Stem Cells International The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. The Cotransplantation of Olfactory Ensheathing Cells with Bone Marrow Mesenchymal Stem Cells Exerts Antiapoptotic Effects in Adult Rats after Spinal Cord Injury Wed, 29 Jul 2015 12:28:51 +0000 The mechanisms behind the repairing effects of the cotransplantation of olfactory ensheathing cells (OECs) with bone marrow mesenchymal stromal cells (BMSCs) have not been fully understood. Therefore, we investigated the effects of the cotransplantation of OECs with BMSCs on antiapoptotic effects in adult rats for which the models of SCI are induced. We examined the changes in body weight, histopathological changes, apoptosis, and the expressions of apoptosis-related proteins after 14 days and 28 days after transplantation. We also assessed animal locomotion using BBB test. We found that treatment with OECs and BMSCs had a remissive effect on behavioral outcome and histopathological changes induced SCI. Furthermore, we observed the significant antiapoptotic effect on cotransplant treated group. In addition, cotransplantation of OECs with BMSCs was found to have more significant repairing effect than that of OECs or BMSCs alone. Furthermore, the recovery of hind limb could be related to antiapoptotic effect of OECs and BMSCs through downregulating the apoptotic pathways. Finally, our data suggested the cotransplantation of OECs with BMSCs holds promise for a potential cure after SCI through the ability to incorporate into the spinal cord. Shifeng Wu, Guanqun Cui, Hua Shao, Zhongjun Du, Jack C. Ng, and Cheng Peng Copyright © 2015 Shifeng Wu et al. All rights reserved. MSCs: Scientific Support for Multiple Therapies Wed, 29 Jul 2015 10:24:51 +0000 Mark F. Pittenger, Katarina Le Blanc, Donald G. Phinney, and Jerry K. Y. Chan Copyright © 2015 Mark F. Pittenger et al. All rights reserved. Mesenchymal Stromal Cells and Viral Infection Wed, 29 Jul 2015 09:41:37 +0000 Mesenchymal Stromal Cells (MSCs) are a subset of nonhematopoietic adult stem cells, readily isolated from various tissues and easily culture-expanded ex vivo. Intensive studies of the immune modulation and tissue regeneration over the past few years have demonstrated the great potential of MSCs for the prevention and treatment of steroid-resistant acute graft-versus-host disease (GvHD), immune-related disorders, and viral diseases. In immunocompromised individuals, the immunomodulatory activities of MSCs have raised safety concerns regarding the greater risk of primary viral infection and viral reactivation, which is a major cause of mortality after allogeneic transplantation. Moreover, high susceptibilities of MSCs to viral infections in vitro could reflect the destructive outcomes that might impair the clinical efficacy of MSCs infusion. However, the interplay between MSCs and virus is like a double-edge sword, and it also provides beneficial effects such as allowing the proliferation and function of antiviral specific effector cells instead of suppressing them, serving as an ideal tool for study of viral pathogenesis, and protecting hosts against viral challenge by using the antimicrobial activity. Here, we therefore review favorable and unfavorable consequences of MSCs and virus interaction with the highlight of safety and efficacy for applying MSCs as cell therapy. Maytawan Thanunchai, Suradej Hongeng, and Arunee Thitithanyanont Copyright © 2015 Maytawan Thanunchai et al. All rights reserved. Comparisons of Differentiation Potential in Human Mesenchymal Stem Cells from Wharton’s Jelly, Bone Marrow, and Pancreatic Tissues Wed, 29 Jul 2015 08:07:30 +0000 Background. Type 1 diabetes mellitus results from autoimmune destruction of β-cells. Insulin-producing cells (IPCs) differentiated from mesenchymal stem cells (MSCs) in human tissues decrease blood glucose levels and improve survival in diabetic rats. We compared the differential ability and the curative effect of IPCs from three types of human tissue to determine the ideal source of cell therapy for diabetes. Methods. We induced MSCs from Wharton’s jelly (WJ), bone marrow (BM), and surgically resected pancreatic tissue to differentiate into IPCs. The in vitro differential function of these IPCs was compared by insulin-to-DNA ratios and C-peptide levels after glucose challenge. In vivo curative effects of IPCs transplanted into diabetic rats were monitored by weekly blood glucose measurement. Results. WJ-MSCs showed better proliferation and differentiation potential than pancreatic MSCs and BM-MSCs. In vivo, WJ-IPCs significantly reduced blood glucose levels at first week after transplantation and maintained significant decrease till week 8. BM-IPCs reduced blood glucose levels at first week but gradually increased since week 3. In resected pancreas-IPCs group, blood glucose levels were significantly reduced till two weeks after transplantation and gradually increased since week 4. Conclusion. WJ-MSCs are the most promising stem cell source for β-cell regeneration in diabetes treatment. Shih-Yi Kao, Jia-Fwu Shyu, Hwai-Shi Wang, Chi-Hung Lin, Cheng-Hsi Su, Tien-Hua Chen, Zen-Chung Weng, and Pei-Jiun Tsai Copyright © 2015 Shih-Yi Kao et al. All rights reserved. Bottlenecks in the Efficient Use of Advanced Therapy Medicinal Products Based on Mesenchymal Stromal Cells Mon, 27 Jul 2015 08:55:27 +0000 Mesenchymal stromal cells (MSCs) have been established as promising candidate sources of universal donor cells for cell therapy due to their contributions to tissue and organ homeostasis, repair, and support by self-renewal and multidifferentiation, as well as by their anti-inflammatory, antiproliferative, immunomodulatory, trophic, and proangiogenic properties. Various diseases have been treated by MSCs in animal models. Additionally, hundreds of clinical trials related to the potential benefits of MSCs are in progress. However, although all MSCs are considered suitable to exert these functions, dissimilarities have been found among MSCs derived from different tissues. The same levels of efficacy and desired outcomes have not always been achieved in the diverse studies that have been performed thus far. Moreover, autologous MSCs can be affected by the disease status of patients, compromising their use. Therefore, collecting information regarding the characteristics of MSCs obtained from different sources and the influence of the host (patient) medical conditions on MSCs is important for assuring the safety and efficacy of cell-based therapies. This review provides relevant information regarding factors to consider for the clinical application of MSCs. Natalia Escacena, Elena Quesada-Hernández, Vivian Capilla-Gonzalez, Bernat Soria, and Abdelkrim Hmadcha Copyright © 2015 Natalia Escacena et al. All rights reserved. Multipotent Mesenchymal Stromal Cells: Possible Culprits in Solid Tumors? Mon, 27 Jul 2015 08:20:46 +0000 The clinical use of bone marrow derived multipotent mesenchymal stromal cells (BM-MSCs) in different settings ranging from tissue engineering to immunotherapies has prompted investigations on the properties of these cells in a variety of other tissues. Particularly the role of MSCs in solid tumors has been the subject of many experimental approaches. While a clear phenotypical distinction of tumor associated fibroblasts (TAFs) and MSCs within the tumor microenvironment is still missing, the homing of bone marrow MSCs in tumor sites has been extensively studied. Both, tumor-promoting and tumor-inhibiting effects of BM-MSCs have been described in this context. This ambiguity requires a reappraisal of the different studies and experimental methods employed. Here, we review the current literature on tumor-promoting and tumor-inhibiting effects of BM-MSCs with a particular emphasis on their interplay with components of the immune system and also highlight a potential role of MSCs as cell of origin for certain mesenchymal tumors. Pascal David Johann and Ingo Müller Copyright © 2015 Pascal David Johann and Ingo Müller. All rights reserved. Modulation of Hyaluronan Synthesis by the Interaction between Mesenchymal Stem Cells and Osteoarthritic Chondrocytes Sun, 26 Jul 2015 12:52:29 +0000 Bone marrow mesenchymal stem cells (BM-MSCs) are considered a good source for cellular therapy in cartilage repair. But, their potential to repair the extracellular matrix, in an osteoarthritic environment, is still controversial. In osteoarthritis (OA), anti-inflammatory action and extracellular matrix production are important steps for cartilage healing. This study examined the interaction of BM-MSC and OA-chondrocyte on the production of hyaluronan and inflammatory cytokines in a Transwell system. We compared cocultured BM-MSCs and OA-chondrocytes with the individually cultured controls (monocultures). There was a decrease in BM-MSCs cell count in coculture with OA-chondrocytes when compared to BM-MSCs alone. In monoculture, BM-MSCs produced higher amounts of hyaluronan than OA-chondrocytes and coculture of BM-MSCs with OA-chondrocytes increased hyaluronan production per cell. Hyaluronan synthase-1 mRNA expression was upregulated in BM-MSCs after coculture with OA-chondrocytes, whereas hyaluronidase-1 was downregulated. After coculture, lower IL-6 levels were detected in BM-MSCs compared with OA-chondrocytes. These results indicate that, in response to coculture with OA-chondrocytes, BM-MSCs change their behavior by increasing production of hyaluronan and decreasing inflammatory cytokines. Our results indicate that BM-MSCs per se could be a potential tool for OA regenerative therapy, exerting short-term effects on the local microenvironment even when cell:cell contact is not occurring. Eliane Antonioli, Carla A. Piccinato, Helena B. Nader, Moisés Cohen, Anna Carla Goldberg, and Mario Ferretti Copyright © 2015 Eliane Antonioli et al. All rights reserved. Low Reactive Level Laser Therapy for Mesenchymal Stromal Cells Therapies Sun, 26 Jul 2015 09:45:19 +0000 Low reactive level laser therapy (LLLT) is mainly focused on the activation of intracellular or extracellular chromophore and the initiation of cellular signaling by using low power lasers. Over the past forty years, it was realized that the laser therapy had the potential to improve wound healing and reduce pain and inflammation. In recent years, the term LLLT has become widely recognized in the field of regenerative medicine. In this review, we will describe the mechanisms of action of LLLT at a cellular level and introduce the application to mesenchymal stem cells and mesenchymal stromal cells (MSCs) therapies. Finally, our recent research results that LLLT enhanced the MSCs differentiation to osteoblast will also be described. Toshihiro Kushibiki, Takeshi Hirasawa, Shinpei Okawa, and Miya Ishihara Copyright © 2015 Toshihiro Kushibiki et al. All rights reserved. Adult Mesenchymal Stem Cells: When, Where, and How Sun, 26 Jul 2015 08:32:19 +0000 Adult mesenchymal stem cells (MSCs) have profound medicinal effects at body sites of tissue injury, disease, or inflammation as either endogenously or exogenously supplied. The medicinal effects are either immunomodulatory or trophic or both. When to deliver these mediators of regeneration, where, and by what delivery apparatus or mechanism will directly determine their medical efficacy. The MSCs help manage the innate regenerative capacity of almost every body tissue and the MSCs have only recently been fully appreciated. Perhaps the most skilled physician-manager of the body’s innate regenerative capacity is in orthopedics where the vigorous regeneration and repair capacity of bone through local MSCs-titers is expertly managed by the orthopaedic physician. The challenge is to extend MSCs expertise to address other tissue dysfunctions and diseases. The medicine of tomorrow will encompass optimizing the tissues’ intrinsic regenerative potential through management of local MSCs. Arnold I. Caplan Copyright © 2015 Arnold I. Caplan. All rights reserved. Regenerative Translation of Human Blood-Vessel-Derived MSC Precursors Sun, 26 Jul 2015 08:21:58 +0000 Mesenchymal stem/stromal cells (MSCs) represent a promising adult progenitor cell source for tissue repair and regeneration. Their mysterious identity in situ has gradually been unveiled by the accumulating evidence indicating an association between adult multipotent stem/progenitor cells and vascular/perivascular niches. Using immunohistochemistry and fluorescence-activated cell sorting, we and other groups have prospectively identified and purified subpopulations of multipotent precursor cells associated with the blood vessels within multiple human organs. The three precursor subsets, myogenic endothelial cells (MECs), pericytes (PCs), and adventitial cells (ACs), are located, respectively, in the three structural tiers of typical blood vessels: intima, media, and adventitia. MECs, PCs, and ACs have been extensively characterized in prior studies and are currently under investigation for their therapeutic potentials in preclinical animal models. In this review, we will briefly discuss the identification, isolation, and characterization of these human blood-vessel-derived stem cells (hBVSCs) and summarize the current status of regenerative applications of hBVSC subsets. William C. W. Chen, Bruno Péault, and Johnny Huard Copyright © 2015 William C. W. Chen et al. All rights reserved. Platelet-Derived Growth Factor Receptor Alpha as a Marker of Mesenchymal Stem Cells in Development and Stem Cell Biology Thu, 16 Jul 2015 10:40:48 +0000 Three decades on, the mesenchymal stem cells (MSCs) have been intensively researched on the bench top and used clinically. However, ambiguity still exists in regard to their anatomical locations, identities, functions, and extent of their differentiative abilities. One of the major impediments in the quest of the MSC research has been lack of appropriate in vivo markers. In recent years, this obstacle has been resolved to some degree as PDGFRα emerges as an important mesenchymal stem cell marker. Accumulating lines of evidence are showing that the PDGFRα+ cells reside in the perivascular locations of many adult interstitium and fulfil the classic concepts of MSCs in vitro and in vivo. PDGFRα has long been recognised for its roles in the mesoderm formation and connective tissue development during the embryogenesis. Current review describes the lines of evidence regarding the role of PDGFRα in morphogenesis and differentiation and its implications for MSC biology. Ramin M. Farahani and Munira Xaymardan Copyright © 2015 Ramin M. Farahani and Munira Xaymardan. All rights reserved. Mesenchymal Stromal Cells Affect Disease Outcomes via Macrophage Polarization Wed, 15 Jul 2015 12:44:44 +0000 Mesenchymal stromal cells (MSCs) are multipotent and self-renewable cells that reside in almost all postnatal tissues. In recent years, many studies have reported the effect of MSCs on the innate and adaptive immune systems. MSCs regulate the proliferation, activation, and effector function of T lymphocytes, professional antigen presenting cells (dendritic cells, macrophages, and B lymphocytes), and NK cells via direct cell-to-cell contact or production of soluble factors including indoleamine 2,3-dioxygenase, prostaglandin E2, tumor necrosis factor-α stimulated gene/protein 6, nitric oxide, and IL-10. MSCs are also able to reprogram macrophages from a proinflammatory M1 phenotype toward an anti-inflammatory M2 phenotype capable of regulating immune response. Because of their capacity for differentiation and immunomodulation, MSCs have been used in many preclinical and clinical studies as possible new therapeutic agents for the treatment of autoimmune, degenerative, and inflammatory diseases. In this review, we discuss the central role of MSCs in macrophage polarization and outcomes of diseases such as wound healing, brain/spinal cord injuries, and diseases of heart, lung, and kidney in animal models. Guoping Zheng, Menghua Ge, Guanguan Qiu, Qiang Shu, and Jianguo Xu Copyright © 2015 Guoping Zheng et al. All rights reserved. Alterations in the Secretome of Clinically Relevant Preparations of Adipose-Derived Mesenchymal Stem Cells Cocultured with Hyaluronan Wed, 15 Jul 2015 12:36:27 +0000 Osteoarthritis (OA) can be a debilitating degenerative disease and is the most common form of arthritic disease. There is a general consensus that current nonsurgical therapies are insufficient for younger OA sufferers who are not candidates for knee arthroplasties. Adipose-derived mesenchymal stem cells (MSCs) therapy for the treatment of OA can slow disease progression and lead to neocartilage formation. The mechanism of action is secretion driven. Current clinical preparations from adipose tissue for the treatment of OA include autologous stromal vascular fraction (SVF), SVF plus mature adipocytes, and culture-purified MSCs. Herein we have combined these human adipose-derived preparations with Hyaluronan (Hylan G-F 20: Synvisc) in vitro and measured alterations in cytokine profile. SVF plus mature adipocytes showed the greatest decreased in the proinflammatory cytokines IL-1β, IFN-, and VEGF. MCP-1 and MIP-1α decreased substantially in the SVF preparations but not the purified MSCs. The purified MSC preparation was the only one to show increase in MIF. Overall the SVF plus mature adipocytes preparation may be most suited of all the preparations for combination with HA for the treatment of OA, based on the alterations of heavily implicated cytokines in OA disease progression. This will require further validation using in vivo models. Peter Succar, Edmond J. Breen, Donald Kuah, and Benjamin R. Herbert Copyright © 2015 Peter Succar et al. All rights reserved. Effect of Increasing Doses of γ-Radiation on Bone Marrow Stromal Cells Grown on Smooth and Rough Titanium Surfaces Wed, 15 Jul 2015 10:03:55 +0000 Radiation therapy for oral and maxillofacial tumors could damage bone marrow stromal cells (BMSCs) in jaw, which caused dental implant failure. However, how radiation affects BMSCs on SLA (sandblasted with large-grits, acid-etched) surfaces is still unknown. The aim of this study was to investigate effect of different dose of γ-radiation on BMSCs on SLA and PT (polished titanium) surfaces. Rat BMSCs were radiated with 2, 4, and 8 Gy γ-radiation and then seeded on both surfaces. Cell adhesion, spreading, and proliferation were tested. The osteogenesis and the adipogenesis ability were examined by Alizarin-Red and Oil-Red staining, respectively. Real-time PCR was performed to detect osteogenic (osteocalcin, OCN; runt-related transcription factor 2, Runx2) and adipogenic (peroxisome proliferator-activated receptor gamma, PPARγ) gene expression at days 7 and 14 postirradiation. Results showed that γ-radiation reduced cell proliferation, adhesion, spreading, and osteogenic differentiation. 2 Gy radiation promoted adipogenic differentiation, but it was significantly decreased when dosage reached 4 Gy. In conclusion, results suggest that γ-radiation influenced BMSCs behaviors in a dosage-dependent manner except adipogenic differentiation, low dose promoted it, and high dose inhibited it. This effect was influenced by surface characteristics, which may explain the different failure rate of various implants in patients after radiation. Bo Huang, Mengkai Guang, Jun Ye, Ping Gong, and Hua Tang Copyright © 2015 Bo Huang et al. All rights reserved. Umbilical Cord Tissue-Derived Cells as Therapeutic Agents Sun, 12 Jul 2015 07:51:44 +0000 Although the characteristics of SC, including UC-derived cells, are a dramatically discussed issue, this review will focus particularly on some controversial issues regarding clinical utility of cells isolated from UC tissue. UC-derived cells have several advantages compared to other types and sources of stem cells. The impact of UC topography on cell characteristics is briefly discussed. The necessity to adapt existing methods of cell isolation and culturing to GMP conditions is mentioned, as well as possible cryopreservation of this material. Light is shed on some future perspectives for UC-derived cells. Olga Maslova, Miroslav Novak, and Peter Kruzliak Copyright © 2015 Olga Maslova et al. All rights reserved. Cell Therapy Augments Functional Recovery Subsequent to Spinal Cord Injury under Experimental Conditions Thu, 09 Jul 2015 11:59:18 +0000 The spinal cord injury leads to enervation of normal tissue homeostasis ultimately leading to paralysis. Until now there is no proper cure for the treatment of spinal cord injury. Recently, cell therapy in animal spinal cord injury models has shown some progress of recovery. At present, clinical trials are under progress to evaluate the efficacy of cell transplantation for the treatment of spinal cord injury. Different types of cells such as pluripotent stem cells derived neural cells, mesenchymal stromal cells, neural stem cells, glial cells are being tested in various spinal cord injury models. In this review we highlight both the advances and lacuna in the field of spinal cord injury by discussing epidemiology, pathophysiology, molecular mechanism, and various cell therapy strategies employed in preclinical and clinical injury models and finally we discuss the limitations and ethical issues involved in cell therapy approach for treating spinal cord injury. Vikram Sabapathy, George Tharion, and Sanjay Kumar Copyright © 2015 Vikram Sabapathy et al. All rights reserved. Oleanolic Acid Induces Differentiation of Neural Stem Cells to Neurons: An Involvement of Transcription Factor Nkx-2.5 Thu, 09 Jul 2015 11:29:22 +0000 Neural stem cells (NSCs) harbor the potential to differentiate into neurons, astrocytes, and oligodendrocytes under normal conditions and/or in response to tissue damage. NSCs open a new way of treatment of the injured central nervous system and neurodegenerative disorders. Thus far, few drugs have been developed for controlling NSC functions. Here, the effect as well as mechanism of oleanolic acid (OA), a pentacyclic triterpenoid, on NSC function was investigated. We found OA significantly inhibited neurosphere formation in a dose-dependent manner and achieved a maximum effect at 10 nM. OA also reduced 5-ethynyl-2′-deoxyuridine (EdU) incorporation into NSCs, which was indicative of inhibited NSC proliferation. Western blotting analysis revealed the protein levels of neuron-specific marker tubulin-βIII (TuJ1) and Mash1 were increased whilst the astrocyte-specific marker glial fibrillary acidic protein (GFAP) decreased. Immunofluorescence analysis showed OA significantly elevated the percentage of TuJ1-positive cells and reduced GFAP-positive cells. Using DNA microarray analysis, 183 genes were differentially regulated by OA. Through transcription factor binding site analyses of the upstream regulatory sequences of these genes, 87 genes were predicted to share a common motif for Nkx-2.5 binding. Finally, small interfering RNA (siRNA) methodology was used to silence Nkx-2.5 expression and found silence of Nkx-2.5 alone did not change the expression of TuJ-1 and the percentage of TuJ-1-positive cells. But in combination of OA treatment and silence of Nkx-2.5, most effects of OA on NSCs were abolished. These results indicated that OA is an effective inducer for NSCs differentiation into neurons at least partially by Nkx-2.5-dependent mechanism. You Ning, Jianhua Huang, Bill Kalionis, Qin Bian, Jingcheng Dong, Junzhen Wu, Xiantao Tai, Shijin Xia, and Ziyin Shen Copyright © 2015 You Ning et al. All rights reserved. Applications of Induced Pluripotent Stem Cells in Studying the Neurodegenerative Diseases Thu, 09 Jul 2015 11:09:23 +0000 Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons. Incurable neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) show dramatic rising trends particularly in the advanced age groups. However, the underlying mechanisms are not yet fully elucidated, and to date there are no biomarkers for early detection or effective treatments for the underlying causes of these diseases. Furthermore, due to species variation and differences between animal models (e.g., mouse transgenic and knockout models) of neurodegenerative diseases, substantial debate focuses on whether animal and cell culture disease models can correctly model the condition in human patients. In 2006, Yamanaka of Kyoto University first demonstrated a novel approach for the preparation of induced pluripotent stem cells (iPSCs), which displayed similar pluripotency potential to embryonic stem cells (ESCs). Currently, iPSCs studies are permeating many sectors of disease research. Patient sample-derived iPSCs can be used to construct patient-specific disease models to elucidate the pathogenic mechanisms of disease development and to test new therapeutic strategies. Accordingly, the present review will focus on recent progress in iPSC research in the modeling of neurodegenerative disorders and in the development of novel therapeutic options. Wenbin Wan, Lan Cao, Bill Kalionis, Shijin Xia, and Xiantao Tai Copyright © 2015 Wenbin Wan et al. All rights reserved. Adipose-Derived Mesenchymal Stem Cells for the Treatment of Articular Cartilage: A Systematic Review on Preclinical and Clinical Evidence Thu, 09 Jul 2015 10:55:57 +0000 Among the current therapeutic approaches for the regeneration of damaged articular cartilage, none has yet proven to offer results comparable to those of native hyaline cartilage. Recently, it has been claimed that the use of mesenchymal stem cells (MSCs) provides greater regenerative potential than differentiated cells, such as chondrocytes. Among the different kinds of MSCs available, adipose-derived mesenchymal stem cells (ADSCs) are emerging due to their abundancy and easiness to harvest. However, their mechanism of action and potential for cartilage regeneration are still under investigation, and many other aspects still need to be clarified. The aim of this systematic review is to give an overview of in vivo studies dealing with ADSCs, by summarizing the main evidence for the treatment of cartilage disease of the knee. Francesco Perdisa, Natalia Gostyńska, Alice Roffi, Giuseppe Filardo, Maurilio Marcacci, and Elizaveta Kon Copyright © 2015 Francesco Perdisa et al. All rights reserved. Efficacy of Surgery Combined with Autologous Bone Marrow Stromal Cell Transplantation for Treatment of Intracerebral Hemorrhage Thu, 09 Jul 2015 10:08:35 +0000 Bone marrow stromal cells (BMSCs) may differentiate into nerve cells under a certain condition; however, the clinical application for treating nervous system disease remains unclear. The aim is to assess the safety profile, feasibility, and effectiveness of surgery combined with autologous BMSCs transplantation for treating ICH. 206 ICH patients who had received surgical procedure were divided into transplantation () or control group (). For transplantation group, BMSCs were injected into the perihemorrhage area in the base ganglia through an intracranial drainage tube 5.5 (3.01–6.89) days after surgery, followed by a second injection into the subarachnoid space through lumbar puncture 4 weeks later. Neurologic impairment and daily activities were assessed with National Institute Stroke Scale (NIHSS), Barthel index, and Rankin scale before transplantation and 6 months and 12 months after transplantation. Our results revealed that, compared with control group, NIHSS score and Rankin scale were both significantly decreased but Barthel index was increased in transplantation group after 6 months. Interestingly, no significant difference was observed between 12 months and 6 months. No transplantation-related adverse effects were investigated during follow-up assessments. Our findings suggest that surgery combined with autologous BMSCs transplantation is safe for treatment of ICH, providing short-term therapeutic benefits. Jianxin Zhu, Yilei Xiao, Zhongmin Li, Fabin Han, Taiwu Xiao, Zhiti Zhang, and Fengyang Geng Copyright © 2015 Jianxin Zhu et al. All rights reserved. In Vitro Effects of Strontium on Proliferation and Osteoinduction of Human Preadipocytes Thu, 09 Jul 2015 09:44:36 +0000 Development of tools to be used for in vivo bone tissue regeneration focuses on cellular models and differentiation processes. In searching for all the optimal sources, adipose tissue-derived mesenchymal stem cells (hADSCs or preadipocytes) are able to differentiate into osteoblasts with analogous characteristics to bone marrow mesenchymal stem cells, producing alkaline phosphatase (ALP), collagen, osteocalcin, and calcified nodules, mainly composed of hydroxyapatite (HA). The possibility to influence bone differentiation of stem cells encompasses local and systemic methods, including the use of drugs administered systemically. Among the latter, strontium ranelate (SR) represents an interesting compound, acting as an uncoupling factor that stimulates bone formation and inhibits bone resorption. The aim of our study was to evaluate the in vitro effects of a wide range of strontium (Sr2+) concentrations on proliferation, ALP activity, and mineralization of a novel finite clonal hADSCs cell line, named PA20-h5. Sr2+ promoted PA20-h5 cell proliferation while inducing the increase of ALP activity and gene expression as well as HA production during in vitro osteoinduction. These findings indicate a role for Sr2+ in supporting bone regeneration during the process of skeletal repair in general, and, more specifically, when cell therapies are applied. V. Nardone, R. Zonefrati, C. Mavilia, C. Romagnoli, S. Ciuffi, S. Fabbri, G. Palmini, G. Galli, A. Tanini, and M. L. Brandi Copyright © 2015 V. Nardone et al. All rights reserved. Use of Adult Stem Cells for Cartilage Tissue Engineering: Current Status and Future Developments Thu, 09 Jul 2015 09:40:06 +0000 Due to their low self-repair ability, cartilage defects that result from joint injury, aging, or osteoarthritis, are the most often irreversible and are a major cause of joint pain and chronic disability. So, in recent years, researchers and surgeons have been working hard to elaborate cartilage repair interventions for patients who suffer from cartilage damage. However, current methods do not perfectly restore hyaline cartilage and may lead to the apparition of fibro- or hypertrophic cartilage. In the next years, the development of new strategies using adult stem cells, in scaffolds, with supplementation of culture medium and/or culture in low oxygen tension should improve the quality of neoformed cartilage. Through these solutions, some of the latest technologies start to bring very promising results in repairing cartilage from traumatic injury or chondropathies. This review discusses the current knowledge about the use of adult stem cells in the context of cartilage tissue engineering and presents clinical trials in progress, as well as in the future, especially in the field of bioprinting stem cells. Catherine Baugé and Karim Boumédiene Copyright © 2015 Catherine Baugé and Karim Boumédiene. All rights reserved. Noninvasive Optical Imaging and In Vivo Cell Tracking of Indocyanine Green Labeled Human Stem Cells Transplanted at Superficial or In-Depth Tissue of SCID Mice Thu, 09 Jul 2015 09:21:12 +0000 Stem cell based therapies hold great promise for the treatment of human diseases; however results from several recent clinical studies have not shown a level of efficacy required for their use as a first-line therapy, because more often in these studies fate of the transplanted cells is unknown. Thus monitoring the real-time fate of in vivo transplanted cells is essential to validate the full potential of stem cells based therapy. Recent studies have shown how real-time in vivo molecular imaging has helped in identifying hurdles towards clinical translation and designing potential strategies that may contribute to successful transplantation of stem cells and improved outcomes. At present, there are no cost effective and efficient labeling techniques for tracking the cells under in vivo conditions. Indocyanine green (ICG) is a safer, economical, and superior labelling technique for in vivo optical imaging. ICG is a FDA-approved agent and decades of usage have clearly established the effectiveness of ICG for human clinical applications. In this study, we have optimized the ICG labelling conditions that is optimal for noninvasive optical imaging and demonstrated that ICG labelled cells can be successfully used for in vivo cell tracking applications in SCID mice injury models. Vikram Sabapathy, Jyothsna Mentam, Paul Mazhuvanchary Jacob, and Sanjay Kumar Copyright © 2015 Vikram Sabapathy et al. All rights reserved. Safety of Allogeneic Umbilical Cord Blood Stem Cells Therapy in Patients with Severe Cerebral Palsy: A Retrospective Study Wed, 08 Jul 2015 05:56:23 +0000 This retrospective study aimed to assess the safety of patients with severe cerebral palsy (CP), who received allogeneic umbilical cord blood stem cells (UCBSCs) treatment from August 2009 to December 2012 in Guangdong Provincial Hospital of Chinese Medicine. A total of 47 patients with average age of years were evaluated in this study. There was no significant association with allogeneic UCBSCs treatments found in the data of the laboratory index . No casualties occurred. Some adverse events during treatments were found in 26 (55.3%) patients, including fever (42.6%) and vomiting (21.2%). Intrathecal infusion and the ages at the initiation of treatment (≤10 years old) were risk factors for the occurrence of adverse events by logistic regression analysis. However, all adverse events disappeared after symptomatic treatment. No treatment related serious adverse events were found in follow-up visits within 6 months. In conclusion, allogeneic UCBSCs treatment was relatively safe for severe CP patients. Mei Feng, Aili Lu, Hongxia Gao, Caiwen Qian, Jun Zhang, Tongxiang Lin, and Yuanqi Zhao Copyright © 2015 Mei Feng et al. All rights reserved. Characterization of Nestin, a Selective Marker for Bone Marrow Derived Mesenchymal Stem Cells Mon, 06 Jul 2015 11:05:44 +0000 Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into multiple cell lineages and contributing to tissue repair and regeneration. Characterization of the physiological function of MSCs has been largely hampered by lack of unique markers. Nestin, originally found in neuroepithelial stem cells, is an intermediate filament protein expressed in the early stages of development. Increasing studies have shown a particular association between Nestin and MSCs. Nestin could characterize a subset of bone marrow perivascular MSCs which contributed to bone development and closely contacted with hematopoietic stem cells (HSCs). Nestin expressing (Nes+) MSCs also play a role in the progression of various diseases. However, Nes+ cells were reported to participate in angiogenesis as MSCs or endothelial progenitor cells (EPCs) in several tissues and be a heterogeneous population comprising mesenchymal cells and endothelial cells in the developing bone marrow. In this review article, we will summarize the progress of the research on Nestin, particularly the function of Nes+ cells in bone marrow, and discuss the feasibility of using Nestin as a specific marker for MSCs. Liang Xie, Xin Zeng, Jing Hu, and Qianming Chen Copyright © 2015 Liang Xie et al. All rights reserved. Stem Cell Hierarchy and Clonal Evolution in Acute Lymphoblastic Leukemia Mon, 06 Jul 2015 09:42:34 +0000 Cancer is characterized by a remarkable intertumoral, intratumoral, and cellular heterogeneity that might be explained by the cancer stem cell (CSC) and/or the clonal evolution models. CSCs have the ability to generate all different cells of a tumor and to reinitiate the disease after remission. In the clonal evolution model, a consecutive accumulation of mutations starting in a single cell results in competitive growth of subclones with divergent fitness in either a linear or a branching succession. Acute lymphoblastic leukemia (ALL) is a highly malignant cancer of the lymphoid system in the bone marrow with a dismal prognosis after relapse. However, stabile phenotypes and functional data of CSCs in ALL, the so-called leukemia-initiating cells (LICs), are highly controversial and the question remains whether there is evidence for their existence. This review discusses the concepts of CSCs and clonal evolution in respect to LICs mainly in B-ALL and sheds light onto the technical controversies in LIC isolation and evaluation. These aspects are important for the development of strategies to eradicate cells with LIC capacity. Common properties of LICs within different subclones need to be defined for future ALL diagnostics, treatment, and disease monitoring to improve the patients’ outcome in ALL. Fabian Lang, Bartosch Wojcik, and Michael A. Rieger Copyright © 2015 Fabian Lang et al. All rights reserved. In Vitro Differentiation Potential of Human Placenta Derived Cells into Skin Cells Wed, 01 Jul 2015 05:52:32 +0000 Skin autografting is the most viable and aesthetic technique for treatment of extensive burns; however, this practice has potential limitations. Harvesting cells from neonatal sources (such as placental tissue) is a simple, inexpensive, and noninvasive procedure. In the current study authors sought to evaluate in vitro potential of human placenta derived stem cells to develop into skin-like cells. After extensive washing, amniotic membrane and umbilical cord tissue were separated to harvest amniotic epithelial cells (AECs) and umbilical cord mesenchymal stem cells (UC-MSCs), respectively. Both types of cells were characterized for the expression of embryonic lineage markers and their growth characteristics were determined. AECs and UC-MSCs were induced to differentiate into keratinocytes-like and dermal fibroblasts-like cells, respectively. After induction, morphological changes were detected by microscopy. The differentiation potential was further assessed using immunostaining and RT-PCR analyses. AECs were positive for cytokeratins and E-Cadherin while UC-MSCs were positive for fibroblast specific makers. AECs differentiated into keratinocytes-like cells showed positive expression of keratinocyte specific cytokeratins, involucrin, and loricrin. UC-MSCs differentiated into dermal fibroblast-like cells indicated expression of collagen type 3, desmin, FGF-7, fibroblast activation protein alpha, procollagen-1, and vimentin. In conclusion, placenta is a potential source of cells to develop into skin-like cells. Ruhma Mahmood, Mahmood S. Choudhery, Azra Mehmood, Shaheen N. Khan, and Sheikh Riazuddin Copyright © 2015 Ruhma Mahmood et al. All rights reserved. Angiogenic Potential of Human Neonatal Foreskin Stromal Cells in the Chick Embryo Chorioallantoic Membrane Model Mon, 29 Jun 2015 07:06:04 +0000 Several studies have demonstrated the multipotentiality of human neonatal foreskin stromal cells (hNSSCs) as being able to differentiate into adipocytes and osteoblasts and potentially other cell types. Recently, we demonstrated that hNSSCs play a role during in vitro angiogenesis and appear to possess a capacity to differentiate into endothelial-like cells; however, their angiogenic potential within an ex vivo environment remains unclear. Current study shows hNSSCs to display significant migration potential in the undifferentiated state and high responsiveness in the in vitro wound healing scratch assay. When hNSSCs were seeded onto the top of the CAM, human von Willebrand factor (hVWF), CD31, smooth muscle actin (SMA), and factor XIIIa positive cells were observed in the chick endothelium. CAMs transplanted with endothelial-differentiated hNSSCs displayed a higher number of blood vessels containing hNSSCs compared to CAMs transplanted with undifferentiated hNSSCs. Interestingly, undifferentiated hNSSCs showed a propensity to differentiate towards ectoderm with indication of epidermal formation with cells positive for CD1a, CK5/6, CK19, FXIIIa, and S-100 cells, which warrant further investigation. Our findings imply a potential angiogenic role for hNSSCs ex vivo in the differentiated and undifferentiated state, with potential contribution to blood vessel formation and potential application in tissue regeneration and vascularization. Radhakrishnan Vishnubalaji, Muhammad Atteya, May Al-Nbaheen, Richard O. C. Oreffo, Abdullah Aldahmash, and Nehad M. Alajez Copyright © 2015 Radhakrishnan Vishnubalaji et al. All rights reserved. Differential Reponses of Hematopoietic Stem and Progenitor Cells to mTOR Inhibition Sun, 28 Jun 2015 11:16:04 +0000 Abnormal activation of the mammalian target of rapamycin (mTOR) signaling pathway has been observed in a variety of human cancers. Therefore, targeting of the mTOR pathway is an attractive strategy for cancer treatment and several mTOR inhibitors, including AZD8055 (AZD), a novel dual mTORC1/2 inhibitor, are currently in clinical trials. Although bone marrow (BM) suppression is one of the primary side effects of anticancer drugs, it is not known if pharmacological inhibition of dual mTORC1/2 affects BM hematopoietic stem and progenitor cells (HSPCs) function and plasticity. Here we report that dual inhibition of mTORC1/2 by AZD or its analogue (KU-63794) depletes mouse BM Lin−Sca-1+c-Kit+ cells in cultures via the induction of apoptotic cell death. Subsequent colony-forming unit (CFU) assays revealed that inhibition of mTORC1/2 suppresses the clonogenic function of hematopoietic progenitor cells (HPCs) in a dose-dependent manner. Surprisingly, we found that dual inhibition of mTORC1/2 markedly inhibits the growth of day-14 cobblestone area-forming cells (CAFCs) but enhances the generation of day-35 CAFCs. Given the fact that day-14 and day-35 CAFCs are functional surrogates of HPCs and hematopoietic stem cells (HSCs), respectively, these results suggest that dual inhibition of mTORC1/2 may have distinct effects on HPCs versus HSCs. Aimin Yang, Xia Xiao, Mingfeng Zhao, Amanda C. LaRue, Bradley A. Schulte, and Gavin Y. Wang Copyright © 2015 Aimin Yang et al. All rights reserved. Advances and Prospects in Tissue-Engineered Meniscal Scaffolds for Meniscus Regeneration Thu, 25 Jun 2015 12:21:28 +0000 The meniscus plays a crucial role in maintaining knee joint homoeostasis. Meniscal lesions are relatively common in the knee joint and are typically categorized into various types. However, it is difficult for inner avascular meniscal lesions to self-heal. Untreated meniscal lesions lead to meniscal extrusions in the long-term and gradually trigger the development of knee osteoarthritis (OA). The relationship between meniscal lesions and knee OA is complex. Partial meniscectomy, which is the primary method to treat a meniscal injury, only relieves short-term pain; however, it does not prevent the development of knee OA. Similarly, other current therapeutic strategies have intrinsic limitations in clinical practice. Tissue engineering technology will probably address this challenge by reconstructing a meniscus possessing an integrated configuration with competent biomechanical capacity. This review describes normal structure and biomechanical characteristics of the meniscus, discusses the relationship between meniscal lesions and knee OA, and summarizes the classifications and corresponding treatment strategies for meniscal lesions to understand meniscal regeneration from physiological and pathological perspectives. Last, we present current advances in meniscal scaffolds and provide a number of prospects that will potentially benefit the development of meniscal regeneration methods. Weimin Guo, Shuyun Liu, Yun Zhu, Changlong Yu, Shibi Lu, Mei Yuan, Yue Gao, Jingxiang Huang, Zhiguo Yuan, Jiang Peng, Aiyuan Wang, Yu Wang, Jifeng Chen, Li Zhang, Xiang Sui, Wenjing Xu, and Quanyi Guo Copyright © 2015 Weimin Guo et al. All rights reserved.