentiation,” PLoS One, vol. 8, no. 8, article e71596, 2013. View at Publisher · View at Google Scholar · View at Scopus
  71. M. Miyauchi, J. Koya, S. Arai et al., “ADAM8 is an antigen of tyrosine kinase inhibitor-resistant chronic myeloid leukemia cells identified by patient-derived induced pluripotent stem cells,” Stem Cell Reports, vol. 10, no. 3, pp. 1115–1130, 2018. View at Publisher · View at Google Scholar · View at Scopus
  72. L. Garcon, J. Ge, S. H. Manjunath et al., “Ribosomal and hematopoietic defects in induced pluripotent stem cells derived from Diamond Blackfan anemia patients,” Blood, vol. 122, no. 6, pp. 912–921, 2013. View at Publisher · View at Google Scholar · View at Scopus
  73. J. Ge, M. Apicella, J. A. Mills et al., “Dysregulation of the transforming growth factor β pathway in induced pluripotent stem cells generated from patients with Diamond Blackfan anemia,” PLoS One, vol. 10, no. 8, article e0134878, 2015. View at Publisher · View at Google Scholar · View at Scopus
  74. M. Sakurai, H. Kunimoto, N. Watanabe et al., “Impaired hematopoietic differentiation of RUNX1-mutated induced pluripotent stem cells derived from FPD/AML patients,” Leukemia, vol. 28, no. 12, pp. 2344–2354, 2014. View at Publisher · View at Google Scholar · View at Scopus
  75. C. Y. Park, D. H. Kim, J. S. Son et al., “Functional correction of large factor VIII gene chromosomal inversions in hemophilia a patient-derived iPSCs using CRISPR-Cas9,” Cell Stem Cell, vol. 17, no. 2, pp. 213–220, 2015. View at Publisher · View at Google Scholar · View at Scopus
  76. Y. Wu, Z. Hu, Z. Li et al., “In situ genetic correction of F8 intron 22 inversion in hemophilia a patient-specific iPSCs,” Scientific Reports, vol. 6, no. 1, article 18865, 2016. View at Publisher · View at Google Scholar · View at Scopus
  77. C. Y. Park, J. Kim, J. Kweon et al., “Targeted inversion and reversion of the blood coagulation factor 8 gene in human iPS cells using TALENs,” Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 25, pp. 9253–9258, 2014. View at Publisher · View at Google Scholar · View at Scopus
  78. J. Pang, Y. Wu, Z. Li et al., “Targeting of the human F8 at the multicopy rDNA locus in hemophilia A patient-derived iPSCs using TALENickases,” Biochemical and Biophysical Research Communications, vol. 472, no. 1, pp. 144–149, 2016. View at Publisher · View at Google Scholar · View at Scopus
  79. C. Olgasi, M. Talmon, S. Merlin et al., “Patient-specific iPSC-derived endothelial cells provide long-term phenotypic correction of hemophilia A,” Stem Cell Reports, vol. 11, no. 6, pp. 1391–1406, 2018. View at Publisher · View at Google Scholar
  80. S. Ramaswamy, N. Tonnu, T. Menon et al., “Autologous and heterologous cell therapy for hemophilia B toward functional restoration of factor IX,” Cell Reports, vol. 23, no. 5, pp. 1565–1580, 2018. View at Publisher · View at Google Scholar · View at Scopus
  81. Q. He, T. C. HH Wang, W. P. Yuan, Y. P. Ma, Y. P. Jiang, and Z. H. Ren, “Genetic correction and hepatic differentiation of hemophilia B-specific human induced pluripotent stem cells,” Chinese Medical Sciences Journal, vol. 32, no. 3, pp. 135–144, 2017. View at Publisher · View at Google Scholar · View at Scopus
  82. C. Lyu, J. Shen, R. Wang et al., “Targeted genome engineering in human induced pluripotent stem cells from patients with hemophilia B using the CRISPR-Cas9 system,” Stem Cell Research & Therapy, vol. 9, no. 1, p. 92, 2018. View at Publisher · View at Google Scholar · View at Scopus
  83. A. G. Kotini, C. J. Chang, I. Boussaad et al., “Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells,” Nature Biotechnology, vol. 33, no. 6, pp. 646–655, 2015. View at Publisher · View at Google Scholar · View at Scopus
  84. X. Yuan, E. M. Braunstein, Z. Ye et al., “Generation of glycosylphosphatidylinositol anchor protein-deficient blood cells from human induced pluripotent stem cells,” Stem Cells Translational Medicine, vol. 2, no. 11, pp. 819–829, 2013. View at Publisher · View at Google Scholar · View at Scopus
  85. J. Saliba, S. Hamidi, G. Lenglet et al., “Heterozygous and homozygous JAK2(V617F) states modeled by induced pluripotent stem cells from myeloproliferative neoplasm patients,” PLoS One, vol. 8, no. 9, article e74257, 2013. View at Publisher · View at Google Scholar · View at Scopus
  86. Z. Ye, H. Zhan, P. Mali et al., “Human-induced pluripotent stem cells from blood cells of healthy donors and patients with acquired blood disorders,” Blood, vol. 114, no. 27, pp. 5473–5480, 2009. View at Publisher · View at Google Scholar · View at Scopus
  87. X. Huang, Y. Wang, W. Yan et al., “Production of gene-corrected adult beta globin protein in human erythrocytes differentiated from patient iPSCs after genome editing of the sickle point mutation,” Stem Cells, vol. 33, no. 5, pp. 1470–1479, 2015. View at Publisher · View at Google Scholar · View at Scopus
  88. N. Sun and H. Zhao, “Seamless correction of the sickle cell disease mutation of the HBB gene in human induced pluripotent stem cells using TALENs,” Biotechnology and Bioengineering, vol. 111, no. 5, pp. 1048–1053, 2014. View at Publisher · View at Google Scholar · View at Scopus
  89. C. W. Chang, Y. S. Lai, E. Westin et al., “Modeling human severe combined immunodeficiency and correction by CRISPR/Cas9-enhanced gene targeting,” Cell Reports, vol. 12, no. 10, pp. 1668–1677, 2015. View at Publisher · View at Google Scholar · View at Scopus
  90. T. Menon, A. L. Firth, D. D. Scripture-Adams et al., “Lymphoid regeneration from gene-corrected SCID-X1 subject-derived iPSCs,” Cell Stem Cell, vol. 16, no. 4, pp. 367–372, 2015. View at Publisher · View at Google Scholar · View at Scopus
  91. X. Niu, W. He, B. Song et al., “Combining single strand oligodeoxynucleotides and CRISPR/Cas9 to correct gene mutations in β-thalassemia-induced pluripotent stem cells,” Journal of Biological Chemistry, vol. 291, no. 32, pp. 16576–16585, 2016. View at Publisher · View at Google Scholar · View at Scopus
  92. F. Xie, L. Ye, J. C. Chang et al., “Seamless gene correction of β-thalassemia mutations in patient-specific iPSCs using CRISPR/Cas9 and piggyBac,” Genome Research, vol. 24, no. 9, pp. 1526–1533, 2014. View at Publisher · View at Google Scholar · View at Scopus
  93. L. Cai, H. Bai, V. Mahairaki et al., “A universal approach to correct various HBB gene mutations in human stem cells for gene therapy of beta-thalassemia and sickle cell disease,” Stem Cells Translational Medicine, vol. 7, no. 1, pp. 87–97, 2018. View at Publisher · View at Google Scholar · View at Scopus
  94. M. Wattanapanitch, N. Damkham, P. Potirat et al., “One-step genetic correction of hemoglobin E/beta-thalassemia patient-derived iPSCs by the CRISPR/Cas9 system,” Stem Cell Research & Therapy, vol. 9, no. 1, p. 46, 2018. View at Publisher · View at Google Scholar · View at Scopus
  95. C. J. Chang and E. E. Bouhassira, “Zinc-finger nuclease-mediated correction of α-thalassemia in iPS cells,” Blood, vol. 120, no. 19, pp. 3906–3914, 2012. View at Publisher · View at Google Scholar · View at Scopus
  96. P. Ingrungruanglert, P. Amarinthnukrowh, R. Rungsiwiwut et al., “Wiskott-Aldrich syndrome iPS cells produce megakaryocytes with defects in cytoskeletal rearrangement and proplatelet formation,” Thrombosis and Haemostasis, vol. 113, no. 04, pp. 792–805, 2015. View at Publisher · View at Google Scholar · View at Scopus
  97. T. J. Laskowski, Y. Van Caeneghem, R. Pourebrahim et al., “Gene correction of iPSCs from a Wiskott-Aldrich syndrome patient normalizes the lymphoid developmental and functional defects,” Stem Cell Reports, vol. 7, no. 2, pp. 139–148, 2016. View at Publisher · View at Google Scholar · View at Scopus
  98. E. A. Copelan, “Hematopoietic stem-cell transplantation,” New England Journal of Medicine, vol. 354, no. 17, pp. 1813–1826, 2006. View at Publisher · View at Google Scholar · View at Scopus
  99. E. Gluckman, H. E. Broxmeyer, A. D. Auerbach et al., “Hematopoietic reconstitution in a patient with Fanconi’s anemia by means of umbilical-cord blood from an HLA-identical sibling,” The New England Journal of Medicine, vol. 321, no. 17, pp. 1174–1178, 1989. View at Publisher · View at Google Scholar · View at Scopus
  100. J. N. Barker, T. P. Krepski, T. E. DeFor, S. M. Davies, J. E. Wagner, and D. J. Weisdorf, “Searching for unrelated donor hematopoietic stem cells: availability and speed of umbilical cord blood versus bone marrow,” Biology of Blood and Marrow Transplantation, vol. 8, no. 5, pp. 257–260, 2002. View at Publisher · View at Google Scholar · View at Scopus
  101. N. Pineault and A. Abu-Khader, “Advances in umbilical cord blood stem cell expansion and clinical translation,” Experimental Hematology, vol. 43, no. 7, pp. 498–513, 2015. View at Publisher · View at Google Scholar · View at Scopus
  102. A. Scaradavou, C. G. Brunstein, M. Eapen et al., “Double unit grafts successfully extend the application of umbilical cord blood transplantation in adults with acute leukemia,” Blood, vol. 121, no. 5, pp. 752–758, 2013. View at Publisher · View at Google Scholar · View at Scopus
  103. J. N. Barker, T. E. D. F. DJ Weisdorf, B. R. Blazar et al., “Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy,” Blood, vol. 105, no. 3, pp. 1343–1347, 2005. View at Publisher · View at Google Scholar · View at Scopus
  104. J. E. Wagner, M. Eapen, S. Carter et al., “One-unit versus two-unit cord-blood transplantation for hematologic cancers,” The New England Journal of Medicine, vol. 371, no. 18, pp. 1685–1694, 2014. View at Publisher · View at Google Scholar · View at Scopus
  105. G. Q. Daley, “Towards the generation of patient-specific pluripotent stem cells for combined gene and cell therapy of hematologic disorders,” Hematology, vol. 2007, no. 1, pp. 17–22, 2007. View at Publisher · View at Google Scholar · View at Scopus
  106. T. Phondeechareon, M. Wattanapanitch, Y. U-pratya et al., “Generation of induced pluripotent stem cells as a potential source of hematopoietic stem cells for transplant in PNH patients,” Annals of Hematology, vol. 95, no. 10, pp. 1617–1625, 2016. View at Publisher · View at Google Scholar · View at Scopus
  107. K. R. Salci, J. H. Lee, S. Laronde et al., “Cellular reprogramming allows generation of autologous hematopoietic progenitors from AML patients that are devoid of patient-specific genomic aberrations,” Stem Cells, vol. 33, no. 6, pp. 1839–1849, 2015. View at Publisher · View at Google Scholar · View at Scopus
  108. J. Hanna, M. Wernig, S. Markoulaki et al., “Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin,” Science, vol. 318, no. 5858, pp. 1920–1923, 2007. View at Publisher · View at Google Scholar · View at Scopus
  109. Y. Wang, C. G. Zheng, Y. Jiang et al., “Genetic correction of β-thalassemia patient-specific iPS cells and its use in improving hemoglobin production in irradiated SCID mice,” Cell Research, vol. 22, no. 4, pp. 637–648, 2012. View at Publisher · View at Google Scholar · View at Scopus
  110. A. Tubsuwan, S. Abed, A. Deichmann et al., “Parallel assessment of globin lentiviral transfer in induced pluripotent stem cells and adult hematopoietic stem cells derived from the same transplanted β-thalassemia patient,” Stem Cells, vol. 31, no. 9, pp. 1785–1794, 2013. View at Publisher · View at Google Scholar · View at Scopus
  111. E. P. Papapetrou, G. Lee, N. Malani et al., “Genomic safe harbors permit high β-globin transgene expression in thalassemia induced pluripotent stem cells,” Nature Biotechnology, vol. 29, no. 1, pp. 73–78, 2011. View at Publisher · View at Google Scholar · View at Scopus
  112. H. Kim and J. S. Kim, “A guide to genome engineering with programmable nucleases,” Nature Reviews. Genetics, vol. 15, no. 5, pp. 321–334, 2014. View at Publisher · View at Google Scholar · View at Scopus
  113. K. Musunuru, “Genome editing of human pluripotent stem cells to generate human cellular disease models,” Disease Models & Mechanisms, vol. 6, no. 4, pp. 896–904, 2013. View at Publisher · View at Google Scholar · View at Scopus
  114. M. A. Vodyanik, J. A. Bork, J. A. Thomson, and I. I. Slukvin, “Human embryonic stem cell-derived CD34+ cells: efficient production in the coculture with OP9 stromal cells and analysis of lymphohematopoietic potential,” Blood, vol. 105, no. 2, pp. 617–626, 2005. View at Publisher · View at Google Scholar · View at Scopus
  115. K. D. Choi, J. Yu, K. Smuga-Otto et al., “Hematopoietic and endothelial differentiation of human induced pluripotent stem cells,” Stem Cells, vol. 27, no. 3, pp. 559–567, 2009. View at Publisher · View at Google Scholar
  116. E. S. Ng, R. P. Davis, L. Azzola, E. G. Stanley, and A. G. Elefanty, “Forced aggregation of defined numbers of human embryonic stem cells into embryoid bodies fosters robust, reproducible hematopoietic differentiation,” Blood, vol. 106, no. 5, pp. 1601–1603, 2005. View at Publisher · View at Google Scholar · View at Scopus
  117. M. Pick, L. Azzola, A. Mossman, E. G. Stanley, and A. G. Elefanty, “Differentiation of human embryonic stem cells in serum-free medium reveals distinct roles for bone morphogenetic protein 4, vascular endothelial growth factor, stem cell factor, and fibroblast growth factor 2 in hematopoiesis,” Stem Cells, vol. 25, no. 9, pp. 2206–2214, 2007. View at Publisher · View at Google Scholar · View at Scopus
  118. M. Kennedy, S. L. D'Souza, M. Lynch-Kattman, S. Schwantz, and G. Keller, “Development of the hemangioblast defines the onset of hematopoiesis in human ES cell differentiation cultures,” Blood, vol. 109, pp. 2679–2687, 2007. View at Publisher · View at Google Scholar · View at Scopus
  119. G. Salvagiotto, S. Burton, C. A. Daigh, D. Rajesh, I. I. Slukvin, and N. J. Seay, “A defined, feeder-free, serum-free system to generate in vitro hematopoietic progenitors and differentiated blood cells from hESCs and hiPSCs,” PLoS One, vol. 6, no. 3, article e17829, 2011. View at Publisher · View at Google Scholar · View at Scopus
  120. A. Niwa, T. Heike, K. Umeda et al., “A novel serum-free monolayer culture for orderly hematopoietic differentiation of human pluripotent cells via mesodermal progenitors,” PLoS One, vol. 6, no. 7, article e22261, 2011. View at Publisher · View at Google Scholar · View at Scopus
  121. L. T. Vo and G. Q. Daley, “De novo generation of HSCs from somatic and pluripotent stem cell sources,” Blood, vol. 125, no. 17, pp. 2641–2648, 2015. View at Publisher · View at Google Scholar · View at Scopus
  122. C. M. Sturgeon, A. Ditadi, G. Awong, M. Kennedy, and G. Keller, “Wnt signaling controls the specification of definitive and primitive hematopoiesis from human pluripotent stem cells,” Nature Biotechnology, vol. 32, no. 6, pp. 554–561, 2014. View at Publisher · View at Google Scholar · View at Scopus
  123. J. P. Creamer, C. Dege, Q. Ren et al., “Human definitive hematopoietic specification from pluripotent stem cells is regulated by mesodermal expression of CDX4,” Blood, vol. 129, no. 22, pp. 2988–2992, 2017. View at Publisher · View at Google Scholar · View at Scopus
  124. A. Ditadi, C. M. Sturgeon, and G. Keller, “A view of human haematopoietic development from the Petri dish,” Nature Reviews. Molecular Cell Biology, vol. 18, no. 1, pp. 56–67, 2017. View at Publisher · View at Google Scholar · View at Scopus
  125. A. Ditadi, C. M. Sturgeon, J. Tober et al., “Human definitive haemogenic endothelium and arterial vascular endothelium represent distinct lineages,” Nature Cell Biology, vol. 17, no. 5, pp. 580–591, 2015. View at Publisher · View at Google Scholar · View at Scopus
  126. F. Duan, R. Huang, F. Zhang et al., “Biphasic modulation of insulin signaling enables highly efficient hematopoietic differentiation from human pluripotent stem cells,” Stem Cell Research & Therapy, vol. 9, no. 1, p. 205, 2018. View at Publisher · View at Google Scholar · View at Scopus
  127. G. Amabile, R. S. Welner, C. Nombela-Arrieta et al., “In vivo generation of transplantable human hematopoietic cells from induced pluripotent stem cells,” Blood, vol. 121, no. 8, pp. 1255–1264, 2013. View at Publisher · View at Google Scholar · View at Scopus
  128. N. Suzuki, S. Yamazaki, T. Yamaguchi et al., “Generation of engraftable hematopoietic stem cells from induced pluripotent stem cells by way of teratoma formation,” Molecular Therapy, vol. 21, no. 7, pp. 1424–1431, 2013. View at Publisher · View at Google Scholar · View at Scopus
  129. S. Doulatov, L. T. Vo, S. S. Chou et al., “Induction of multipotential hematopoietic progenitors from human pluripotent stem cells via respecification of lineage-restricted precursors,” Cell Stem Cell, vol. 13, no. 4, pp. 459–470, 2013. View at Publisher · View at Google Scholar · View at Scopus
  130. R. Sugimura, D. K. Jha, A. Han et al., “Haematopoietic stem and progenitor cells from human pluripotent stem cells,” Nature, vol. 545, no. 7655, pp. 432–438, 2017. View at Publisher · View at Google Scholar · View at Scopus
  131. Y. T. Tan, L. Ye, F. Xie et al., “Respecifying human iPSC-derived blood cells into highly engraftable hematopoietic stem and progenitor cells with a single factor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 9, pp. 2180–2185, 2018. View at Publisher · View at Google Scholar · View at Scopus
  132. R. G. Rowe, J. Mandelbaum, L. I. Zon, and G. Q. Daley, “Engineering hematopoietic stem cells: lessons from development,” Cell Stem Cell, vol. 18, no. 6, pp. 707–720, 2016. View at Publisher · View at Google Scholar · View at Scopus
  133. J. Sivalingam, A. T. Lam, H. Y. Chen et al., “Superior red blood cell generation from human pluripotent stem cells through a novel microcarrier-based embryoid body platform,” Tissue Engineering. Part C, Methods, vol. 22, no. 8, pp. 765–780, 2016. View at Publisher · View at Google Scholar · View at Scopus
  134. C. T. Yang, R. Ma, R. A. Axton et al., “Activation of KLF1 enhances the differentiation and maturation of red blood cells from human pluripotent stem cells,” Stem Cells, vol. 35, no. 4, pp. 886–897, 2017. View at Publisher · View at Google Scholar · View at Scopus
  135. N. Uchida, J. J. Haro-Mora, A. Fujita et al., “Efficient generation of β-globin-expressing erythroid cells using stromal cell-derived induced pluripotent stem cells from patients with sickle cell disease,” Stem Cells, vol. 35, no. 3, pp. 586–596, 2017. View at Publisher · View at Google Scholar · View at Scopus
  136. Q. Feng, N. Shabrani, J. N. Thon et al., “Scalable generation of universal platelets from human induced pluripotent stem cells,” Stem Cell Reports, vol. 3, no. 5, pp. 817–831, 2014. View at Publisher · View at Google Scholar · View at Scopus
  137. A. K. Borger, D. Eicke, C. Wolf et al., “Generation of HLA-universal iPSC-derived megakaryocytes and platelets for survival under refractoriness conditions,” Molecular Medicine, vol. 22, no. 1, pp. 1–285, 2016. View at Publisher · View at Google Scholar · View at Scopus
  138. T. Moreau, L. V. AL Evans, M. R. Tijssen et al., “Large-scale production of megakaryocytes from human pluripotent stem cells by chemically defined forward programming,” Nature Communications, vol. 7, no. 1, article 11208, 2016. View at Publisher · View at Google Scholar · View at Scopus
  139. Y. Ito, S. Nakamura, N. Sugimoto et al., “Turbulence activates platelet biogenesis to enable clinical scale ex vivo production,” Cell, vol. 174, no. 3, pp. 636–648.e18, 2018. View at Publisher · View at Google Scholar · View at Scopus
  140. M. Ando, T. Nishimura, S. Yamazaki et al., “A safeguard system for induced pluripotent stem cell-derived rejuvenated T cell therapy,” Stem Cell Reports, vol. 5, no. 4, pp. 597–608, 2015. View at Publisher · View at Google Scholar · View at Scopus
  141. T. Maeda, S. Nagano, H. Ichise et al., “Regeneration of CD8αβ T cells from T-cell–derived iPSC imparts potent tumor antigen-specific cytotoxicity,” Cancer Research, vol. 76, no. 23, pp. 6839–6850, 2016. View at Publisher · View at Google Scholar · View at Scopus
  142. T. Nishimura, S. Kaneko, A. Kawana-Tachikawa et al., “Generation of rejuvenated antigen-specific T cells by reprogramming to pluripotency and redifferentiation,” Cell Stem Cell, vol. 12, no. 1, pp. 114–126, 2013. View at Publisher · View at Google Scholar · View at Scopus
  143. M. Themeli, C. C. Kloss, G. Ciriello et al., “Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy,” Nature Biotechnology, vol. 31, no. 10, pp. 928–933, 2013. View at Publisher · View at Google Scholar · View at Scopus
  144. R. Vizcardo, K. Masuda, D. Yamada et al., “Regeneration of human tumor antigen-specific T cells from iPSCs derived from mature CD8(+) T cells,” Cell Stem Cell, vol. 12, no. 1, pp. 31–36, 2013. View at Publisher · View at Google Scholar · View at Scopus
  145. A. Minagawa, T. Yoshikawa, M. Yasukawa et al., “Enhancing T cell receptor stability in rejuvenated iPSC-derived T cells improves their use in cancer immunotherapy,” Cell Stem Cell, vol. 23, no. 6, pp. 850–858.e4, 2018. View at Publisher · View at Google Scholar
  146. D. A. Knorr, Z. Ni, D. Hermanson et al., “Clinical‐scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy,” Stem Cells Translational Medicine, vol. 2, no. 4, pp. 274–283, 2013. View at Publisher · View at Google Scholar · View at Scopus
  147. J. Zeng, S. Y. Tang, L. L. Toh, and S. Wang, “Generation of “off-the-shelf” natural killer cells from peripheral blood cell-derived induced pluripotent stem cells,” Stem Cell Reports, vol. 9, no. 6, pp. 1796–1812, 2017. View at Publisher · View at Google Scholar · View at Scopus
  148. Y. Li, D. L. Hermanson, B. S. Moriarity, and D. S. Kaufman, “Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity,” Cell Stem Cell, vol. 23, no. 2, pp. 181–192.e5, 2018. View at Publisher · View at Google Scholar · View at Scopus
  149. D. Focosi and G. Amabile, “Induced pluripotent stem cell-derived red blood cells and platelet concentrates: from bench to bedside,” Cell, vol. 7, no. 1, 2017. View at Publisher · View at Google Scholar
  150. E. A. Kimbrel and R. Lanza, “Current status of pluripotent stem cells: moving the first therapies to the clinic,” Nature Reviews. Drug Discovery, vol. 14, no. 10, pp. 681–692, 2015. View at Publisher · View at Google Scholar · View at Scopus
  151. P. M. Brauer, I. M. Pessach, E. Clarke et al., “Modeling altered T-cell development with induced pluripotent stem cells from patients with RAG1-dependent immune deficiencies,” Blood, vol. 128, no. 6, pp. 783–793, 2016. View at Publisher · View at Google Scholar · View at Scopus
  152. T. Nishimura and H. Nakauchi, “Generation of antigen-specific T cells from human induced pluripotent stem cells,” Methods in Molecular Biology, vol. 1899, pp. 25–40, 2019. View at Publisher · View at Google Scholar
  153. S. Shukla, M. A. Langley, J. Singh et al., “Progenitor T-cell differentiation from hematopoietic stem cells using Delta-like-4 and VCAM-1,” Nature Methods, vol. 14, no. 5, pp. 531–538, 2017. View at Publisher · View at Google Scholar · View at Scopus
  154. E. A. Kimbrel and R. Lanza, “Pluripotent stem cells: the last 10 years,” Regenerative Medicine, vol. 11, no. 8, pp. 831–847, 2016. View at Publisher · View at Google Scholar · View at Scopus
  155. B. Samata, D. Doi, K. Nishimura et al., “Purification of functional human ES and iPSC-derived midbrain dopaminergic progenitors using LRTM1,” Nature Communications, vol. 7, no. 1, article 13097, 2016. View at Publisher · View at Google Scholar · View at Scopus
  156. A. Bedel, F. Beliveau, I. Lamrissi-Garcia et al., “Preventing pluripotent cell teratoma in regenerative medicine applied to hematology disorders,” Stem Cells Translational Medicine, vol. 6, no. 2, pp. 382–393, 2017. View at Publisher · View at Google Scholar · View at Scopus
  157. M. O. Lee, S. H. Moon, H. C. Jeong et al., “Inhibition of pluripotent stem cell-derived teratoma formation by small molecules,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 35, pp. E3281–E3290, 2013. View at Publisher · View at Google Scholar · View at Scopus
  158. U. Ben-David, Q.-F. Gan, T. Golan-Lev et al., “Selective elimination of human pluripotent stem cells by an oleate synthesis inhibitor discovered in a high-throughput screen,” Cell Stem Cell, vol. 12, no. 2, pp. 167–179, 2013. View at Publisher · View at Google Scholar · View at Scopus
  159. L. Zhang, Y. Pan, G. Qin et al., “Inhibition of stearoyl-coA desaturase selectively eliminates tumorigenic Nanog-positive cells: improving the safety of iPS cell transplantation to myocardium,” Cell Cycle, vol. 13, no. 5, pp. 762–771, 2014. View at Publisher · View at Google Scholar · View at Scopus
  160. T. Nagashima, K. Shimizu, R. Matsumoto, and H. Honda, “Selective elimination of human induced pluripotent stem cells using medium with high concentration of L-alanine,” Scientific Reports, vol. 8, no. 1, article 12427, 2018. View at Publisher · View at Google Scholar · View at Scopus
  161. K. Matsuura, K. Ito, N. Shiraki, S. Kume, N. Hagiwara, and T. Shimizu, “Induced pluripotent stem cell elimination in a cell sheet by methionine-free and 42°C condition for tumor prevention,” Tissue Engineering Part C, Methods, vol. 24, no. 10, pp. 605–615, 2018. View at Publisher · View at Google Scholar · View at Scopus
  162. F. Chen, B. Cai, Y. Gao et al., “Suicide gene-mediated ablation of tumor-initiating mouse pluripotent stem cells,” Biomaterials, vol. 34, no. 6, pp. 1701–1711, 2013. View at Publisher · View at Google Scholar · View at Scopus
  163. B. Zhong, K. L. Watts, J. L. Gori et al., “Safeguarding nonhuman primate iPS cells with suicide genes,” Molecular Therapy, vol. 19, no. 9, pp. 1667–1675, 2011. View at Publisher · View at Google Scholar · View at Scopus
  164. A. Rampoldi, S. N. Crooke, M. K. Preininger et al., “Targeted elimination of tumorigenic human pluripotent stem cells using suicide-inducing virus-like particles,” ACS Chemical Biology, vol. 13, no. 8, pp. 2329–2338, 2018. View at Publisher · View at Google Scholar · View at Scopus
  165. H. Tateno and S. Saito, “Engineering of a potent recombinant lectin-toxin fusion protein to eliminate human pluripotent stem cells,” Molecules, vol. 22, no. 7, 2017. View at Publisher · View at Google Scholar
  166. C. J. Parr, S. Katayama, K. Miki et al., “MicroRNA-302 switch to identify and eliminate undifferentiated human pluripotent stem cells,” Scientific Reports, vol. 6, no. 1, article 32532, 2016. View at Publisher · View at Google Scholar · View at Scopus
  167. H.-C. Jeong, S.-J. Cho, M.-O. Lee, and H.-J. Cha, “Technical approaches to induce selective cell death of pluripotent stem cells,” Cellular and Molecular Life Sciences, vol. 74, no. 14, pp. 2601–2611, 2017. View at Publisher · View at Google Scholar · View at Scopus
  168. C. de Rham and J. Villard, “Potential and limitation of HLA-based banking of human pluripotent stem cells for cell therapy,” Journal of Immunology Research, vol. 2014, Article ID 518135, 6 pages, 2014. View at Publisher · View at Google Scholar · View at Scopus
  169. M. Turner, S. Leslie, N. G. Martin et al., “Toward the development of a global induced pluripotent stem cell library,” Cell Stem Cell, vol. 13, no. 4, pp. 382–384, 2013. View at Publisher · View at Google Scholar · View at Scopus
  170. Z. Karabekian, H. Ding, G. Stybayeva et al., “HLA class I depleted hESC as a source of hypoimmunogenic cells for tissue engineering applications,” Tissue Engineering Part A, vol. 21, no. 19-20, pp. 2559–2571, 2015. View at Publisher · View at Google Scholar · View at Scopus
  171. D. Wang, Y. Quan, Q. Yan, J. E. Morales, and R. A. Wetsel, “Targeted disruption of the β2-microglobulin gene minimizes the immunogenicity of human embryonic stem cells,” Stem Cells Translational Medicine, vol. 4, no. 10, pp. 1234–1245, 2015. View at Publisher · View at Google Scholar · View at Scopus
  172. L. Riolobos, R. K. Hirata, C. J. Turtle et al., “HLA engineering of human pluripotent stem cells,” Molecular Therapy, vol. 21, no. 6, pp. 1232–1241, 2013. View at Publisher · View at Google Scholar · View at Scopus
  173. T. Deuse, X. Hu, A. Gravina et al., “Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients,” Nature Biotechnology, vol. 37, no. 3, pp. 252–258, 2019. View at Publisher · View at Google Scholar
  174. S. Mattapally, K. M. Pawlik, V. G. Fast et al., “Human leukocyte antigen class I and II knockout human induced pluripotent stem cell–derived cells: universal donor for cell therapy,” Journal of the American Heart Association, vol. 7, no. 23, 2018. View at Publisher · View at Google Scholar
  175. G. G. Gornalusse, R. K. Hirata, S. E. Funk et al., “HLA-E-expressing pluripotent stem cells escape allogeneic responses and lysis by NK cells,” Nature Biotechnology, vol. 35, no. 8, pp. 765–772, 2017. View at Publisher · View at Google Scholar · View at Scopus
  176. H. Xu, B. Wang, M. Ono et al., “Targeted disruption of HLA genes via CRISPR-Cas9 generates iPSCs with enhanced immune compatibility,” Cell Stem Cell, vol. 24, no. 4, pp. 566–578.e7, 2019. View at Publisher · View at Google Scholar