Source Of Mesenchymal Stem Cells Research Articles

Therapeutic Potential in Wound Healing of Allogeneic Use of Equine Umbilical Cord Mesenchymal Stem Cells.

Wound healing after skin injury is a complex process, particularly in equines where leg wounds are prevalent and their repair is complicated due to the anatomical characteristics. Conventional treatments are not effective enough. The umbilical cord offers an unlimited source of adult mesenchymal stem cells (ucMSCs) from Wharton's jelly tissue. The present study aims to demonstrate the safety and therapeutic potential of the allogeneic use of equine ucMSCs (e-ucMSCs) in the healing of severe equine leg wounds. The methods employed were the isolation, culture and expansion of e-ucMSCs. Flow cytometry and a PCR assay were used for cell characterization. This study included an immunomodulation assay, a murine pre-clinical trial and the first phase of an equine clinical trial. Our results showed that e-ucMSCs express a functional HLA-G homolog, EQMHCB2. In the immunomodulation assay, the e-ucMSCs inhibited the proliferation of activated equine peripheral blood mononuclear cells (e-PBMCs). In the murine pre-clinical trial, e-ucMSCs reduced healing time by 50%. In the equine clinical trial, the injection of e-ucMSCs into severe leg lesions improved the closure time and quality of the tissues involved, regenerating them without fibrous tissue scar formation. In conclusion, the results of this study suggest that e-ucMSCs can be used allogeneically for wound healing by creating a tolerogenic environment.

Adipose Tissue and Umbilical Cord Tissue: Potential Sources of Mesenchymal Stem Cells for Liver Fibrosis Treatment

Purpose of the studyMesenchymal stem cells (MSCs) are potential alternatives for liver fibrosis treatment; however, their optimal sources remain uncertain. This study compares the ex-vivo expansion characteristics of MSCs obtained from adipose tissue (AT) and umbilical cord (UC) and assesses their therapeutic potential for liver fibrosis treatment. MethodsSince MSCs from early to mid-passage numbers (P2–P6) are preferable for cellular therapy, we investigated the growth kinetics of AT-MSCs and UC-MSCs up to P6 and evaluated their therapeutic effects in a rat model of liver fibrosis induced by diethylnitrosamine. ResultsResults from the expansion studies demonstrated that both cell types exhibited bonafide characteristics of MSCs, including surface antigens, pluripotent gene expression, and differentiation potential. However, AT-MSCs demonstrated a shorter doubling time (58.2 ± 7.3 vs. 82.3 ± 4.3 h; p < 0.01) and a higher population doubling level (10.1 ± 0.7 vs. 8.2 ± 0.3; p < 0.01) compared to UC-MSCs, resulting in more cellular yield (230 ± 9.0 vs. 175 ± 13.2 million) in less time. Animal studies demonstrated that both MSC types significantly reduced liver fibrosis (p < 0.05 vs. the control group) while also improving liver function and downregulating fibrosis-associated gene expression. ConclusionAT-MSCs and UC-MSCs effectively reduce liver fibrosis. However, adipose cultures display an advantage by yielding a higher number of MSCs in a shorter duration, rendering them a viable choice for scenarios requiring immediate single-dose administration, often encountered in clinical settings.

A Narrative Review on the Management of Severe COVID-19 Infection Using Stem Cell-based therapies with a Focus on the Registered Clinical Trials

The emergence of SARS-CoV-2 has led to a concerning global pandemic. The severity of COVID-19 symptoms may be enhanced due to underlying medical conditions. Several studies demonstrated severe COVID-19 infection can lead to innate and adaptive immune dysregulation, cytokine storms as well and the formation of fibromyxoid exudate in the respiratory alveolar, ultimately resulting in pulmonary fibrosis and ARDS as the leading cause of mortality and morbidity. Currently, there is a widespread global endeavor in finding efficient drugs or vaccines to manage COVID-19. Although some FDA-approved treatments have been introduced for COVID-19, alternative therapies might decrease the mortality rates. Various sources of pluripotent and mesenchymal stem cells as cell-based therapies have been applied on moderate to severe COVID-19 patients with acute respiratory distress syndrome, leading to positive results. Cell-based therapies by modulating the cytokine cascades and cellular apoptosis can probably inhibit tissue remodeling and subsequent end-organ damage. The present review aims to discuss the advantages of stem cell-based therapies in the treatment of COVID-19 patients and the possible challenges associated with their application.

Systematic review and network meta‐analysis of mesenchymal stem cells in treating diabetic skin ulcers in animal models

AbstractBackgroundDiabetic cutaneous ulcers often pose considerable challenges in the healing process. These challenges stem from factors including inadequate perfusion of the ulcer's surrounding environment, persistent inflammation, tissue damage and microbial proliferation. The existing standard treatment modalities prove insufficient in fully addressing the complex pathogenesis of these ulcers. As a novel approach, researchers are exploring cellular therapies employing mesenchymal stem cells (MSCs) for the treatment of diabetic skin ulcers. MSCs are readily found in various tissues, including bone marrow, adipose tissue, placenta, amniotic membrane, amniotic fluid and umbilical cord. However, the optimal source of MSCs for effectively treating diabetic skin ulcers remains a topic of ongoing discussion.MethodsWe conducted a comprehensive search of Embase, PubMed and Web of Science databases, spanning from their inception to November 2022. Subsequently, we rigorously screened the literature following predetermined inclusion and exclusion criteria and evaluated the quality of the selected studies using the SYRCLE scale. Finally, the included literature underwent analysis, employing the Bayesian school of thought‐based R language. To ensure transparency and accountability, we registered this study with PROSPERO's International Systematic Review Prospective Registry, with the Registration ID: CRD42023387421.ResultsWe included a total of 11 articles in our analysis, all of which were randomized controlled studies involving 218 animal models. Among these studies, two utilized adipose‐derived MSCs, six employed bone marrow‐derived MSCs, one utilized amniotic membrane‐derived MSCs and three utilized umbilical cord‐derived MSCs. Our network meta‐analysis results revealed that there were no statistically significant differences in the healing rates of diabetic skin ulcers among MSCs derived from amniotic membrane, adipose tissue, umbilical cord and bone marrow on days 7–8, 10–12 and 12–14. Notably, according to the probability ranking table, the most effective treatment for diabetic wounds was found to be amniotic membrane‐derived MSCs.ConclusionThere was no statistically significant difference in the efficacy of MSCs derived from amniotic membrane, adipose, umbilical cord and bone marrow in the treatment of diabetic skin ulcers during the short‐term observation period, and the probability ranking graphs indicate that amniotic membrane‐derived MSCs may be the best choice for the treatment of diabetic skin ulcers.

Influential factors for optimizing and strengthening mesenchymal stem cells and hematopoietic stem cells co-culture.

Mesenchymal stem cells (MSCs) and Hematopoietic stem cells (HSCs) are two types of bone marrow stem cells that can proliferate and differentiate into different cell lineages. HSCs interact with MSCs under protective conditions, called niche. Numerous studies have indicated supportive effects of MSCs on HSCs proliferation and differentiation. Furthermore, HSCs have many clinical applications and could treat different hematologic and non-hematologic diseases. For this purpose, there is a need to perform in vitro studies to optimize their expansion. Therefore, various methods including co-culture with MSCs are used to address the limitations of HSCs culture. Some parameters that might be effective for improving the MSC/ HSC co-culture systems. Manipulating culture condition to enhance MSC paracrine activity, scaffolds, hypoxia, culture medium additives, and the use of various MSC sources, have been examined in different studies. In this article, we investigated the potential factors for optimizing HSCs/ MSCs co-culture. It might be helpful to apply a suitable approach for providing high-quality HSCs and improving their therapeutic applications.

The Concept behind the Suitability of Menstrual Blood-Derived Stem Cells for the Management of Vaginal Atrophy among BRCA Mutation Carriers after RRSO.

Risk-reducing bilateral salpingo-oophorectomy (RRSO) is recommended for breast cancer gene 1 (BRCA1) and 2 (BRCA2) mutation carriers. A major consequence of RRSO is surgical menopause associated with severe menopausal symptoms, mostly genitourinary complaints. Due to the inherent breast cancer risk, estrogen-based therapies are generally avoided in these patients. So far, the non-hormonal approaches available are not efficient to successfully treat the disabling vaginal atrophy-related symptoms. In regenerative medicine, mesenchymal stem cells (MSC) are the most frequently used cell type due to their remarkable and regenerative characteristics. Therapies based on MSC have revealed positive outcomes regarding symptoms and signs associated with vaginal atrophy by promoting angiogenesis, vaginal restoration, and the proliferation of vaginal mucosa cells. Menstrual blood-derived stem cells (MenSC) are a novel source of MSC, with promising therapeutic potential directly linked to their high proliferative rates; low immunogenicity; non-invasive, easy, and periodic acquisition; and almost no associated ethical issues. In this review, we update the current knowledge and research regarding the potential value of previously preserved MenSC in the therapy of vaginal atrophy among BRCA mutation carriers subjected to RRSO.

SOURCE OF MESENCHYMAL STEM CELLS IS VITAL FOR BONE-REGENERATIVE APPLICATIONS

Mesenchymal stem cells (MSC) have been used for bone regenerative applications as an alternative approach to bone grafting. Selecting the appropriate source of MSC is vital for the success of this therapeutic approach. MSC can be obtained from various tissues, but the most used sources of MSC are Bone marrow (BMSC), followed by adipose tissue (ASC). A donor-matched comparison of these two sources of MSC ensures robust and reliable results.Despite the similarities in morphology and immunophenotype of donor-matched ASC and BMSC, differences existed in their proliferation and in vitro differentiation potential, particularly osteogenic differentiation that was superior for BMSC, compared to ASC. However, these differences were substantially influenced by donor variations. In vivo, although the upregulated expression of osteogenesis-related genes in both ASC and BMSC, more bone was regenerated in the calvarial defects treated with BMSC compared to ASC, especially during the initial period of healing. According to these findings, compared to ASC, BMSC may result in faster regeneration and healing, when used for bone regenerative applications.

DOES INFLAMMATORY AND METABOLOMIC ACTIVITY ON NORMAL AND OSTEOARTHRITIC CHONDROCYTES DIFFER BETWEEN MESENCHYMAL STEM CELLS (MSCS) DERIVED FROM THE INFRAPATELLAR FAT, SYNOVIUM, AND SUBCUTANEOUS TISSUES?

Osteoarthritis (OA) is a disabling disease depriving the quality of life of patients. Mesenchymal stem cells (MSCs) are recently used to modify the inflammatory and degenerative cascade of the disease. Source of MSCs could change the progression and symptoms of OA due to their different metabolomic activities. We asked whether MSCs derived from the infrapatellar fat (IPF), synovium (Sy) and subcutaneous (SC) tissues will decrease inflammatory and degenerative markers of normal and OA chondrocytes and improve regeneration in culture. Tissues were obtained from three male patients undergoing arthroscopic knee surgery due to sports injuries after ethical board approval. TNFa concentration decreased in all MSC groups (Sy=156,6±79, SC=42,1±6 and IPF=35,5±3 pg/ml; p=0,036) on day 14 in culture. On day seven (Sy=87,4±43,7, SC=23±8,9 and IPF=14,7±3,3 pg/ml, p=0,043) and 14 (Sy=29,1±11,2, SC=28,3±18,5 and IPF=20,3±16,2 pg/ml, p=0,043), MMP3 concentration decreased in all groups. COMP concentration changes however were not significant. Plot scores of tissues for PC2-13,4% were significantly different. Based on the results of liquid chromatography-mass spectrometry (LC-MS) metabolomics coupled with recent data processing strategies, clinically relevant seven metabolites (L-fructose, a-tocotrienol, coproporphyrin, nicotinamide, bilirubin, tauro-deoxycholic acid and galactose-sphingosine) were found statistically different (p&lt;0.05 and fold change&gt;1.5) ratios in tissue samples. Focusing on these metabolites as potential therapeutics could enhance MSC therapies.Acknowledgment: Hacettepe University, Scientific Research Projects Coordination Unit (#THD-2020-18692) and Turkish Society of Orthopedics and Traumatology (#TOTBID-89) funded this project. Feza Korkusuz MD is a member of the Turkish Academy of Sciences (TÜBA).

TRANSLATIONAL POTENTIAL OF MESENCHYMAL STEM CELL THERAPY FOR INTERVERTEBRAL DISC REGENERATION

The use of mesenchymal stem cell (MSCs) for intervertebral disc (IVD) regeneration has been extensively explored in the last two decades. MSCs are potent cell types that can be easily and safely harvested due to their abundancy and availability. Moreover, they are characterized by the capacity to differentiate towards IVD cells as well as release growth factors to support resident cell metabolism and recruit local progenitor cells to induce endogenous repair of degenerated IVDs. This talk will outline the characteristics of the main MSC sources and their effect towards IVD regeneration based on available preclinical and clinical evidence. In addition, innovative aspects of MSC-derived cell-free therapies will also be discussed.

Advances in Mesenchymal Stem Cell Research Applications for Female Infertility-Mechanisms, Efficacy Parameters, Challenges and Future Roadmap.

Infertility affects approximately 15-20% of couples globally, with female factors contributing to nearly half of cases. Conditions such as polycystic ovary syndrome, endometriosis, tubal damage and premature ovarian failure are leading causes of female infertility. Current treatments like in vitro fertilization (IVF) have limitations and risks. Mesenchymal stem cells (MSCs) have shown therapeutic potential due to their ability to differentiate, secrete trophic factors, and exhibit immunomodulatory and anti-inflammatory properties. They have been demonstrated to repair and regenerate reproductive organs in various preclinical models of infertility related conditions. MSCs have reduced endometriotic lesions, regenerated lost follicles in premature ovarian failure (POF) models, and promoted tubal repair in damage models. Some clinical and preclinical studies have reported improved outcomes with MSC therapy in endometriosis and premature ovarian failure patients. This review discusses the properties and sources of MSCs, their mechanisms of action, preclinical evidence for applications in conditions like POF, polycystic ovary syndrome (PCOS), endometriosis, Asherman syndrome, and preeclampsia, and preliminary clinical data on MSC therapy for female infertility management.

Therapeutic and regenerative potential of different sources of mesenchymal stem cells for cardiovascular diseases

Therapeutic and regenerative potential of different sources of mesenchymal stem cells for cardiovascular diseases

Isolation and Characterization of Human Dental Pulp Stem Cells Derived from Dental Pulp of Permanent Teeth.

Dental pulp stem cells (DPSCs) are a promising alternative to the source of mesenchymal stem cells (MSCs), as they are readily available in minimally invasive procedures compared to more invasive methods associated with harvesting other MSCs sources. Despite the encouraging pre-clinical outcomes in animal disease models, culture-expanding procedures are needed to obtain a sufficient number of MSCs required for delivery to the damaged site. However, this contributes to increasing regulatory difficulties in translating stem cells and tissue engineering therapy to clinical use. Moreover, discussions continue as to which isolation method is to be preferred when obtaining DPSCs from extracted molars. This protocol describes a simple explant isolation technique of human dental pulp stem cells from the dental pulp of permanent teeth based upon the plastic adherence of MSCs and subsequent outgrowth of cells out of tissue fragments with high efficacy.

A Comparative Study on the Effects of Mesenchymal Stem Cells and Their Conditioned Medium on Caco-2 Cells as an In Vitro Model for Inflammatory Bowel Disease.

Recent research indicates that mesenchymal stem cells (MSCs), known for their anti-inflammatory and anti-infectious properties, could be a promising alternative for treating inflammatory diseases such as inflammatory bowel disease (IBD). This study examined how MSCs and their derivatives, when cocultured with interleukin-1β (IL-1β)-stimulated Caco-2 cells, affect the expression of genes related to inflammation, microbes, and apoptosis. In the experiment, Caco-2 cells were exposed to 10 ng/mL of IL-1β for 24 h. MSCs were sourced from human bone marrow, adipose tissue (AD-MSC), and menstrual blood. These MSCs and their conditioned medium (CM) were then cocultured with the IL-1β-induced Caco-2 cells. After 48 h, gene expression levels were analyzed using real-time PCR, and the data were statistically evaluated using T-tests, U-Mann-Whitney, and Tukey's post hoc analyses. The results indicated that IL-1β at 10 ng/mL was the optimal concentration for inducing Caco-2 cells with the highest viability and minimal damage. Among the MSCs tested, AD-MSCs were the most effective in regulating gene expression. Specifically, AD-MSC treatment significantly reduced the mRNA expression of TNF-α and IL-1β, both of which are crucial in sustaining inflammatory responses (p ≤ 0.05). This study concludes that AD-MSCs have superior effects compared to other MSC sources in modulating genes associated with inflammation, antibacterial effects, and apoptosis in an in vitro model of IBD using Caco-2 cells.

Comparative Analysis of the Therapeutic Effects of MSCs From Umbilical Cord, Bone Marrow, and Adipose Tissue and Investigating the Impact of Oxidized RNA on Radiation-Induced Lung Injury.

Radiation-induced lung injury (RILI) is frequently observed in patients undergoing radiotherapy for thoracic malignancies, constituting a significant complication that hampers the effectiveness and utilization of tumor treatments. Ionizing radiation exerts both direct and indirect detrimental effects on cellular macromolecules, including DNA, RNA and proteins, but the impact of oxidized RNA in RILI remains inadequately explored. Mesenchymal stem cells (MSCs) can repair injured tissues, and the reparative potential and molecular mechanism of MSCs in treating RILI remains incompletely understood. This study aimed to investigate the therapeutic effects and mechanisms of action of three distinct sources of MSCs, including human umbilical cord mesenchymal stem cells (UCMSCs), bone marrow mesenchymal stem cells (BMSCs), and adipose-derived stem cells (ADSCs), in thoracically irradiated mice. Comparative analysis revealed that all three types of MSCs exhibited the ability to mitigate radiation-induced inflammatory infiltration, alveolar hemorrhage, and alveolar wall thickening in the lung tissue of the mice. MSCs also attenuated RILI by decreasing inflammatory factors, upregulating anti-inflammatory factor expression, and reducing collagen accumulation. Immunohistochemical results showed that all three MSCs reduced radiation-induced cell apoptosis and promoted the regeneration of lung tissue cells. The analysis of malondialdehyde (MDA) and 8-hydroyguanosine (8-OHG) content indicated that MSCs possess reparative properties against radiation-induced oxidative damage in lung tissue. The study provides evidence that UCMSCs are a more appropriate therapeutic option for RILI compared to BMSCs and ADSCs. Additionally, MSCs effectively reduce the accumulation of oxidized RNA in RILI, thereby, presenting a unique avenue for investigating the underlying mechanism of MSC-based treatment for RILI.

Safe and Noninvasive Method for Generating Induced Mesenchymal Stem Cells from Urinary Epithelial Cells.

Mesenchymal stem cells (MSCs) exhibit remarkable versatility and hold immense potential for tissue regeneration. They are actively investigated in clinical trials for various diseases and injuries, showcasing their therapeutic promise. However, traditional sources of MSCs have limitations in terms of scalability and storage. To address these challenges, this study aims to provide a method of creating an alternative source of induced pluripotent stem cells (iPSCs)-derived MSCs (iMSCs) from urinary epithelial cells (UECs) through a noninvasive procedure. This distinct subset of UECs found in urine samples offers an invaluable resource for generating autologous UE-iPSCs. iPSCs have distinct advantages over embryonic stem cells, as they can be generated from somatic cells, eliminating the need for human embryos and associated ethical concerns. Advancements in iPSC technology enable the differentiation of iMSCs, allowing researchers to create disease models, gain insights into disease mechanisms, and develop targeted therapies. This straightforward and noninvasive method aims to enhance the production of high-quality, autologous iMSCs with significant replicative and differentiation potential, making them suitable for regenerative therapy.

Mesenchymal stem cells from different sources for sepsis treatment: prospects and limitations.

Sepsis is a systemic inflammatory response syndrome in which the host response to infection is dysregulated, leading to circulatory dysfunction and multi-organ damage. It has a high mortality rate and its incidence is increasing year by year, posing a serious threat to human life and health. Mesenchymal stem cells (MSC) have the following properties: hematopoietic support, provision of nutrients, activation of endogenous stem/progenitor cells, repair of tissue damage, elimination of inflammation, immunomodulation, promotion of neovascularization, chemotaxis and migration, anti-apoptosis, anti-oxidation, anti-fibrosis, homing, and many other effects. A large number of studies have confirmed that MSC from different sources have their own characteristics. This article reviews the pathogenesis of sepsis, the biological properties of MSC, and the advantages and disadvantages of different sources of MSC for the treatment of sepsis and their characteristics.

Immunomodulatory Effects of Primed Tonsil-Derived Mesenchymal Stem Cells on Atopic Dermatitis via B Cell Regulation.

Mesenchymal stem cells (MSCs) ameliorate T-and B cell-mediated immune responses. In particular, tonsil-MSCs (T-MSCs) are attractive candidates for practical and clinical applications because of their ease of acquisition and relatively low immunogenicity compared with other MSC sources. The use of MSCs as a therapeutic tool in atopic dermatitis (AD) has been investigated, but that of T-MSCs remains to be explored. Therefore, we investigated the immunomodulatory effects of primed T-MSCs in AD pathogenesis. In our animal study, primed T-MSCs showed greater immunological suppressive effects than naïve T-MSCs. Additionally, in vitro, the proliferation of B cells was downregulated by the addition of primed T-MSCs compared with naïve T-MSCs. The activation of B cells to differentiate into antibody-secreting cells and produce IgE was also reduced when primed T-MSCs were added. Moreover, under CD40-knockdown conditions, we found that CD40 in primed T-MSCs played a critical role as a regulator of B cell activation and was mediated by the non-canonical NF-κB pathway. Therefore, our findings suggest a promising role for primed T-MSCs in the treatment of AD by regulating B cell-mediated inflammatory responses, which are dependent on CD40 expression on primed T-MSCs mediated through the non-canonical NF-κB pathway.

Role of Infrapatellar Fat Tissue in the Pathogenesis of Knee Osteoarthritis: A Review

Osteoarthritis (OA) is one of the most common joint diseases in the adult population. The role of indolent inflammation and predominance of catabolic cytokines over anabolic ones in OA has now been proven. The influence of obesity on the development of OA by releasing inflammatory mediators by fat tissue has been confirmed. Infrapatellar fat tissue (Hoffa’s fat pad) is a potential donor of proinflammatory cytokines, including specific fat tissue proinflammatory cytokines - adipokines. In a healthy person, infrapatellar fat tissue contributes to the distribution of mechanical load on the joint and metabolism of the synovial fluid. Infiltration of infrapatellar fat tissue by macrophages and lymphocytes leads not only to the production of proinflammatory cytokines with chondrolytic properties, but also to the maintenance of chronic inflammation in the synovial membrane, articular cartilage, and subchondral bone. Morphologic changes in Hoffa’s fat pad can be both an indicator of the inflammatory process in the joint cavity and a predictor of pathologic changes of the joint. Among histological changes, infiltration with macrophages and lymphocytes, fibrosis, thickening of the interlobular septa, reduction in the size of fat lobules and adipocytes, and increased vascularization are important for the course of OA. Morphologic changes can be assessed using a non-invasive method - magnetic resonance imaging, which makes it possible to evaluate the presence and severity of synovitis, thickening of the synovial membrane, edema, thickening of the interlobular septa, and a decrease in the volume of Hoffa’s fat pad. Histologic and tomographic signs can potentially be used to assess the severity of OA and develop prognostic scales. Infrapatellar fat tissue is also a source of mesenchymal stem cells phenotypically similar to chondrocytes, which can be used for regeneration of joint cartilage tissue with minimally invasive intervention to harvest them.

Translating mesenchymal stem cell and their exosome research into GMP compliant advanced therapy products: Promises, problems and prospects.

Mesenchymal stem cells (MSCs) are one of the few stem cell types used in clinical practice as therapeutic agents for immunomodulation and ischemic tissue repair, due to their unique paracrine capacity, multiple differentiation potential, active components in exosomes, and effective mitochondria donation. At present, MSCs derived from tissues such as bone marrow and umbilical cord are widely applied in preclinical and clinical studies. Nevertheless, there remain challenges to the maintenance of consistently good quality MSCs derived from different donors or tissues, directly impacting their application as advanced therapy products. In this review, we discuss the promises, problems, and prospects associated with translation of MSC research into a pharmaceutical product. We review the hurdles encountered in translation of MSCs and MSC-exosomes from the research bench to an advanced therapy product compliant with good manufacturing practice (GMP). These difficulties include how to set up GMP-compliant protocols, what factors affect raw material selection, cell expansion to product formulation, establishment of quality control (QC) parameters, and quality assurance to comply with GMP standards. To avoid human error and reduce the risk of contamination, an automatic, closed system that allows real-time monitoring of QC should be considered. We also highlight potential advantages of pluripotent stem cellsas an alternative source for MSC and exosomes generation and manufacture.

Adipose-derived mesenchymal stem cells (MSCs) are a superior cell source for bone tissue engineering

Effective bone regeneration through tissue engineering requires a combination of osteogenic progenitors, osteoinductive biofactors and biocompatible scaffold materials. Mesenchymal stem cells (MSCs) represent the most promising seed cells for bone tissue engineering. As multipotent stem cells that can self-renew and differentiate into multiple lineages including bone and fat, MSCs can be isolated from numerous tissues and exhibit varied differentiation potential. To identify an optimal progenitor cell source for bone tissue engineering, we analyzed the proliferative activity and osteogenic potential of four commonly-used mouse MSC sources, including immortalized mouse embryonic fibroblasts (iMEF), immortalized mouse bone marrow stromal stem cells (imBMSC), immortalized mouse calvarial mesenchymal progenitors (iCAL), and immortalized mouse adipose-derived mesenchymal stem cells (iMAD). We found that iMAD exhibited highest osteogenic and adipogenic capabilities upon BMP9 stimulation in vitro, whereas iMAD and iCAL exhibited highest osteogenic capability in BMP9-induced ectopic osteogenesis and critical-sized calvarial defect repair. Transcriptomic analysis revealed that, while each MSC line regulated a distinct set of target genes upon BMP9 stimulation, all MSC lines underwent osteogenic differentiation by regulating osteogenesis-related signaling including Wnt, TGF-β, PI3K/AKT, MAPK, Hippo and JAK-STAT pathways. Collectively, our results demonstrate that adipose-derived MSCs represent optimal progenitor sources for cell-based bone tissue engineering.