Production Of Mesenchymal Stem Cells Research Articles

Atorvastatin: an efficient step forward in mesenchymal stem cell therapy of diabetic retinopathy

Diabetic retinopathy (DR), a leading cause of vision loss and a significant source of morbidity, is the most common ocular complication of prolonged diabetes mellitus. Most therapeutic approaches address DR by preventing or destroying neovasculature; however, this fails to eliminate pathogenic causes. Mesenchymal stem cells (MSCs) are a promising candidate for cell therapy because they have unique regenerative potential and provide an option to manage retinal injuries. Transplantation of MSCs in rats with diabetes induced by streptozocin administration was shown to ameliorate DR. However, the poor viability and homing of MSCs after transplantation may reduce the efficacy of cell therapy. Intravitreal transplantation of MSCs was shown to augment vascular endothelial growth factor (VEGF). More recent studies have found a central role for VEGF in vascular lesion formation in DR and proposed blockage of VEGF as an effective approach to manage DR. Atorvastatin, a 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor, has been proven to decrease VEGF production of MSCs under hypoxic conditions. It has also been demonstrated that atorvastatin increases the viability of MSCs through the adenosine monophosphate-activated protein kinase-endothelial nitric oxide synthase signaling pathway. There is also evidence that nitric oxide improves homing of MSCs by increasing chemokine-related receptor CXCR4 expression. It could be hypothesized that co-administration of MSCs with atorvastatin may be a significant step forward in development of an efficient MSC therapy of DR through preventing excess VEGF production by MSCs under hypoxic conditions as well as increasing the viability and homing of transplanted MSCs.

Optimization of culture of mesenchymal stem cells: a comparison of conventional plate and microcarrier cultures

There has been increasing interest in mesenchymal stem cells (MSCs) because of their potential use for regenerative therapy; however, there is no well-defined protocol for MSCs culture. This study compares techniques of conventional plate and microcarrier culturing of MSCs. Here, different conditions for isolation and expansion of rat MSCs have been examined and it was found that plating density and plating time in primary culture played important roles for culture of these rat MSCs. When plated at 10(8) /cm(2) density for 72 h, in primary culture, recycling stem cells (RS cells) predominated, and characteristics of rat MSCs (including morphology, growth rate, phenotype and differentiation potentials) remained stable during expansion until passage 14. For subculture of the cells, it was found that their growth rate when incubated at 33 °C was higher than those incubated at 37 °C, and maximal increase was 10- and 6-fold respectively. When cultured using microcarriers, at a density of 1 × 10(5) /mg beads, growth kinetics, phenotype and differentiation potentials also remained constant for cells between passage 2nd and 14th; their maximal number increased 16-fold. Compared to conventional plate culture, culture using gelatine porous microcarrier Cultispher-S was superior for large-scale production of rat MSCs.

Changes in Expression of the Antioxidant Enzyme SOD3 Occur Upon Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells In Vitro

The discovery that mesenchymal stem cells (MSCs) secrete SOD3 may help explain studies in which MSCs have direct antioxidant activities both in vivo and in vitro. SOD3 is an antioxidant enzyme that dismutes toxic free radicals produced during inflammatory processes. Therefore, MSC production and secretion of active and therapeutically significant levels of SOD3 would further support the use of MSCs as a cellular based antioxidant therapy. The aim of this study was therefore to investigate in vitro if MSC differentiation down the adipogenic, chondrogenic, and osteogenic lineages influences the expression of the antioxidant molecule SOD3. Human bone marrow MSCs and their differentiated progeny were cultured under standard conditions and both the SOD3 gene and protein expression examined. Following adipogenesis, cultures demonstrated that both SOD3 protein and gene expression are significantly increased, and conversely, following chondrogenesis SOD3 protein and gene expression is significantly decreased. Following osteogenesis there were no significant changes in SOD3 protein or gene expression. This in vitro study describes the initial characterization of SOD3 expression and secretion by differentiated MSCs. This should help guide further in vivo work establishing the therapeutic and antioxidative potential of MSC and their differentiated progeny.

Isolation and characterization of mesenchymal stem cells from whole human umbilical cord applying a single enzyme approach

Mesenchymal stem cells (MSCs) are multipotent cells traditionally derived from bone marrow (BM). They have been demonstrated to be widely applied in tissue regeneration and cellular therapy. As an alternative to BM, an umbilical cord (UC) is considered as a potential source of MSCs. Here, we showed that human UC-MSCs were easily isolated by a single enzymatic digestion and characteristic of plastic adherence and fibroblast-like morphology. UC-MSCs isolation was successful in 15 of 15 samples. The colony-forming unit-fibroblast frequency was obtained 54 ± 1.33 from 10³ UC-MSCs at passage 3, and the doubling time was (24.15 ± 0.49) h. Almost 10¹⁰ UC-MSCs were largely produced in about 30 days. By flow cytometry analysis, the adherent cells displayed an abundant presence of CD73, CD90 and CD105 and absence of CD34, CD45 and HLA-DR. When cultured in differentiation media, they can be differentiated into adipocytes, osteocytes and chondrocytes. RT-PCR reactions confirmed that their multidifferentiation related genes were positive. Moreover, stem cell-related transcription factors Nanog, Oct-4 and Sox-2 were positively expressed in UC-MSCs. On the basis of these findings, the single enzyme method is a good method to obtain large-scale production of MSCs from whole human UC in a short time, and the UC can be considered as a novel and convenient source of adult MSCs displaying high expansion potential and primitive pluripotent stem cells.

Injectable Hydrogel for Mesenchymal Stem Cell and Protein Delivery to the Degenerate Intervertebral Disk

IntroductionInstability of the motion segment as a result of intervertebral disk degeneration is well known as a major cause of lower back pain. In recent years, a number of tissue engineering and stem cell approaches have been investigated in an attempt to regenerate the degenerate IVD. However, many of the proposed therapies would entail lengthy/risky operations to “implant” the tissue regeneration scaffold. Our vision is to develop a novel, injectable biomaterial delivery system which will deliver mesenchymal stem cells (MSCs) to the degenerate nucleus pulposus (NP) to stimulate regeneration, it will also deliver inhibitors of degeneration, while providing mechanical support to the motion segment during this process. Here, we investigate a novel hydrogel system, which can be maintained as a liquid ex vivo and can potentially be injected into the IVD where it will gel in situ. Materials and MethodsHuman MSCs were labelled with a green fluorescent membrane dye to enable visualization before culture within or on hydrogel systems. Effects on cell viability, migration characteristics, matrix production, and differentiation capacity of MSCs were investigated. Additionally, the feasibility of injection through narrow bore needles, into a model degenerate IVDs using collagenase digested bovine caudal disks, was investigated. In addition, effects of the degenerate tissue niche were investigated on MSC behavior to determine whether inhibitors of degeneration would need to be codelivered. MSC were treated with IL-1beta and induction of matrix degrading enzymes and expression of IL-1 family genes investigated. ResultsViability of MSCs were unaffected by coculture with hydrogel systems, or following growth on or in such systems over time periods of up to 6 weeks. MSCs adhered to the hydrogel systems and were shown to migrate through the system when applied to the upper surface of a preset hydrogel system. Additionally, MSCs mixed with liquid hydrogel before setting and maintained at 37°C for up to 4 weeks, survived, proliferated, synthesized collagen type II and aggrecan matrix (Fig. 1) similar to that seen within the NP including aggrecan, gene expression analysis demonstrated expression of key genes. Liquid hydrogel was successfully injected into degenerated bovine disks where it fill both the large voids and the smaller branches induced by collagenase digestion. MSC treated with IL-1 induced expression of IL-1, IL-1Ra, MMP3 and MMP13 were also upregulated. IL-Ra was successfully incorporated into the hydrogel system. ConclusionWe have developed a hydrogel system with the potential to deliver MSCs via minimally invasive injection via narrow bore needles, decreasing the risk of damage to the annulus fibrosus. The system is nontoxic, supports MSC growth, differentiation and shows potential to provide mechanical support to the motion segment while regeneration takes place. Such a therapy combined with inhibition of degeneration shows immense potential for early and midstages of spinal degeneration.I confirm having declared any potential conflict of interest for all authors listed on this abstractYesDisclosure of InterestNone declared

Injectable Hydrogel for Mesenchymal Stem Cell and Protein Delivery to the Degenerate Intervertebral Disk

Introduction Instability of the motion segment as a result of intervertebral disk degeneration is well known as a major cause of lower back pain. In recent years, a number of tissue engineering and stem cell approaches have been investigated in an attempt to regenerate the degenerate IVD. However, many of the proposed therapies would entail lengthy/risky operations to “implant” the tissue regeneration scaffold. Our vision is to develop a novel, injectable biomaterial delivery system which will deliver mesenchymal stem cells (MSCs) to the degenerate nucleus pulposus (NP) to stimulate regeneration, it will also deliver inhibitors of degeneration, while providing mechanical support to the motion segment during this process. Here, we investigate a novel hydrogel system, which can be maintained as a liquid ex vivo and can potentially be injected into the IVD where it will gel in situ. Materials and Methods Human MSCs were labelled with a green fluorescent membrane dye to enable visualization before culture within or on hydrogel systems. Effects on cell viability, migration characteristics, matrix production, and differentiation capacity of MSCs were investigated. Additionally, the feasibility of injection through narrow bore needles, into a model degenerate IVDs using collagenase digested bovine caudal disks, was investigated. In addition, effects of the degenerate tissue niche were investigated on MSC behavior to determine whether inhibitors of degeneration would need to be codelivered. MSC were treated with IL-1beta and induction of matrix degrading enzymes and expression of IL-1 family genes investigated. Results Viability of MSCs were unaffected by coculture with hydrogel systems, or following growth on or in such systems over time periods of up to 6 weeks. MSCs adhered to the hydrogel systems and were shown to migrate through the system when applied to the upper surface of a preset hydrogel system. Additionally, MSCs mixed with liquid hydrogel before setting and maintained at 37°C for up to 4 weeks, survived, proliferated, synthesized collagen type II and aggrecan matrix (Fig. 1) similar to that seen within the NP including aggrecan, gene expression analysis demonstrated expression of key genes. Liquid hydrogel was successfully injected into degenerated bovine disks where it fill both the large voids and the smaller branches induced by collagenase digestion. MSC treated with IL-1 induced expression of IL-1, IL-1Ra, MMP3 and MMP13 were also upregulated. IL-Ra was successfully incorporated into the hydrogel system. Conclusion We have developed a hydrogel system with the potential to deliver MSCs via minimally invasive injection via narrow bore needles, decreasing the risk of damage to the annulus fibrosus. The system is nontoxic, supports MSC growth, differentiation and shows potential to provide mechanical support to the motion segment while regeneration takes place. Such a therapy combined with inhibition of degeneration shows immense potential for early and midstages of spinal degeneration. I confirm having declared any potential conflict of interest for all authors listed on this abstract Yes Disclosure of Interest None declared

Clinical Applications and Biosafety of Human Adult Mesenchymal Stem Cells

Mesenchymal Stem Cells (MSCs) are a population of adherent cells that can differentiate into mesenchymal lineage populations (cartilage, bone and fat tissue). In addition, they seem to be able to differentiate also into a broader type of lineages other than the original mesodermal germ layer. Bone marrow MSCs are a standard in the field of adult stem cell biology and clinical applications; however adipose-derived MSCs are becoming an attractive alternative due to their minimally invasive accessibility and availability in the body. MSCs modulate several effector immune functions by interacting both with innate and adoptive immune responses. Several local signals from the tissue microenvironment, together with cytokine and soluble factors released by MSCs influence anti-inflammatory and tissue repair properties of infused MSCs. Therefore, cellular therapies utilizing ex vivo expanded MSCs may be an interesting approach for inflammatory and autoimmune diseases. Biosafety is still one of the most important aspects; therefore the production of clinical-grade MSCs requires the careful identification and control of all the phases of cell manipulation and release. Many clinical applications of adult MSCs are in progress and are using bone marrow or adipose tissue-derived MSCs for the treatment of Graft Versus Host Disease (GVHD), inflammatory joint diseases and osteocartilagineous defects, digestive tract, cardiovascular and neurological diseases.

Basic fibroblast growth factor modulates cell cycle of human umbilical cord‐derived mesenchymal stem cells

Mesenchymal stem cells (MSC) have great potential in regenerative medicine, immunotherapy and gene therapy due to their unique properties of self-renewal, high plasticity, immune modulation and ease for genetic modification. However, production of MSC at sufficient clinical scale remains an issue as in vitro generation of MSC inadequately fulfils the demand with respect to patients. This study has aimed to establish optimum conditions to generate and characterize MSC from human umbilical cord (UC-MSC). To optimize MSC population growth, basic fibroblast growth factor (bFGF) was utilized in culture media. Effects of bFGF on expansion kinetics, cell cycle, survival of UC-MSC, cytokine secretion, expression of early stem-cell markers and immunomodulation were investigated. bFGF supplementation profoundly enhanced UC-MSC proliferation by reducing population doubling time without altering immunophenotype and immunomodulatory function of UC-MSC. However, cell cycle studies revealed that bFGF drove the cells into the cell cycle, as a higher proportion of cells resided in S phase and progressed into M phase. Consistent with this, bFGF was shown to promote expression of cyclin D proteins and their relevant kinases to drive UC-MSC to transverse cell cycle check points, thus, committing the cells to DNA synthesis. Furthermore, supplementation with bFGF changed the cytokine profiles of the cells and reduced their apoptotic level. Our study showed that bFGF supplementation of UC-MSC culture enhanced the cells' growth kinetics without compromising their nature.

The effects of β-tricalcium phosphate 3D scaffold in-situ cryopreservation on the migration rate and osteogenic ability of mesenchymal stem cells

To readily supply seed cells for tissue engineering and ensure their constant availability for experiments, it is imperative to establish an in-situ cryopreservation method for cell storage. We investigated the effects of a β-tricalcium phosphate (β-TCP) 3D scaffold in-situ cryopreservation method on the migration rate and osteogenic ability of mesenchymal stem cells (MSCs). Compared to using a 2D plate culture and trypsinized cryopreservation, MSCs on β-TCP 3D scaffolds demonstrated a higher amplification rate, and the harvest and survival rates (HSR) increased from 55.9 to 81.3% when the 3D in-situ cryopreservation method was applied. The cell migration rate and alkaline phosphatase (ALP) activity were unaffected after in-situ cryopreservation, and unexpectedly, the Specific ALP activity of migrating cells was higher than that of non-cryopreserved cells, suggesting that the cell-scaffold combination could be cryopreserved using the present protocol without loss of proliferative or osteogenic potential. These findings highlight a methodology for 3D scaffold in-situ cryopreservation and passage for MSC production in bone tissue engineering, and present the possibility of designing a perfusion cells/scaffold factory for scale-up production.

Cell therapy medicinal product regulatory framework in Europe and its application for MSC-based therapy development

Advanced therapy medicinal products (ATMPs), including cell therapy products, form a new class of medicines in the European Union. Since the ATMPs are at the forefront of scientific innovation in medicine, specific regulatory framework has been developed for these medicines and implemented from 2009. The Committee for Advanced Therapies (CAT) has been established at the European Medicines Agency (EMA) for centralized classification, certification and evaluation procedures, and other ATMP-related tasks. Guidance documents, initiatives, and interaction platforms are available to make the new framework more accessible for small- and medium-sized enterprises, academia, hospitals, and foundations. Good understanding of the centralized and national components of the regulatory system is required to plan product development. It is in the best interests of the cell therapy developers to utilize the resources provided starting with the pre-clinical stage. Whilst there have been no mesenchymal stem cell (MSC)-based medicine authorizations in the EU, three MSC products have received marketing approval in other regions since 2011. The information provided on the regulatory requirements, procedures, and initiatives is aimed at facilitating MSC-based medicinal product development and authorization in the EU.

Mesenchymal Stem Cells Differentiation on Hierarchically Micro/Nano‐Structured Titanium Substrates

AbstractSurface topography of a biomaterial plays an essential role in the regulation of cell adhesion, proliferation, and differentiation. To investigate the influence of hierarchically micro/nano‐structured substrates on the differentiation of mesenchymal stem cells (MSCs), a series of micro‐, nano‐, and micro/nano‐structured titanium substrates were fabricated via dual acid etching and/or anodic oxidation. The morphologies of titanium substrates were characterized by field emission scanning electron microscopy (FE‐SEM) and contact angle measurement, respectively. The differentiation of MSCs adhered to different substrates was investigated in vitro. Compared to native titanium, micro/nano‐structured titanium substrates improved the alkaline phosphatase (ALP) production and mineralization of MSCs. More importantly, micro/nano‐structured titanium substrates demonstrated great potential to induce the differentiation of MSCs, which was revealed by the expressions of osteocalcin (OCN) and osteopontin (OPN). The study provides a potential alternative to generate hierarchically micro/nano‐structured titanium‐based implant for enhanced osseointegration.

Optimisation of culture and cardiogenic differentiation of rats mesenchymal stem cells

There has been an increasing interest in mesenchymal stem cells (MSCs) because of their potential use for regenerative therapy, especially for cardiovascular disease, however there is still no well-defined protocol...

Optimisation of culture and cardiogenic differentiation of rat mesenchymal stem cells

There has been an increasing interest in mesenchymal stem cells (MSCs) because of their potential use for regenerative therapy, especially for cardiovascular disease, however there is still no well-defined protocol...

The metabolism of human mesenchymal stem cells during proliferation and differentiation

Human mesenchymal stem cells (MSCs) reside under hypoxic conditions in vivo, between 4% and 7% oxygen. Differentiation of MSCs under hypoxic conditions results in inhibited osteogenesis, while chondrogenesis is unaffected. The reasons for these results may be associated with the inherent metabolism of the cells. The present investigation measured the oxygen consumption, glucose consumption and lactate production of MSCs during proliferation and subsequent differentiation towards the osteogenic and chondrogenic lineages. MSCs expanded under normoxia had an oxygen consumption rate of ∼98 fmol/cell/h, 75% of which was azide-sensitive, suggesting that these cells derive a significant proportion of ATP from oxidative phosphorylation in addition to glycolysis. By contrast, MSCs differentiated towards the chondrogenic lineage using pellet culture had significantly reduced oxygen consumption after 24 h in culture, falling to ∼12 fmol/cell/h after 21 days, indicating a shift towards a predominantly glycolytic metabolism. By comparison, MSCs retained an oxygen consumption rate of ∼98 fmol/cell/h over 21 days of osteogenic culture conditions, indicating that these cells had a more oxidative energy metabolism than the chondrogenic cultures. In conclusion, osteogenic and chondrogenic MSC cultures appear to adopt the balance of oxidative phosphorylation and glycolysis reported for the respective mature cell phenotypes. The addition of TGF-β to chondrogenic pellet cultures significantly enhanced glycosaminoglycan accumulation, but caused no significant effect on cellular oxygen consumption. Thus, the differences between the energy metabolism of chondrogenic and osteogenic cultures may be associated with the culture conditions and not necessarily their respective differentiation.

Prediction of in vivo bone forming potency of bone marrow-derived human mesenchymal stem cells

Human mesenchymal stem cells (MSC) have attracted much attention for tissue regeneration including repair of non-healing bone defects. Heterogeneity of MSC cultures and considerable donor variability however, still preclude standardised production of MSC and point on functional deficits for some human MSC populations. We aimed to identify functional correlates of donor-dependency of bone formation in order to develop a potency assay predicting the therapeutic capacity of human MSC before clinical transplantation. MSC from 29 donors were characterised in vitro and results were correlated to bone formation potency in a beta-tricalcium-phosphate (β-TCP)-scaffold after subcutaneous implantation into immunocompromised mice. In contrast to osteogenic in vitro differentiation parameters, a doubling time below 43.23 hours allowed to predict ectopic bone formation at high sensitivity (81.8%) and specificity (100%). Enriched conditions adapted from embryonic stem cell expansion rescued bone formation of inferior MSC populations while growth arrest of potent MSC by mitomycin C abolished bone formation, establishing a causal relationship between neo-bone formation and growth. Gene expression profiling confirmed a key role for proliferation status for the bone forming ability suggesting that a rate limiting anabolism and open chromatin determined and predicted the therapeutic potency of culture-expanded MSC. Proliferation-based potency testing and switch to enriched expansion conditions may pave the way for standardised production of MSC for bone repair.

Intracoronary Mesenchymal Stem Cells Promote Postischemic Myocardial Functional Recovery, Decrease Inflammation, and Reduce Apoptosis via a Signal Transducer and Activator of Transcription 3 Mechanism

Signal transducer and activator of transcription 3 (STAT3) regulates myocardial apoptosis, cellular proliferation, and the immune response after ischemia/reperfusion (I/R). STAT3 is also necessary for the production of vascular endothelial growth factor (VEGF) by mesenchymal stem cells (MSCs), which are known to reduce myocardial injury after I/R. However, it remains unknown whether STAT3 is an important mediator of MSC-based cardioprotection. We hypothesized that knockout of stem cell STAT3 would reduce MSC-derived myocardial functional recovery and increase myocardial inflammatory and apoptotic signaling. With a Langendorff apparatus, male rat hearts were subjected to 15 minutes of equilibration and 25 minutes of ischemia, followed by 40 minutes of reperfusion. Immediately before ischemia, hearts received intracoronary infusions of vehicle, wild-type MSCs (WT MSCs) or STAT3 knockout MSCs (STAT3KO MSCs). Heart function was measured continuously. Myocardial homogenates were analyzed for production of interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α). Additionally, MSC production of hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1) were measured in vitro. Hearts treated with WT MSCs exhibited the greatest functional recovery, and those treated with STAT3KO MSCs had equivalent recovery to vehicle. The highest proinflammatory cytokine levels were seen in vehicle-treated hearts, and the lowest in the WT MSC group. STAT3KO MSCs produced less IGF-1, but more HGF than WT MSCs. Finally, hearts treated with STAT3KO MSCs or vehicle had significantly higher caspase-3 levels than those treated with WT MSCs. Intracoronary infusions of MSCs improve postischemic left ventricular function and reduce proapoptotic and proinflammatory signaling via a STAT3-dependent mechanism.

Mesenchymal-stem-cell-based experimental and clinical trials: current status and open questions

Introduction: Mesenchymal stem cells (MSCs) possess remarkable self-renewal ability and are able to differentiate into various cell lineages. MSCs can also enhance tissue repair and angiogenesis through a paracrine mechanism. It has been recognized that these cells hold great promise for tissue regeneration and treatment of immune-related diseases.Areas covered: This review aims at discussing the mechanisms of MSC-mediated immunomodulation and tissue repair and the related clinical trials, with special emphasis on factors that influence the efficiency of MSC-based therapy, including the source of MSCs, cell passage, cell dose, timing and route of administration.Expert opinion: MSCs may facilitate tissue repair through cell replacement and/or improving the microenvironment by releasing growth factors. Some of these factors also mediate the immunomodulatory effects of MSCs. It is important to establish global guidelines, protocols and standards for production and clinical trials of MSCs, so that MSCs can become a therapeutic agent with a reliable efficacy and good safety.

Generation of mesenchymal stem cell from human umbilical cord tissue using a combination enzymatic and mechanical disassociation method

MSCs (mesenchymal stem cells) promise a great potential for regenerative medicine due to their unique properties of self-renewal, high plasticity, modulation of immune response and the flexibility for genetic modification. Therefore, the increasing demand for cellular therapy necessitates a larger-scale production of MSC; however, the technical and ethical issues had put a halt on it. To date, studies have shown that MSC could be derived from human UC (umbilical cord), which is once considered as clinical waste. We have compared the two conventional methods which are classic enzymatic digestion and explant method with our newly tailored enzymatic-mechanical disassociation method to generate UC-MSC. The generated UC-MSCs from the methods above were characterized based on their immunophenotyping, early embryonic transcription factors expression and mesodermal differentiation ability. Our results show that enzymatic-mechanical disassociation method increase the initial nucleated cell yield greatly (approximately 160-fold) and maximized the successful rate of UC-MSC generation. Enzymatic-mechanical disassociation-derived UC-MSC exhibited fibroblastic morphology and surface markers expression of CD105, CD73, CD29, CD90 and MHC class I. Furthermore, these cells constitutively express early embryonic transcription factors (Nanog, Oct-4, Sox-2 and Rex-1), as confirmed by RT-PCR, indicating their multipotency and high self-renewal capacity. They are also capable of differentiating into osteoblasts and adipocytes when given an appropriate induction. The present study demonstrates a new and efficient approach in generating MSC from UC, hence serving as ideal alternative source of mesenchymal stem cell for clinical and research use.

Mesenchymal stem cells in transplantation and tissue regeneration

Mesenchymal stem cells in transplantation and tissue regeneration

Mesenchymal stem cells: biological properties and clinical applications

Importance of the field: In the last decade, knowledge of mesenchymal stem cells (MSCs) has evolved rapidly; their immunomodulatory properties and paracrine interactions with specific cell types in damaged tissues and promising results in some clinical applications have made these cells an attractive option for the treatment of certain diseases.Areas covered in this review: We present some relevant methodological issues and biological properties of MSCs, as well as clinical applications of MSC therapies with particular emphasis in the treatment of graft versus host disease (GVHD), complex perianal fistula and refractory metastatic neuroblastoma. Other topical aspects relevant to the application of cellular therapies such as biosafety studies and cellular production of MSCs are also discussed in this review.What the reader will gain: The growing optimism regarding MSCs research is based on the promising results obtained in in vitro and in vivo studies. The rapid translational research with MSCs necessitated standardization of methodology and terminology and greater focus on other aspects such as biosafety and cellular production, especially for clinical use of MSCs.Take home message: Much has been learned about the biology and applications of MSCs and much remains to be learned.