Stem Cells International The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Dynamic Support Culture of Murine Skeletal Muscle-Derived Stem Cells Improves Their Cardiogenic Potential In Vitro Tue, 18 Aug 2015 06:42:44 +0000 Ischemic heart disease is the main cause of death in western countries and its burden is increasing worldwide. It typically involves irreversible degeneration and loss of myocardial tissue leading to poor prognosis and fatal outcome. Autologous cells with the potential to regenerate damaged heart tissue would be an ideal source for cell therapeutic approaches. Here, we compared different methods of conditional culture for increasing the yield and cardiogenic potential of murine skeletal muscle-derived stem cells. A subpopulation of nonadherent cells was isolated from skeletal muscle by preplating and applying cell culture conditions differing in support of cluster formation. In contrast to static culture conditions, dynamic culture with or without previous hanging drop preculture led to significantly increased cluster diameters and the expression of cardiac specific markers on the protein and mRNA level. Whole-cell patch-clamp studies revealed similarities to pacemaker action potentials and responsiveness to cardiac specific pharmacological stimuli. This data indicates that skeletal muscle-derived stem cells are capable of adopting enhanced cardiac muscle cell-like properties by applying specific culture conditions. Choosing this route for the establishment of a sustainable, autologous source of cells for cardiac therapies holds the potential of being clinically more acceptable than transgenic manipulation of cells. Klaus Neef, Philipp Treskes, Guoxing Xu, Florian Drey, Sureshkumar Perumal Srinivasan, Tomo Saric, Erastus Nembo, Judith Semmler, Filomain Nguemo, Christof Stamm, Douglas B. Cowan, Antje-Christin Deppe, Maximilian Scherner, Thorsten Wittwer, Jürgen Hescheler, Thorsten Wahlers, and Yeong-Hoon Choi Copyright © 2015 Klaus Neef et al. All rights reserved. Morphometric Analysis of Human Embryonic Stem Cell-Derived Ventricular Cardiomyocytes: Determining the Maturation State of a Population by Quantifying Parameters in Individual Cells Mon, 17 Aug 2015 13:55:58 +0000 Quantitative methods were established to determine the level of maturation of human embryonic stem cell-derived ventricular cardiomyocytes (hESC-vCMs) that were treated with different metabolic stimulants (i.e., isoproterenol and oleic acid) during early differentiation. Cells were double-immunolabeled with α-actinin and COX IV antibodies, to label the myofibrils and mitochondria, respectively, after which images were acquired via confocal microscopy. In order to determine the extent of differentiation, image analysis protocols were then used to quantify cell shape and area, as well as the degree of myofibrillar organization and intercalation of mitochondria between the myofibrils within the cells. We demonstrated that oleic acid or isoproterenol alone, or a combination of the two, induced a more elongated hESC-vCM phenotype than the untreated controls. In addition, cells treated with isoproterenol alone exhibited a similar level of myofibrillar organization as the controls, but those treated with oleic acid with/without isoproterenol exhibited a more organized (parallel) orientation of myofibrils. The combined isoproterenol/oleic acid treatment also resulted in enhanced intercalation of mitochondria between the myofibrils. We suggest that these quantitative morphometric methods might serve as simple and effective tools that can be utilized in the determination of the level of structural maturation of hESC-vCMs. Harvey Y. S. Chan, Wendy Keung, Ronald A. Li, Andrew L. Miller, and Sarah E. Webb Copyright © 2015 Harvey Y. S. Chan et al. All rights reserved. Human Amniotic Fluid Mesenchymal Stem Cells from Second- and Third-Trimester Amniocentesis: Differentiation Potential, Molecular Signature, and Proteome Analysis Mon, 17 Aug 2015 08:04:23 +0000 Human amniotic fluid stem cells have become an attractive stem cell source for potential applications in regenerative medicine and tissue engineering. The aim of this study was to characterize amniotic fluid-derived mesenchymal stem cells (AF-MSCs) from second- and third-trimester of gestation. Using two-stage protocol, MSCs were successfully cultured and exhibited typical stem cell morphological, specific cell surface, and pluripotency markers characteristics. AF-MSCs differentiated into adipocytes, osteocytes, chondrocytes, myocytes, and neuronal cells, as determined by morphological changes, cell staining, and RT-qPCR showing the tissue-specific gene presence for differentiated cell lineages. Using SYNAPT G2 High Definition Mass Spectrometry technique approach, we performed for the first time the comparative proteomic analysis between undifferentiated AF-MSCs from late trimester of gestation and differentiated into myogenic, adipogenic, osteogenic, and neurogenic lineages. The analysis of the functional and expression patterns of 250 high abundance proteins selected from more than 1400 demonstrated the similar proteome of cultured and differentiated AF-MSCs but the unique changes in their expression profile during cell differentiation that may help the identification of key markers in differentiated cells. Our results provide evidence that human amniotic fluid of second- and third-trimester contains stem cells with multilineage potential and may be attractive source for clinical applications. Jurate Savickiene, Grazina Treigyte, Sandra Baronaite, Giedre Valiuliene, Algirdas Kaupinis, Mindaugas Valius, Audrone Arlauskiene, and Ruta Navakauskiene Copyright © 2015 Jurate Savickiene et al. All rights reserved. Intravenous Cardiac Stem Cell-Derived Exosomes Ameliorate Cardiac Dysfunction in Doxorubicin Induced Dilated Cardiomyopathy Mon, 17 Aug 2015 08:02:01 +0000 Despite the efficacy of cardiac stem cells (CSCs) for treatment of cardiomyopathies, there are many limitations to stem cell therapies. CSC-derived exosomes (CSC-XOs) have been shown to be responsible for a large portion of the regenerative effects of CSCs. Using a mouse model of doxorubicin induced dilated cardiomyopathy, we study the effects of systemic delivery of human CSC-XOs in mice. Mice receiving CSC-XOs showed improved heart function via echocardiography, as well as decreased apoptosis and fibrosis. In spite of using immunocompetent mice and human CSC-XOs, mice showed no adverse immune reaction. The use of CSC-XOs holds promise for overcoming the limitations of stem cells and improving cardiac therapies. Adam C. Vandergriff, James Bizetto Meira de Andrade, Junnan Tang, M. Taylor Hensley, Jorge A. Piedrahita, Thomas G. Caranasos, and Ke Cheng Copyright © 2015 Adam C. Vandergriff et al. All rights reserved. Physical, Spatial, and Molecular Aspects of Extracellular Matrix of In Vivo Niches and Artificial Scaffolds Relevant to Stem Cells Research Sun, 16 Aug 2015 09:29:49 +0000 Extracellular matrix can influence stem cell choices, such as self-renewal, quiescence, migration, proliferation, phenotype maintenance, differentiation, or apoptosis. Three aspects of extracellular matrix were extensively studied during the last decade: physical properties, spatial presentation of adhesive epitopes, and molecular complexity. Over 15 different parameters have been shown to influence stem cell choices. Physical aspects include stiffness (or elasticity), viscoelasticity, pore size, porosity, amplitude and frequency of static and dynamic deformations applied to the matrix. Spatial aspects include scaffold dimensionality (2D or 3D) and thickness; cell polarity; area, shape, and microscale topography of cell adhesion surface; epitope concentration, epitope clustering characteristics (number of epitopes per cluster, spacing between epitopes within cluster, spacing between separate clusters, cluster patterns, and level of disorder in epitope arrangement), and nanotopography. Biochemical characteristics of natural extracellular matrix molecules regard diversity and structural complexity of matrix molecules, affinity and specificity of epitope interaction with cell receptors, role of non-affinity domains, complexity of supramolecular organization, and co-signaling by growth factors or matrix epitopes. Synergy between several matrix aspects enables stem cells to retain their function in vivo and may be a key to generation of long-term, robust, and effective in vitro stem cell culture systems. Maria Akhmanova, Egor Osidak, Sergey Domogatsky, Sergey Rodin, and Anna Domogatskaya Copyright © 2015 Maria Akhmanova et al. All rights reserved. Extracellular Vesicles from MSC Modulate the Immune Response to Renal Allografts in a MHC Disparate Rat Model Thu, 13 Aug 2015 14:07:33 +0000 Application of mesenchymal stromal cells (MSC) has been proposed for solid organ transplantation based on their potent immunomodulatory effects. Since side effects from the injection of large cells cannot be excluded, the hypothesis rises that extracellular vesicles (EV) may cause immunomodulatory effects comparable to MSC without additional side effects. We used MSC-derived EV in a rat renal transplant model for acute rejection. We analysed peripheral blood leukocytes (PBL), kidney function, graft infiltrating cells, cytokines in the graft, and alloantibody development in animals without (allo) and with EV application (allo EV). There was no difference in kidney function and in the PBL subpopulation including Tregs between allo and allo EV. In the grafts T- and B-cell numbers were significantly higher and NK-cells lower in the allo EV kidneys compared to allo. TNF-α transcription was lower in allo EV grafts compared to allo; there was no difference regarding IL-10 and in the development of alloantibodies. In conclusion, the different cell infiltrates and cytokine transcription suggest distinct immunomodulatory properties of EV in allotransplantation. While the increased T- and B-cells in the allo EV grafts may represent a missing or negative effect on the adaptive immune system, EV seem to influence the innate immune system in a contrary fashion. M. Koch, A. Lemke, and C. Lange Copyright © 2015 M. Koch et al. All rights reserved. HLA-E: Presentation of a Broader Peptide Repertoire Impacts the Cellular Immune Response—Implications on HSCT Outcome Wed, 12 Aug 2015 12:25:38 +0000 The HLA-E locus encodes a nonclassical class Ib molecule that serves many immune functions from inhibiting NK cells to activating CTLs. Structural analysis of HLA-E/NKG2A complexes visualized fine-tuning of protective immune responses through AA interactions between HLA-E, the bound peptide, and NKG2A/CD94. A loss of cellular protection through abrogation of the HLA-E/NKG2A engagement is dependent on the HLA-E bound peptide. The role of HLA-E in posttransplant outcomes is not well understood but might be attributed to its peptide repertoire. To investigate the self-peptide repertoire of HLA-01:01 in the absence of protective HLA class I signal peptides, we utilized soluble HLA technology in class I negative LCL cells in order to characterize HLA-01:01-bound ligands by mass-spectrometry. To understand the immunological impact of these analyzed ligands on NK cell reactivity, we performed cellular assays. Synthesized peptides were loaded onto recombinant T2 cells expressing HLA-01:01 molecules and applied in cytotoxicity assays using the leukemia derived NK cell line (NKL) as effector. HLA-E in complex with the self-peptides demonstrated a shift towards cytotoxicity and a loss of cell protection. Our data highlights the fact that the HLA-E-peptidome is not as restricted as previously thought and support the suggestion of a posttransplant role for HLA-E. Thomas Kraemer, Alexander A. Celik, Trevor Huyton, Heike Kunze-Schumacher, Rainer Blasczyk, and Christina Bade-Döding Copyright © 2015 Thomas Kraemer et al. All rights reserved. In Vitro and In Vivo Hepatic Differentiation of Adult Somatic Stem Cells and Extraembryonic Stem Cells for Treating End Stage Liver Diseases Wed, 05 Aug 2015 06:27:15 +0000 The shortage of liver donors is a major handicap that prevents most patients from receiving liver transplantation and places them on a waiting list for donated liver tissue. Then, primary hepatocyte transplantation and bioartificial livers have emerged as two alternative treatments for these often fatal diseases. However, another problem has emerged. Functional hepatocytes for liver regeneration are in short supply, and they will dedifferentiate immediately in vitro after they are isolated from liver tissue. Alternative stem-cell-based therapeutic strategies, including hepatic stem cells (HSCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and mesenchymal stem cells (MSCs), are more promising, and more attention has been devoted to these approaches because of the high potency and proliferation ability of the cells. This review will focus on the general characteristics and the progress in hepatic differentiation of adult somatic stem cells and extraembryonic stem cells in vitro and in vivo for the treatment of end stage liver diseases. The hepatic differentiation of stem cells would offer an ideal and promising source for cell therapy and tissue engineering for treating liver diseases. Chenxia Hu and Lanjuan Li Copyright © 2015 Chenxia Hu and Lanjuan Li. All rights reserved. Application of Adult Stem Cells in Medicine Tue, 04 Aug 2015 11:18:46 +0000 Pritha Ray, Abhijit De, Shahriar Yaghoubi, and Aparna Khanna Copyright © 2015 Pritha Ray et al. All rights reserved. Stem Cell Differentiation and Therapeutic Use Tue, 04 Aug 2015 11:12:21 +0000 Matthew S. Alexander, Juan Carlos Casar, and Norio Motohashi Copyright © 2015 Matthew S. Alexander et al. All rights reserved. Mesenchymal Stem Cells for Cardiac Regenerative Therapy: Optimization of Cell Differentiation Strategy Mon, 03 Aug 2015 12:19:45 +0000 With the high mortality rate, coronary heart disease (CHD) has currently become a major life-threatening disease. The main pathological change of myocardial infarction (MI) is the induction of myocardial necrosis in infarction area which finally causes heart failure. Conventional treatments cannot regenerate the functional cell efficiently. Recent researches suggest that mesenchymal stem cells (MSCs) are able to differentiate into multiple lineages, including cardiomyocyte-like cells in vitro and in vivo, and they have been used for the treatment of MI to repair the injured myocardium and improve cardiac function. In this review, we will focus on the recent progress on MSCs derived cardiomyocytes for cardiac regeneration after MI. Han Shen, Ying Wang, Zhiwei Zhang, Junjie Yang, Shijun Hu, and Zhenya Shen Copyright © 2015 Han Shen et al. All rights reserved. Modifications of Human Subcutaneous ADMSC after PPARγ Activation and Cold Exposition Mon, 03 Aug 2015 12:10:35 +0000 Mesenchymal stem cells are a diverse population of cells with a wide range of potential therapeutic applications. In particular, cells from adipose tissue have the distinction of being easily accessible and contain a lot of stem cells. ADMSCs can be induced to mature adipocyte and activate the energy expenditure upon treatment with total PPARγ agonists. Additionally these cells may respond to cold by activating the thermogenic program. In the present study, we determined the effect of partial agonism of PPARγ and temperature reduction on phenotype and metabolic activity of ADMSCs from human adipose subcutaneous tissue. We found that adipocytes differentiated with total and partial agonists of PPARγ and exposed to 31°C are able to respond to cold significantly increasing the expression of thermogenic proteins such as UCP1, PGC1α, and CITED1, a marker of beige phenotype. Additionally, we found that adipocyte cells subjected to cold had a reduction in triglycerides and increased adiponectin levels. These data confirm the promising role of ADMSCs as a treatment for metabolic disorders since it is possible to induce them to mature adipocytes and modulate their phenotype toward a cell with high-energy expenditure and metabolic beneficial effect. Diana Vargas, Wendy Rosales, and Fernando Lizcano Copyright © 2015 Diana Vargas et al. All rights reserved. Study of Bone Marrow Mesenchymal and Tendon-Derived Stem Cells Transplantation on the Regenerating Effect of Achilles Tendon Ruptures in Rats Mon, 03 Aug 2015 11:29:47 +0000 Comparative therapeutic significance of tendon-derived stem cells (TDSCs) and bone marrow mesenchymal stem cells (BMSCs) transplantation to treat ruptured Achilles tendon was studied. Three groups of SD rats comprising 24 rats each, designated as TDSCs and BMSCs, and nontreated were studied for regenerative effects through morpho-histological evaluations and ultimate failure load. For possible mechanism in tendon repair/regeneration through TDSCs and BMSCs, we measured Collagen-I (Col-I), Col-III gene expression level by RT-PCR, and Tenascin-C expression via immunofluorescent assay. TDSCs showed higher agility in tendon healing with better appearance density and well-organized longitudinal fibrous structure, though BMSCs also showed positive effects. Initially the ultimate failure load was considerably higher in TDSCs than other two study groups during the weeks 1 and 2, but at week 4 it attained an average or healthy tendon strength of 30.2 N. Similar higher tendency in Col-I/III gene expression level during weeks 1, 2, and 4 was observed in TDSCs treated group with an upregulation of 1.5-fold and 1.1-fold than the other two study groups. Immunofluorescent assay revealed higher expression of Tenascin-C in TDSCs at week 1, while both TDSCs and BMSCs treated groups showed detectable CM-Dil-labelled cells at week 4. Compared with BMSCs, TDSCs showed higher regenerative potential while treating ruptured Achilles tendons in rats. Mohanad Kh Al-ani, Kang Xu, Yanjun Sun, Lianhong Pan, ZhiLing Xu, and Li Yang Copyright © 2015 Mohanad Kh Al-ani et al. All rights reserved. Rat Nasal Respiratory Mucosa-Derived Ectomesenchymal Stem Cells Differentiate into Schwann-Like Cells Promoting the Differentiation of PC12 Cells and Forming Myelin In Vitro Mon, 03 Aug 2015 08:09:16 +0000 Schwann cell (SC) transplantation as a cell-based therapy can enhance peripheral and central nerve repair experimentally, but it is limited by the donor site morbidity for clinical application. We investigated weather respiratory mucosa stem cells (REMSCs), a kind of ectomesenchymal stem cells (EMSCs), isolated from rat nasal septum can differentiate into functional Schwann-like cells (SC-like cells). REMSCs proliferated quickly in vitro and expressed the neural crest markers (nestin, vimentin, SOX10, and CD44). Treated with a mixture of glial growth factors for 7 days, REMSCs differentiated into SC-like cells. The differentiated REMSCs (dREMSCs) exhibited a spindle-like morphology similar to SC cells. Immunocytochemical staining and Western blotting indicated that SC-like cells expressed the glial markers (GFAP, S100β, Galc, and P75) and CNPase. When cocultured with dREMSCs for 5 days, PC12 cells differentiated into mature neuron-like cells with long neurites. More importantly, dREMSCs could form myelin structures with the neurites of PC12 cells at 21 days in vitro. Our data indicated that REMSCs, a kind of EMSCs, could differentiate into SC-like cells and have the ability to promote the differentiation of PC12 cells and form myelin in vitro. Jian Zhang, Xin Gao, Hongjun Zou, Jinbo Liu, and Zhijian Zhang Copyright © 2015 Jian Zhang et al. All rights reserved. Acute Lymphoblastic Leukemia Cells Inhibit the Differentiation of Bone Mesenchymal Stem Cells into Osteoblasts In Vitro by Activating Notch Signaling Mon, 03 Aug 2015 08:08:14 +0000 The disruption of normal hematopoiesis has been observed in leukemia, but the mechanism is unclear. Osteoblasts originate from bone mesenchymal stem cells (BMSCs) and can maintain normal hematopoiesis. To investigate how leukemic cells inhibit the osteogenic differentiation of BMSCs and the role of Notch signaling in this process, we cocultured BMSCs with acute lymphoblastic leukemia (ALL) cells in osteogenic induction medium. The expression levels of Notch1, Hes1, and the osteogenic markers Runx2, Osteopontin (OPN), and Osteocalcin (OCN) were assessed by real-time RT-PCR and western blotting on day 3. Alkaline phosphatase (ALP) activity was analyzed using an ALP kit, and mineralization deposits were detected by Alizarin red S staining on day 14. And then we treated BMSCs with Jagged1 and anti-Jagged1 neutralizing Ab. The expression of Notch1, Hes1, and the abovementioned osteogenic differentiation markers was measured. Inhibition of the expression of Runx2, OPN, and OCN and reduction of ALP activity and mineralization deposits were observed in BMSCs cocultured with ALL cells, while Notch signal inhibiting rescued these effects. All these results indicated that ALL cells could inhibit the osteogenic differentiation of BMSCs by activating Notch signaling, resulting in a decreased number of osteoblastic cells, which may impair normal hematopoiesis. Gui-Cun Yang, You-Hua Xu, Hong-Xia Chen, and Xiao-Jing Wang Copyright © 2015 Gui-Cun Yang et al. All rights reserved. Stem Cells and Regenerative Medicine: Myth or Reality of the 21th Century Sun, 02 Aug 2015 14:22:30 +0000 Since the 1960s and the therapeutic use of hematopoietic stem cells of bone marrow origin, there has been an increasing interest in the study of undifferentiated progenitors that have the ability to proliferate and differentiate into various tissues. Stem cells (SC) with different potency can be isolated and characterised. Despite the promise of embryonic stem cells, in many cases, adult or even fetal stem cells provide a more interesting approach for clinical applications. It is undeniable that mesenchymal stem cells (MSC) from bone marrow, adipose tissue, or Wharton’s Jelly are of potential interest for clinical applications in regenerative medicine because they are easily available without ethical problems for their uses. During the last 10 years, these multipotent cells have generated considerable interest and have particularly been shown to escape to allogeneic immune response and be capable of immunomodulatory activity. These properties may be of a great interest for regenerative medicine. Different clinical applications are under study (cardiac insufficiency, atherosclerosis, stroke, bone and cartilage deterioration, diabetes, urology, liver, ophthalmology, and organ’s reconstruction). This review focuses mainly on tissue and organ regeneration using SC and in particular MSC. J.-F. Stoltz, N. de Isla, Y. P. Li, D. Bensoussan, L. Zhang, C. Huselstein, Y. Chen, V. Decot, J. Magdalou, N. Li, L. Reppel, and Y. He Copyright © 2015 J.-F. Stoltz et al. All rights reserved. Cell Therapy in Patients with Critical Limb Ischemia Sun, 02 Aug 2015 14:21:24 +0000 Critical limb ischemia (CLI) represents the most advanced stage of peripheral arterial obstructive disease (PAOD) with a severe obstruction of the arteries which markedly reduces blood flow to the extremities and has progressed to the point of severe rest pain and/or even tissue loss. Recent therapeutic strategies have focused on restoring this balance in favor of tissue survival using exogenous molecular and cellular agents to promote regeneration of the vasculature. These are based on stimulation of angiogenesis by extracellular and cellular components. This review article carries out a systematic analysis of the most recent scientific literature on the application of stem cells in patients with CLI. The results obtained from the detailed analysis of the recent literature data have confirmed the beneficial role of cell therapy in reducing the rate of major amputations in patients with CLI and improving their quality of life. Rita Compagna, Bruno Amato, Salvatore Massa, Maurizio Amato, Raffaele Grande, Lucia Butrico, Stefano de Franciscis, and Raffaele Serra Copyright © 2015 Rita Compagna et al. All rights reserved. Analysis of the Pro- and Anti-Inflammatory Cytokines Secreted by Adult Stem Cells during Differentiation Sun, 02 Aug 2015 14:20:38 +0000 Adipose-derived stromal/stem cells (ASCs) are adult stem cells that have the potential to differentiate into mesenchymal lineage cells. The abundance of ASCs in adipose tissue and easy accessibility with relatively little donor site morbidity make them attractive candidate cells for tissue engineering and regenerative medicine. However, the underlying inflammatory process that occurs during ASC differentiation into adipocytes and osteoblast has not been extensively investigated. ASCs cultured in osteogenic and adipogenic differentiation medium were characterized by oil red o staining and alizarin red staining, respectively. ASCs undergoing osteogenic and adipogenic differentiation were isolated on days 7, 14, and 21 and assessed by qRT-PCR for the expression of pro- and anti-inflammatory cytokines. ASCs undergoing osteogenic differentiation expressed a distinct panel of cytokines that differed from the cytokine profile of ASCs undergoing adipogenic differentiation at each of the time points analyzed. Mapping the cytokine expression profile during ASC differentiation will provide insight into the role of inflammation in this process and identify potential targets that may aid in enhancing osteogenic or adipogenic differentiation for the purposes of tissue engineering and regenerative medicine. Amy L. Strong, Jeffrey M. Gimble, and Bruce A. Bunnell Copyright © 2015 Amy L. Strong et al. All rights reserved. SDF-1/CXCR4 Axis Promotes MSCs to Repair Liver Injury Partially through Trans-Differentiation and Fusion with Hepatocytes Sun, 02 Aug 2015 14:10:19 +0000 MSCs have become a popular target for developing end-stage liver therapies. In this study, two models of bone marrow chimeric mice were used to construct the liver failure models. Then it was found that MSCs can transdifferentiate into hepatocyte-like cells and these hepatocyte-like cells can significantly express albumin. Furthermore it was also found that MSCs can fuse with the hepatocytes and these cells had the proliferation activity. However, the percentage of transdifferentiation was significantly higher than fusion. So it was considered that MSCs which transdifferentiated into hepatocyte-likes cells played important roles for repairing the injuring liver function. Ning-Bo Hao, Chang-Zhu Li, Mu-Han Lü, Bo Tang, Su-Min Wang, Yu-Yun Wu, Guang-Ping Liang, and Shi-Ming Yang Copyright © 2015 Ning-Bo Hao et al. All rights reserved. Adipose-Derived Mesenchymal Stem Cell Exosomes Suppress Hepatocellular Carcinoma Growth in a Rat Model: Apparent Diffusion Coefficient, Natural Killer T-Cell Responses, and Histopathological Features Sun, 02 Aug 2015 14:02:31 +0000 We sought to evaluate the effects of adipose-derived mesenchymal stem cells (ADMSCs) exosomes on hepatocellular carcinoma (HCC) in rats using apparent diffusion coefficient (ADC), natural killer T-cell (NKT-cell) responses, and histopathological features. ADMSC-derived exosomes appeared as nanoparticles (30–90 nm) on electron microscopy and were positive for CD63, tumor susceptibility gene-101, and -catenin on western blotting. The control () and exosome-treated () rats with N1S1-induced HCC underwent baseline and posttreatment day 10 and day 20 magnetic resonance imaging and measurement of ADC. Magnetic resonance imaging showed rapidly enlarged HCCs with low ADCs in the controls. The exosome-treated rats showed partial but nonsignificant tumor reduction, and significant ADC and ADC ratio increases on day 10. On day 20, the exosome-treated rats harbored significantly smaller tumors and volume ratios, higher ADC and ADC ratios, more circulating and intratumoral NKT-cells, and low-grade HCC ( for all comparisons) compared to the controls. The ADC and volume ratios exhibited significant inverse correlations (, ). ADMSC-derived exosomes promoted NKT-cell antitumor responses in rats, thereby facilitating HCC suppression, early ADC increase, and low-grade tumor differentiation. ADC may be an early biomarker of treatment response. Sheung-Fat Ko, Hon-Kan Yip, Yen-Yi Zhen, Chen-Chang Lee, Chia-Chang Lee, Chung-Cheng Huang, Shu-Hang Ng, and Jui-Wei Lin Copyright © 2015 Sheung-Fat Ko et al. All rights reserved. Priming Mesenchymal Stem Cells with Endothelial Growth Medium Boosts Stem Cell Therapy for Systemic Arterial Hypertension Sun, 02 Aug 2015 13:47:06 +0000 Systemic arterial hypertension (SAH), a clinical syndrome characterized by persistent elevation of arterial pressure, is often associated with abnormalities such as microvascular rarefaction, defective angiogenesis, and endothelial dysfunction. Mesenchymal stem cells (MSCs), which normally induce angiogenesis and improve endothelial function, are defective in SAH. The central aim of this study was to evaluate whether priming of MSCs with endothelial growth medium (EGM-2) increases their therapeutic effects in spontaneously hypertensive rats (SHRs). Adult female SHRs were administered an intraperitoneal injection of vehicle solution , MSCs cultured in conventional medium (DMEM plus 10% FBS, ), or MSCs cultured in conventional medium followed by 72 hours in EGM-2 (pMSC, ). Priming of the MSCs reduced the basal cell death rate in vitro. The administration of pMSCs significantly induced a prolonged reduction (10 days) in arterial pressure, a decrease in cardiac hypertrophy, an improvement in endothelium-dependent vasodilation response to acetylcholine, and an increase in skeletal muscle microvascular density compared to the vehicle and MSC groups. The transplanted cells were rarely found in the hearts and kidneys. Taken together, our findings indicate that priming of MSCs boosts stem cell therapy for the treatment of SAH. Lucas Felipe de Oliveira, Thalles Ramos Almeida, Marcus Paulo Ribeiro Machado, Marilia Beatriz Cuba, Angélica Cristina Alves, Marcos Vinícius da Silva, Virmondes Rodrigues Júnior, and Valdo José Dias da Silva Copyright © 2015 Lucas Felipe de Oliveira et al. All rights reserved. Hematopoietic Stem and Immune Cells in Chronic HIV Infection Sun, 02 Aug 2015 07:37:12 +0000 Hematopoietic stem cell (HSC) belongs to multipotent adult somatic stem cells. A single HSC can reconstitute the entire blood system via self-renewal, differentiation into all lineages of blood cells, and replenishment of cells lost due to attrition or disease in a person’s lifetime. Although all blood and immune cells derive from HSC, immune cells, specifically immune memory cells, have the properties of HSC on self-renewal and differentiation into lineage effector cells responding to the invading pathogens. Moreover, the interplay between immune memory cell and viral pathogen determines the course of a viral infection. Here, we state our point of view on the role of blood stem and progenitor cell in chronic HIV infection, with a focus on memory CD4 T-cell in the context of HIV/AIDS eradication and cure. Jielin Zhang and Clyde Crumpacker Copyright © 2015 Jielin Zhang and Clyde Crumpacker. 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.