Clinical Application Of Stem Cells Research Articles

Bone marrow mesenchymal stem cells and condition media diminish inflammatory adhesion molecules of pulmonary endothelial cells in an ovalbumin-induced asthmatic rat model

ObjectivesAlthough excitements related to stem cell therapeutic outcomes have been highlighted enormously in asthma, the vast majority of works were conducted by researchers in animal models. Elucidating the mechanisms underlying the therapeutic effects of MSCs in asthmatic rats will provide a rational basis for assuring maximal safety of future clinical application of stem cells. In the current study, we sought to investigate the possible paracrine mechanism by which direct injection of MSCs and/or CM attenuate efficiently Th2-mediated inflammation in asthmatic lung tissues with the focus on ICAM-1 and VCAM-1 expression. MethodsMale rats were divided into four experimental groups (n = 6); healthy rats received PBS intratracheally (group C), sensitized rats received PBS intratracheally (group S), sensitized rats received CM intratracheally (group S + CM), and sensitized rats received PBS intratracheally containing 2 × 106 rBMMSCs (group S + MSCs). Two weeks post-transplantation, the expression of interleukin (IL)-5, -12 and INF-γ, ICAM-1 and VCAM-1 were assessed along with pathological injuries and the homing of MSCs into the lung tissues. ResultsOur results showed CM, and notably rBMMSCs, returned the expression of IL-5, IL-12, INF-γ, ICAM-1, and VCAM-1 (p < 0.001 to p < 0.05) to the normal levels. Based on data, pathological injuries in pulmonary specimens of asthmatic rats were significantly attenuated (p < 0.001 to p < 0.05). Moreover, rBMMSCs had potential to successfully home to an asthmatic niche in cell-administrated rats. ConclusionsOur data noted the potency of CM and especially MSCs in ameliorating pathological changes via intra-tracheal route presumably by targeting ICAM-1 and VCAM-1 in lung tissues in rat asthma model.

Characterization and cost-benefit analysis of automated bioreactor-expanded mesenchymal stem cells for clinical applications.

Expanding quantities of mesenchymal stem cells (MSCs) sufficient to treat large numbers of patients in cellular therapy and regenerative medicine clinical trials is an ongoing challenge for cell manufacturing facilities. We evaluated options for scaling up large quantities of bone marrow-derived MSCs (BM-MSCs) using methods that can be performed in compliance with Good Manufacturing Practices (GMP). We expanded BM-MSCs from fresh marrow aspirate in αMEM supplemented with 5% human platelet lysate using both an automated cell expansion system (Quantum, Terumo BCT) and a manual flask-based method using multilayer flasks. We compared MSCs expanded using both methods and assessed their differentiation to adipogenic and osteogenic tissue, capacity to suppress T-cell proliferation, cytokines, and growth factor secretion profile and cost-effectiveness of manufacturing enough BM-MSCs to administer a single dose of 100 × 106 cells per subject in a clinical trial of 100 subjects. We have established that large quantities of clinical-grade BM-MSCs manufactured with an automated hollow-fiber bioreactor were phenotypically (CD73, CD90, CD105) and functionally (adipogenic and osteogenic differentiation and cytokine and growth factor secretion) similar to manually expanded BM-MSCs. In addition, MSC manufacturing costs significantly less and required less time and effort when using the Quantum automated cell expansion system over the manual multilayer flasks method. MSCs manufactured by an automated bioreactor are physically and functionally equivalent to the MSCs manufactured by the manual flask method and have met the standards required for clinical application.

Evolving Visions for Global Stem Cell Institutes

Evolving Visions for Global Stem Cell Institutes

Characterization of induced tissue-specific stem cells from pancreas by a synthetic self-replicative RNA

Induced pluripotent stem (iPS) cells have significant implications for overcoming most of the ethical issues associated with embryonic stem (ES) cells. Furthermore, our recent study demonstrated the generation of induced tissue-specific stem (iTS) cells by transient overexpression of the reprogramming factors using a plasmid combined with tissue-specific selection. In this study, we were able to generate RNA-based iTS cells that utilize a single, synthetic, self-replicating VEE-RF RNA replicon expressing four reprogramming factors (OCT4, KLF4, SOX2, and GLIS1). A single VEE-RF RNA transfection into mouse pancreatic tissue resulted in efficient generation of iTS cells from pancreas (iTS-P cells) with genetic markers of endoderm and pancreatic progenitors and differentiation into insulin-producing cells more efficiently than ES cells. Subcutaneous transplantation of iTS-P cells into immunodeficient mice resulted in no teratoma formation. Bisulfite genomic sequencing demonstrated that the promoters of Oct4 and Nanog remained partially methylated in iTS-P cells. We compared the global gene-expression profiles of ES cells, iTS-P cells, and pancreatic islets. Microarray analyses confirmed that the iTS-P cells were similar but not identical to ES cells compared with islets. These data suggest that iTS-P cells are cells that inherit numerous components of epigenetic memory from pancreas cells and acquire self-renewal potential. The generation of iTS cells may have important implications for the clinical application of stem cells.

Advances in the research of effects of exosomes on acute lung injury

Acute lung injury (ALI) is a clinically common critical disease with various treatment methods. Stem cell has drawn great attention for excellent performance in treatment of ALI. However, due to its high apoptosis rate, the further clinical application of stem cell is restricted. Exosomes are a kind of extracellular vesicles secreted by cells, which play important role in injury repair with further research about exosomes. This article reviews current situation, brief introduction to exosomes, repair effects of exosomes on ALI, and the potential signal pathway.

Recent Advances in Tracking the Transplanted Stem Cells Using Near-Infrared Fluorescent Nanoprobes: Turning from the First to the Second Near-Infrared Window.

Stem cell-based regenerative medicine has attracted tremendous attention for its great potential to treat numerous incurable diseases. Tracking and understanding the fate and regenerative capabilities of transplanted stem cells is vital for improving the safety and therapeutic efficacy of stem cell-based therapy, therefore accelerating the clinical application of stem cells. Fluorescent nanoparticles (NPs) have been widely used for in vivo tracking of the transplanted stem cells. Among these fluorescent NPs, near-infrared (NIR) NPs have greatly improved the sensitivity, tissue penetration depth, spatial and temporal resolutions of the fluorescence imaging-based stem cell tracking technologies due to the reduced absorption, scattering, and autofluorescence of NIR fluorescence in tissues. Here, this review summarizes the recent studies regarding the tracking of transplanted stem cells using NIR NPs and emphasizes the recent advances of fluorescence imaging in the second NIR window (NIR-II, 1000-1700 nm). Furthermore, the challenges and future prospects of the NIR NP-based technologies are also discussed.

Basic and clinical study of stem cell treatment for diabetes mellitus in China

Pancreatic islet beta cell dysfunction and insulin resistance are the main mechanisms underlying the development of diabetes mellitus. The current anti-diabetic treatments only alleviate symptoms and may delay the progression of the disease, but cannot cure the disease. Stem cells improve the function of islet beta cells by promoting in situ regeneration and repair mechanisms that improve autophagy of islet beta cells and modulate macrophage function. They also ameliorate the insulin resistance in peripheral tissues by activating the IRS-1-AKT-GLUT4 signaling pathway in skeletal muscle, fat, and liver. Stem cell therapy has provided a new direction for the precise treatment of diabetes. Researchers in China have carried out a series of experiments on different sources of stem cell therapy for diabetes mellitus using different infusion methods, and they have achieved good clinical effects without serious adverse reactions. These results have provided a basis for the clinical application of stem cells in the treatment of diabetes mellitus.

Stem Cells in Dentistry: Types of Intra- and Extraoral Tissue-Derived Stem Cells and Clinical Applications.

Stem cells are undifferentiated cells, capable of renewing themselves, with the capacity to produce different cell types to regenerate missing tissues and treat diseases. Oral facial tissues have been identified as a source and therapeutic target for stem cells with clinical interest in dentistry. This narrative review report targets on the several extraoral- and intraoral-derived stem cells that can be applied in dentistry. In addition, stem cell origins are suggested in what concerns their ability to differentiate as well as their particular distinguishing quality of convenience and immunomodulatory for regenerative dentistry. The development of bioengineered teeth to replace the patient's missing teeth was also possible because of stem cell technologies. This review will also focus our attention on the clinical application of stem cells in dentistry. In recent years, a variety of articles reported the advantages of stem cell-based procedures in regenerative treatments. The regeneration of lost oral tissue is the target of stem cell research. Owing to the fact that bone imperfections that ensue after tooth loss can result in further bone loss which limit the success of dental implants and prosthodontic therapies, the rehabilitation of alveolar ridge height is prosthodontists' principal interest. The development of bioengineered teeth to replace the patient's missing teeth was also possible because of stem cell technologies. In addition, a “dental stem cell banking” is available for regenerative treatments in the future. The main features of stem cells in the future of dentistry should be understood by clinicians.

An Intelligent Neural Stem Cell Delivery System for Neurodegenerative Diseases Treatment.

Transplanted stem cells constitute a new therapeutic strategy for the treatment of neurological disorders. Emerging evidence indicates that a negative microenvironment, particularly one characterized by the acute inflammation/immune response caused by physical injuries or transplanted stem cells, severely impacts the survival of transplanted stem cells. In this study, to avoid the influence of the increased inflammation following physical injuries, an intelligent, double-layer, alginate hydrogel system is designed. This system fosters the matrix metalloproeinases (MMP) secreted by transplanted stem cell reactions with MMP peptide grafted on the inner layer and destroys the structure of the inner hydrogel layer during the inflammatory storm. Meanwhile, the optimum concentration of the arginine-glycine-aspartate (RGD) peptide is also immobilized to the inner hydrogels to obtain more stem cells before arriving to the outer hydrogel layer. It is found that blocking Cripto-1, which promotes embryonic stem cell differentiation to dopamine neurons, also accelerates this process in neural stem cells. More interesting is the fact that neural stem cell differentiation can be conducted in astrocyte-differentiation medium without other treatments. In addition, the system can be adjusted according to the different parameters of transplanted stem cells and can expand on the clinical application of stem cells in the treatment of this neurological disorder.

Application of Stem Cells to Infertility Treatment with Emphasis on Mesenchymal Stem Cells and Ovarian Stem Cells.

Stem cells are a population of undifferentiated cells that originated from embryonic and fetal stages of development. Stem cells possess the potency to produce cells that ultimately form different tissues and organs. They are considered as potential alternative novel therapeutic agents for patients suffering from infertility due to their unlimited source and high differentiation potency. There are several studies that have shown that different types of stem cells (mesenchymal stem cells, embryonic, endometrial, and ovarian stem cells) can be differentiated into both spermatozoa and oocytes in vitro, proving their potential clinical use in management and cure of infertility issues. Furthermore, mouse model studies have shown that ovarian stem cells, when cultured in vitro, can differentiate into a mature oocyte; however, there are still a lot of debates and complications attached to this concept. In addition, this is yet to be established using human ovarian stem cells, but, if established, would be a novel fertility preservation and treatment technique for women with infertility-related complications. This review gives comprehensive details of the available clinical application of stem cells in infertility treatment.

Exosome-Mediated Ultra-Effective Direct Conversion of Human Fibroblasts into Neural Progenitor-like Cells

Exosomes, naturally secreted nanoparticles, have been introduced as vehicles for horizontal transfer of genetic material. We induced autologous exosomes containing a cocktail of reprogramming factors ("reprosomes") to convert fibroblasts into neural progenitor cells (NPCs). The fibroblasts were treated with ultrasound and subsequently cultured in neural stem cell medium for 1 day to induce the release of reprosomes composed of reprogramming factors associated with chromatin remodeling and neural lineage-specific factors. After being treated with reprosomes, fibroblasts were converted into NPCs (rNPCs) with great efficiency via activation of chromatin remodeling, so quickly that only 5 days were required for the formation of 1500 spheroids showing an NPC-like phenotype. The rNPCs maintained self-renewal and proliferative properties for several weeks and successfully differentiated into neurons, astrocytes, and oligodendrocytes in vitro and in vivo. Reprosome-mediated cellular reprogramming is simple, safe, and efficient to produce autologous stem cells for clinical application.

Ethical and Safety Issues of Stem Cell-Based Therapy.

Results obtained from completed and on-going clinical studies indicate huge therapeutic potential of stem cell-based therapy in the treatment of degenerative, autoimmune and genetic disorders. However, clinical application of stem cells raises numerous ethical and safety concerns.In this review, we provide an overview of the most important ethical issues in stem cell therapy, as a contribution to the controversial debate about their clinical usage in regenerative and transplantation medicine.We describe ethical challenges regarding human embryonic stem cell (hESC) research, emphasizing that ethical dilemma involving the destruction of a human embryo is a major factor that may have limited the development of hESC-based clinical therapies. With previous derivation of induced pluripotent stem cells (iPSCs) this problem has been overcome, however current perspectives regarding clinical translation of iPSCs still remain. Unlimited differentiation potential of iPSCs which can be used in human reproductive cloning, as a risk for generation of genetically engineered human embryos and human-animal chimeras, is major ethical issue, while undesired differentiation and malignant transformation are major safety issues.Although clinical application of mesenchymal stem cells (MSCs) has shown beneficial effects in the therapy of autoimmune and chronic inflammatory diseases, the ability to promote tumor growth and metastasis and overestimated therapeutic potential of MSCs still provide concerns for the field of regenerative medicine.This review offers stem cell scientists, clinicians and patient's useful information and could be used as a starting point for more in-depth analysis of ethical and safety issues related to clinical application of stem cells.

The Development of Cancer through the Transient Overexpression of Reprogramming Factors.

Although induced pluripotent stem (iPS) cells have significant implications for overcoming most of the ethical issues associated with embryonic stem cells, several issues related to the use of iPS cells in clinical applications remain unresolved, including the issue of teratoma formation. We previously reported that the induction of induced tissue-specific stem (iTS) cells from the pancreas (iTS-P) or liver (iTS-L) by the transient overexpression of reprogramming factors, combined with tissue-specific selection and the generation of iTS cells, could have important implications for the clinical application of stem cells. At the same time, we also generated “induced fibroblast-like (iF) cells” that were capable of self-renewal, which had a similar morphology to fibroblast cells. In this study, we evaluated iF cells. iF cells are unlikely to show adipogenic/osteogenic differentiation. Moreover, iF cells have the ability to form tumors and behave similarly to pancreatic cancer cells. The technology used in the generation of iPS/iTS cells is also associated with the risk of generating cancer-like cells.

The Significance of Single-Cell Biomedicine in Stem Cells.

Clinical application of stem cells (SCs) progresses significantly in the treatment of a large number of diseases, e.g. leukemia, respiratory diseases, kidney disease, cerebral palsy, autism, or autoimmune diseases. Of those, the population, biological phenotypes, and functions of individual SCs are mainly concerned, due to the lack of cell separation and purification processes. The single-cell technology, including microfluidic technology and single-cell genome amplification technology, is widely used to study SCs and gains some recognitions. The present review will address the importance of single-cell technologies in the recognition and heterogeneity of SCs and highlight the significance of current single-cell approaches in the understanding of SC phenotypes. We also discuss the values of single-cell studies to overcome the bottleneck in explore of biological mechanisms and reveal the therapeutic potentials of SCs in diseases, especially tumor-related diseases, as new diagnostic and therapeutic strategies.

Stem Cell Applications for Treatment of Cancer and Autoimmune Diseases: Its Promises, Obstacles, and Future Perspectives.

Since the original discovery of stem cells, a new era of promising results has emerged in the clinical application of stem cells for the treatment of several important diseases, including cancer and autoimmune diseases. The plentiful research on stem cells during the past decades has provided significant information on the developmental, morphological, and physiological processes that govern tissue and organ formation, maintenance, and regeneration; cellular differentiation; molecular processes; and tissue homeostasis. In this review, we present the history of the use of stem cells in different clinical applications. Furthermore, we discuss the various therapeutic options for stem cells in cancer, followed by the role of stem cells in the treatment of autoimmune disorders. Additionally, we highlight the risks of and obstacles to the application of stem cells in clinical practice. Ultimately, we show future perspectives in stem cell use, with an aim to improve the clinical usefulness of stem cells.

Modification of mesenchymal stem cells for clinical application

Modification of mesenchymal stem cells for clinical application

Concise review: Umbilical cord derived mesenchymal stem cell bank

Mesenchymal stem cells (MSCs) are the most promising stem cells for clinical applications. MSCs are widely used in disease treatment in some different countries. Recently, some MSC banks are developed to cryopreserve MSCs from umbilical cord tissues, adipose tissues and bone marrow. This review aims to discuss some techniques, some advantages as well as disadvantages of umbilical cord derived mesenchymal stem cell banking (UCMSCB). From 2010 to date, there are more than 10 UCMSCBs established in the world. There are two methods to isolate UCMSCs including tissue culture and single cell culture. Then they are cryopreserved in the liquid nitrogen for long time. Although, UCMSCBs can provide more the choice to store the MSCs from umbilical cord, allogenic MSC transplantation with high efficacy in disease treatment suggests that UCMSCBs should change the with new approaches to use the cryopreserved samples.

Stem-Cell Therapy Advances in China.

Stem-cell therapy is a promising method for treating patients with a wide range of diseases and injuries. Increasing government funding of scientific research has promoted rapid developments in stem-cell research in China, as evidenced by the substantial increase in the number and quality of publications in the past 5 years. Multiple high-quality studies have been performed in China that concern cell reprogramming, stem-cell homeostasis, gene modifications, and immunomodulation. The number of translation studies, including basic and preclinical investigations, has also increased. Around 100 stem-cell banks have been established in China, 10 stem-cell drugs are currently in the approval process, and >400 stem cell-based clinical trials are currently registered in China. With continued state funding, advanced biotechnical support, and the development of regulatory standards for the clinical application of stem cells, further innovations are expected that will lead to a boom in stem-cell therapies. This review highlights recent achievements in stem-cell research in China and discusses future prospects.

Coordinated microRNA/mRNA expression profiles reveal a putative mechanism of corneal epithelial cell transdifferentiation from skin epidermal stem cells.

Skin epidermal stem cells (SESCs), which share a single origin with corneal epithelial cells (CECs), are considered to be one of the most ideal seed cells for the construction of tissue engineered corneas. However, the mechanism underlying the transdifferentiation of SESCs to CECs has not been fully elucidated. In the present study, to identify critical microRNAs (miRNAs/miRs) and genes that regulate the transdifferentiation of SESCs to CECs, SESCs and CECs were collected from sheep and used for small RNA sequencing and mRNA microarray analyses. Among the differentially expressed miRNAs and genes, 36 miRNAs were downregulated and 123 genes were upregulated in the CECs compared with those in the SESCs. miR-10b exhibited the largest change in expression between the cell types. Target genes of the 36 downregulated miRNAs were predicted and a computational approach demonstrated that these target genes may be involved in several signaling pathways, including the 'PI3K signaling pathway', the 'Wnt signaling pathway' and the 'MAPK signaling pathway', as well as in 'focal adhesion'. Comparison of these target genes to the 123 upregulated genes identified 43 intersection genes. A regulatory network of these 43 intersection genes and its correlative miRNAs were constructed, and three genes (dedicator of cytokinesis 9, neuronal differentiation 1 and activated leukocyte cell adhesion molecule) were found to have high interaction frequencies. The expression levels of 7 randomly selected miRNAs and the 3 intersection genes were further validated by reverse transcription-quantitative polymerase chain reaction. It was found that miR-10b, the Wnt signaling pathway and the 3 intersection genes may act together and serve a critical role in the transdifferentiation process. This study identified miRNAs and genes that were expressed in SESCs and CECs that may assist in uncovering its underlying molecular mechanism, as well as promote corneal tissue engineering using epidermal stem cells for clinical applications.

Neuroprotective Potential and Paracrine Activity of Stromal Vs. Culture-Expanded hMSC Derived from Wharton Jelly under Co-Cultured with Hippocampal Organotypic Slices

Regardless of enormous translational progress in stem cell clinical application, our knowledge about biological determinants of transplantation-related protection is still limited. In addition to adequate selection of the cell source well dedicated to a specific disease and optimal standardization of all other pre-transplant procedures, we have decided to focus more attention to the impact of culture time and environment itself on molecular properties and regenerative capacity of cell cultured in vitro. The aim of this investigation was to determine neuroprotection-linked cell phenotypic and functional changes that could spontaneously take place when freshly isolated Wharton’s jelly mesenchymal stem cell (WJ-MSC) undergo standard selection, growth, and spontaneous differentiation throughout passaging in vitro. For determining their neuroprotective potential, we used experimental model of human WJ-MSC co-culture with intact or oxygen-glucose-deprived (OGD) rat organotypic hippocampal culture (OHC). It has been shown that putative molecular mechanisms mediating regenerative interactions between WJ-MSC and OHC slices relies mainly on mesenchymal cell paracrine activity. Interestingly, it has been also found that the strongest protective effect is exerted by the co-culture with freshly isolated umbilical cord tissue fragments and by the first cohort of human mesenchymal stem cells (hMSCs) migrating out of these fragments (passage 0). Culturing of WJ-derived hMSC in well-controlled standard conditions under air atmosphere up to fourth passage caused unexpected decline of neuroprotective cell effectiveness toward OGD-OHC in the co-culture model. This further correlated with substantial changes in the WJ-MSC phenotype, profile of their paracrine activities as well as with the recipient tissue reaction evaluated by changes in the rat-specific neuroprotection-linked gene expression.