Types Of Mesenchymal Stem Cells Research Articles

Comparison of the therapeutic effects of mesenchymal stem cells derived from human dental pulp (DP), adipose tissue (AD), placental amniotic membrane (PM), and umbilical cord (UC) on postmenopausal osteoporosis.

Background: Osteoporosis is a systemic bone disease characterized by bone loss and microstructural degeneration. Recent preclinical and clinical trials have further demonstrated that the transplantation of mesenchymal stem cells (MSCs) derived from human adipose tissue (AD), dental pulp (DP), placental amniotic membrane (AM), and umbilical cord (UC) tissues can serve as an effective form of cell therapy for osteoporosis. However, MSC-mediated osteoimmunology and the ability of these cells to regulate osteoclast-osteoblast differentiation varies markedly among different types of MSCs. Methods: In this study, we investigated whether transplanted allogeneic MSCs derived from AD, DP, AM, and UC tissues were able to prevent osteoporosis in an ovariectomy (OVX)-induced mouse model of osteoporosis. The homing and immunomodulatory ability of these cells as well as their effects on osteoblastogenesis and the maintenance of bone formation were compared for four types of MSCs to determine the ideal source of MSCs for the cell therapy-based treatment of OVX-induced osteoporosis. The bone formation and bone resorption ability of these four types of MSCs were analyzed using micro-computed tomography analyses and histological staining. In addition, cytokine array-based analyses of serological markers and bioluminescence imaging assays were employed to evaluate cell survival and homing efficiency. Immune regulation was determined by flow cytometer assay to reflect the mechanisms of osteoporosis treatment. Conclusion: These analyses demonstrated that MSCs isolated from different tissues have the capacity to treat osteoporosis when transplanted in vivo. Importantly, DP-MSCs infusion was able to maintain trabecular bone mass more efficiently with corresponding improvements in trabecular bone volume, mineral density, number, and separation. Among the tested MSC types, DP-MSCs were also found to exhibit greater immunoregulatory capabilities, regulating the Th17/Treg and M1/M2 ratios. These data thus suggest that DP-MSCs may represent an effective tool for the treatment of osteoporosis.

Adipose Tissue and Bone Marrow-Derived Mesenchymal Stem Cells are not Really the Same: Investigating the Differences in Their Immunomodulatory, Migratory, and Adhesive Profile.

Mesenchymal stem cells (MSCs) are the most widely used stem cells in regenerative medicine. They can be isolated from multiple sources, most commonly bone marrow and adipose tissue. MSCs derived from different sources show similar molecular and biological characteristics, but there is ongoing debate regarding the best source of MSCs and the potential biological differences between MSCs from different origins. Bone marrow derived-MSCs (BM-MSCs) and adipose tissue-derived MSCs (AD-MSCs) share many molecular and immunomodulatory properties. In this study, we compared the levels of major immunomodulatory, adhesive, and migratory factors in human BM-MSCs and AD-MSCs under normal conditions, which will help determine the suitability and specificity of each type for certain therapeutic applications. WST1 assay and fluorescent assay SUC-LLVY-AMC were used to measure MSC proliferation and 26S proteasome activity, respectively. Western blotting, ELISA Assays, and bright field live imaging were also used. AD-MSCs and BM-MSCs exhibited similar morphology and proliferation rate. A significantly higher 26S proteasome activity was detected in AD-MSCs than in BM-MSCs. Levels of ICAM-1, integrin α5 and integrin α6 were significantly higher in AD-MSCs compared to BM-MSCs, while no significant difference in CXCR4 levels was observed. Expression of IDO and factor H was significantly higher in AD-MSCs, while CTLA-4 and IL-10 levels were higher in BM-MSCs. This indicates that AD-MSCs and BM-MSCs have different immunomodulatory and adhesion profiles. MSCs isolated from different sources may show differences in their biological and immunomodulatory properties, suggesting a potential suitability of certain MSCs type for specific conditions. Also, combination of different MSCs types could help optimize therapeutic outcomes.

Comparison between the Regenerative and Therapeutic Impacts of Bone Marrow Mesenchymal Stem Cells and Adipose Mesenchymal Stem Cells Pre-Treated with Melatonin on Liver Fibrosis.

The distinctive feature of liver fibrosis is the progressive replacement of healthy hepatic cells by the extracellular matrix protein, which is abundant in collagen I and III, with impaired matrix remodeling. The activation of myofibroblastic cells enhances the fibrogenic response of complex interactions of hepatic stellate cells, fibroblasts, and inflammatory cells to produce the excessive deposition of the extracellular protein matrix. This process is activated by multiple fibrogenic mediators and cytokines, such as TNF-α and IL-1β, accompanied with a decrease in the anti-fibrogenic factor NF-κβ. Mesenchymal stem cells (MSCs) represent a promising therapy for liver fibrosis, allowing for a more advanced regenerative influence when cultured with extrinsic or intrinsic proliferative factors, cytokines, antioxidants, growth factors, and hormones such as melatonin (MT). However, previous studies showed conflicting findings concerning the therapeutic effects of adipose (AD) and bone marrow (BM) MSCs; therefore, the present work aimed to conduct a comparative and comprehensive study investigating the impact of MT pre-treatment on the immunomodulatory, anti-inflammatory, and anti-apoptotic effects of AD- and BM-MSCs and to critically analyze whether MT-pre-treated AD-MSCs and BM-MSCs reveal equal or different therapeutic and regenerative potentials in a CCl4-injured liver experimental rat model. Six groups of experimental rats were used, with ten rats in each group: group I (control group), group II (CCl4-treated group), group III (CCl4- and BM-MSC-treated group), group IV (CCl4 and MT-pre-treated BM-MSC group), group V (CCl4- and AD-MSC-treated group), and group VI (CCl4 and MT-pre-treated AD-MSC group). Liver function tests and the gene expression of inflammatory, fibrogenic, apoptotic, and proliferative factors were analyzed. Histological and immunohistochemical changes were assessed. The present study compared the ability of AD- and BM-MSCs, with and without MT pre-treatment, to reduce hepatic fibrosis. Both types of MSCs improved hepatocyte function by reducing the serum levels of ALT, aspartate aminotransferase (AST), alkaline phosphatase (AKP), and total bilirubin (TBIL). In addition, the changes in the hepatocellular architecture, including the hepatocytes, liver sinusoids, central veins, portal veins, biliary ducts, and hepatic arteries, showed a decrease in hepatocyte injury and cholestasis with a reduction in inflammation, apoptosis, and necrosis of the hepatic cells, together with an inhibition of liver tissue fibrosis. These results were augmented by an analysis of the expression of the pro-inflammatory cytokines TNFα and IL-1β, the anti-fibrogenic factor NF-κβ, the apoptotic factor caspase-3, and the proliferative indicators antigen Ki-67 and proliferating cell nuclear antigen (PCNA). These findings were found to be statistically significant, with the restoration of normal parameters in the rats that received AD-MSCs pre-treated with MT, denoting optimal regenerative and therapeutic effects. AD-MSCs pre-treated with MT are the preferred choice in improving hepatic fibrosis and promoting the therapeutic and regenerative ability of liver tissue. They represent a very significant tool for future stem cell use in the tissue regeneration strategy for the treatment of liver diseases.

Isolation, identification and osteogenic capability analysis of mesenchymal stem cells derived from different layers of human maxillary sinus membrane.

To discover the populations of mesenchymal stem cells (MSCs) derived from different layers of human maxillary sinus membrane (hMSM) and evaluate their osteogenic capability. hMSM was isolated into a monolayer using the combined method of physical separation and enzymatic digestion. The localization of MSCs in hMSM was performed by immunohistological staining and other techniques. Lamina propria layer-derived MSCs (LMSCs) and periosteum layer-derived MSCs (PMSCs) from hMSM were expanded using the explant cell culture method and identified by multilineage differentiation assays, colony formation assay, flow cytometry and so on. The biological characteristics of LMSCs and PMSCs were compared using RNA sequencing, reverse transcription and quantitative polymerase chain reaction, immunofluorescence staining, transwell assay, western blotting and so forth. LMSCs and PMSCs from hMSMs were both CD73-, CD90- and CD105-positive, and CD34-, CD45- and HLA-DR-negative. LMSCs and PMSCs were identified as CD171+ /CD90+ and CD171- /CD90+ , respectively. LMSCs displayed stronger proliferation capability than PMSCs, and PMSCs presented stronger osteogenic differentiation capability than LMSCs. Moreover, PMSCs could recruit and promote osteogenic differentiation of LMSCs. This study identified and isolated two different types of MSCs from hMSMs. Both MSCs served as good potential candidates for bone regeneration.

Priming and Combined Strategies for the Application of Mesenchymal Stem Cells in Ischemic Stroke: A Promising Approach.

Ischemic stroke (IS) is a leading cause of death and disability worldwide. Tissue plasminogen activator (tPA) administration and mechanical thrombectomy are the main treatments but have a narrow time window. Mesenchymal stem cells (MSCs), which are easily scalable in vitro and lack ethical concerns, possess the potential to differentiate into various types of cells and secrete a great number of growth factors for neuroprotection and regeneration. Moreover, MSCs have low immunogenicity and tumorigenic properties, showing safety and preliminary efficacy both in preclinical studies and clinical trials of IS. However, it is unlikely that MSC treatment alone will be sufficient to maximize recovery due to the low survival rate of transplanted cells and various mechanisms of ischemic brain damage in the different stages of IS. Preconditioning was used to facilitate the homing, survival, and secretion ability of the grafted MSCs in the ischemic region, while combination therapies are alternatives that can maximize the treatment effects, focusing on multiple therapeutic targets to promote stroke recovery. In this case, the combination therapy can yield a synergistic effect. In this review, we summarize the type of MSCs, preconditioning methods, and combined strategies as well as their therapeutic mechanism in the treatment of IS to accelerate the transformation from basic research to clinical application.

Human Umbilical Cord Mesenchymal Stem Cells Alleviate Chronic Salpingitis by Modulating Macrophage-Associated Inflammatory Factors.

Mesenchymal stem cells (MSCs) have been widely studied because of their established anti-inflammatory properties. During chronic salpingitis (CS), infiltrated macrophages have vital roles in inflammation and tissue remodeling. We employed the type of MSCs, human umbilical cord (huc) MSCs in an experimental CS model and therapeutic efficacy was assessed. hucMSCs exerted this therapeutic effect by regulating macrophage function. To verify the regulatory effects of hucMSCs on the macrophage, macrophage line RAW264.7 markers were analyzed under LPS stimulation with or without co-culturing with hucMSCs for 12h and 24h. In addition, flow cytometry analysis was applied to reveal the interaction of co-culture. For animal studies, CS was induced by the MoPn strain Chlamydia trachomatis(CT), hucMSCs were intravaginally injected in the CS, and we analyzed the infiltrated macrophage by immunofluorescence. We found the markers IL-10 was markedly increased and IL-1β, caspase-1 was notably downregulated after co-culturing with hucMSCs by RT-PCR. hucMSCs promote macrophage line RAW264.7 apoptosis. We also found that hucMSCs treatment can alleviate CS by decreasing the mRNA expression of IL-1β, caspase-1 and MCP-1 in the tubal tissue by RT-PCR and decreasing the protein expression of IL-1β, caspase-1 and TGF-β by western blotting. These results suggest that macrophage function may be related to the immune-modulating characteristics of hucMSCs that contribute to CS.

Stem Cell Administration to Repair Torn Menisci

The meniscus is a crescent-shaped, fibrocartilaginous padding in the knee that contains variable vascularization and histology. This structure enables proper loadbearing, knee movement, and protection of articular cartilage and bone of the tibiofemoral joint. The meniscus is subject to tears from acute injury and degenerative stresses. Many meniscal tears do not heal naturally due to poor vascularization and high stresses placed on the meniscus. These often result in pain and mechanical symptoms and are highly correlated to osteoarthritis (OA) development. While there are a wide variety of suggested treatments for meniscal tears, studies indicate common surgical interventions have little to no significant improvements in abating patient symptoms or limiting osteoarthritic progression, with high failure rates. Therefore, alternative treatments are being actively explored for meniscal tear repair. One of the most-researched treatment options is using mesenchymal stem cells (MSC), a type of adult multilineage progenitor cell capable of facilitating meniscal tissue regeneration. Many different types of MSCs and supplemental, cuttingedge techniques are being tested to maximize tear healing. MSCs hold great promise for regenerating meniscal tissue, limiting OA, and restoring joint functionality. However, more research is required to prove the significance of stem cell treatments in humans and define the conditions for their use.

Prospect of Exosome in Ligament Healing: A Systematical Review.

The relationship between ligaments and bone is a complex and heterogeneous junction involving bone, mineralized fibro cartilage, non-mineralized fibro cartilage and ligaments. Mesenchymal stem cells (MSC) can be used in vivo to control inflammation and aid in tissue repair, according to studies. This review focused on using exosomes as an alternative to MSC, as a cell-free therapy for modulating the remodelling process. To conduct a systematic review of the literature, the phrases "exosome" and "ligament" or "tendon" and "extracellular vesicle" and "stem cells" were used as the search keywords in PubMed (MEDLINE), OVID, the Cochrane Library, and Science Direct. From the literature, 73 studies in all were found. Six studies were included in this systematic review after full-text evaluation. Six included studies covered a range of MSC types, isolation techniques, animal models, and interventions. Biomechanical results consistently indicated the beneficial impact of conditioned media, vesicles, and exosomes on treating tendons and ligaments. Noteworthy findings were the reduction of inflammation by iMSC-IEVs, chondrocyte protection by iPSC-EVs (extracellular vesicles generated by inflammation-primed adipose-derived stem cells), osteolysis treatment using DPSC-sEVs (small extracellular vesicles derived from dental pulp stem cells), and the contribution of exosome-educated macrophages to ligament injury wound healing. Exosomes may serve as a cell-free therapeutic substitute for modulating the remodelling process, particularly in ligament healing.

MSCProfiler: a single cell image processing workflow to investigate mesenchymal stem cell heterogeneity.

Single cell cytometry has demonstrated plausible immuno-heterogeneity of mesenchymal stem cells (MSCs) owing to their multivariate stromal origin. To contribute successfully to next-generation stem cell therapeutics, a deeper understanding of their cellular morphology and immunophenotype is important. In this study, the authors describe MSCProfiler, an image analysis pipeline developed using CellProfiler software. This workflowcan extract geometrical and texture features such as shape, size, eccentricity and entropy, along with intensity values of the surface markers from multiple single cell images obtained using imaging flow cytometry. This screening pipeline can be used to analyze geometrical and texture features of all types of MSCs across different passages hallmarked by enhanced feature extraction potential from brightfield and fluorescent images of the cells.

Chondrogen™ Injection for Knee Osteoarthritis using Stem Cells from Wharton's Jelly

Knee osteoarthritis constitutes a prominent source of pain and functional impairment, with its prevalence showing a consistent yearly increase. Current therapeutic strategies primarily revolve around addressing symptoms and, in severe cases, resorting to prosthetic joint replacement, yet they fail to target the underlying pathophysiological mechanisms driving degeneration. In this context, there is a growing interest in investigating mesenchymal stem cell (MSC) therapy as a potential remedy for osteoarthritis. Among the various MSC types under scrutiny, using Wharton's Jelly-derived mesenchymal stem cells (WJ-MSCs) has garnered relatively scant attention. The present study represents a Phase I clinical trial of an open-label, single-arm design within this context. Its principal aim is to assess the safety and efficacy of administering mesenchymal stem cells derived from Wharton's Jelly via intra-articular injection for patients diagnosed with knee osteoarthritis. Throughout six months, this investigation discerned a statistically significant overall improvement in clinical presentation relative to baseline. This improvement manifested as reduced analgesic consumption, diminished Visual Analog Scale (VAS) scores (19.5 to 18.7 mm, p = .00), and augmented functional assessment scores, including the IKDC Score (enhanced from 62.2 to 100, p = .00), KOOS Symptoms and Stiffness subscales (elevated from 76.8% to 10.6%, p = .00), as well as KOOS Pain subscale (upgraded from 74.4% to 10.1%, p = .00). The study encouragingly reported no significant adverse effects during the observation period. However, upon radiographic evaluation, no significant alterations were observed in terms of deformity angle (p = 0.957) or medial (p = 0.871) and lateral (p = 0.520) compartment joint space widths. To further elucidate the comparative efficacy of this treatment, it is prudent to contemplate a randomised controlled trial comparing it against the conventional hyaluronic acid regimen, thereby contributing to an enriched understanding of its therapeutic potential.

Expression profiles of human somatic mesenchymal stem cells derived from fresh endometrium, ectopic-endometrium and umbilical cord.

The study investigated the stem cell expression profiles and differentiation capacities of mesenchymal stem cells (MSCs) from different tissues, specifically human eutopic endometrium MSCs (eut-MSCs), ectopic endometrium MSCs (ect-MSCs), and umbilical cord MSCs (UC-MSCs). Our aim was to identify any similarities in subpopulations among these MSCs and lay a foundation for MSCs repair. MSCs were isolated from endometrial tissue (n = 5), endometriosis tissue (n = 6), and umbilical cords (n = 7). Flow cytometry was used to examine cell phenotype, and three lineage tests were conducted to evaluate the differentiation capacity of the MSCs. Eut-MSCs expressed CD44 (98.00 ± 0.96%), CD73 (99.54 ± 0.02%), CD140b (99.16 ± 0.50%), CD146 (93.87 ± 2.27%), SUSD2 (50.76 ± 8.15%), and CD271 (2.1 ± 1.22%). Ect-MSCs expressed CD44 (98.23 ± 1.60%), CD73 (99.63 ± 0.04%), CD140b (98.13 ± 0.53%), CD146 (93.88 ± 3.19%), SUSD2 (49.33 ± 6.36%), and CD271 (2.85 ± 1.17%). UC-MSCs expressed CD44 (99.11 ± ± 0.42%), CD73 (99.65 ± 0.12%), CD140b (99.84 ± 0.42%), CD146 (88.09 ± 4.20%), SUSD2 (72.87 ± 7.13%), and CD271 (6.19 ± 2.08%). The expression of SUSD2 and CD271 in UC-MSCs was slightly but not significantly higher than that in ect-MSCs and eut-MSCs. However, CD44, CD73, CD140b, and CD146 showed similar expression levels in UC-MSCs, ect-MSCs, and eut-MSCs. All three types of MSCs demonstrated the capacity to differentiate into osteoblasts, adipocytes, and chondrocytes. Our findings indicate that ect-MSCs, eut-MSCs, and UC-MSCs have similar stem cell phenotypes and the ability to differentiate into three lineages.

Adipose-derived Mesenchymal Stem Cells are Ideal for the Cell-based Treatment of Refractory Wounds: Strong Potential for Angiogenesis.

Although Mesenchymal Stem Cells (MSCs)-based therapy has been proposed as a promising strategy for the treatment of chronic lower-extremity ulcers, their optimal sources, amounts, and delivery methods are urgently needed to be determined. In this study, we compared the heterogeneity of the human MSCs derived from bone marrow (BMSCs), umbilical cord (UCMSCs), and adipose tissue (ADSCs) in accelerating wound healing and promoting angiogenesis and explored the underlying mechanism. Briefly, a diabetic rat model with a full-thickness cutaneous wound on the dorsal foot was developed. The wound was topically administered with three types of MSCs. Additionally, we carried out in vitro and in vivo analysis of the angiogenic properties of the MSCs. Moreover, the molecular mechanism of the heterogeneity of the MSCs derived from the three tissues was explored by transcriptome sequencing. When compared with the BMSCs- and UCMSCs-treated groups, the ADSCs-treated group exhibited markedly accelerated healing efficiency, characterized by increased wound closure rates, enhanced angiogenesis, and collagen deposition at the wound site. The three types of MSCs formed three-dimensional capillary-like structures and promoted angiogenesis in vitro and in vivo, with ADSCs exhibiting the highest capacity for tube formation and pro-angiogenesis. Furthermore, transcriptome sequencing revealed that ADSCs had higher expression levels of angiogenesis-associated genes. Our findings indicate that MSCs-based therapy accelerates the healing of ischemia- and diabetes-induced lower-extremity ulcers and that adipose tissue-derived MSCs might be ideal for therapeutic angiogenesis and treatment of chronic ischemic wounds.

Mesenchymal Stem Cell Transplantation in Type 1 Diabetes Treatment: Current Advances and Future Opportunity.

Type 1 Diabetes (T1D) is characterized by hyperglycemia, and caused by a lack of insulin secretion. At present there is no cure for T1D and patients are dependent on exogenous insulin for lifelong, which seriously affects their lives. Mesenchymal stem cells (MSCs) can be differentiated to β cell-like cells to rescue the secretion of insulin and reconstruct immunotolerance to preserve the function of islet β cells. Due to the higher proportion of children and adolescents in T1D patients, the efficacy and safety issue of the application of MSC's transplant in T1D was primarily demonstrated and identified by human clinical trials in this review. Then we clarified the mechanism of MSCs to relieve the symptom of T1D and found out that UC-MSCs have no obvious advantage over the other types of MSCs, the autologous MSCs from BM or menstrual blood with less expanded ex vivo could be the better choice for clinical application to treat with T1D through documentary analysis. Finally, we summarized the advances of MSCs with different interventions such as genetic engineering in the treatment of T1D, and demonstrated the advantages and shortage of MSCs intervened by different treatments in the transplantation, which may enhance the clinical efficacy and overcome the shortcomings in the application of MSCs to T1D in future.

Augmenting mesenchymal stem cell therapy for osteoarthritis via inflammatory priming: a comparative study on mesenchymal stem cells derived from various perinatal tissue sources.

Background: Osteoarthritis (OA), a degenerative disease prevalent among the elderly, poses significant challenges due to its high incidence and disability rates. Regrettably, there exists a lack of effective regenerative therapies for the irreversible degradation of cartilage in OA. Mesenchymal stem cells (MSCs), known for their robust differentiation and immune regulatory capabilities, have emerged as promising candidates for OA treatment. MSCs sourced from perinatal tissues offer the dual advantage of convenience in extraction and ethical non-controversy. However, the heterogeneous nature of MSCs derived from different perinatal tissue sources gives rise to varying therapeutic indications. Moreover, the immune response of MSCs may be modulated under the influence of inflammatory factors. Methods: In this study, we isolated mesenchymal stem cells from distinct parts of human perinatal tissue: umbilical cord-derived MSCs (UC-MSCs), fetal placenta-derived MSCs (FP-MSCs), and umbilical cord placental junction-derived MSCs (CPJ-MSCs). These cells were cultured in vitro and subjected to a 24-hour treatment with the inflammatory mediator Interleukin-1β (IL-1β). Subsequently, the MSCs were evaluated for changes in proliferation, migration, and regulatory capabilities. To assess the comparative anti-injury potential of MSCs from different sources, primary articular chondrocytes (ACs) were exposed to H2O2-induced injury and co-cultured with IL-1β-primed MSCs. Changes in the proliferation, migration, and regulatory abilities of ACs resembling those observed in OA were examined. Results: Following IL-1β treatment, all three types of MSCs displayed decreased rates of proliferation and migration. Notably, their chondrogenic differentiation capacities exhibited an enhancement. Additionally, diverse MSCs exhibited a degree of efficacy in restoring damaged ACs in vitro. Among these, CPJ-MSCs demonstrated superior potential in promoting cartilage cell proliferation, while FP-MSCs displayed notable anti-inflammatory effects. Conclusion: Our findings underscore the substantial capacity of primed FP-MSCs and CPJ-MSCs to alleviate the injury in OA-like ACs. Consequently, this study advocates for the prospective use of preconditioning strategies involving FP-MSCs and CPJ-MSCs in forthcoming OA therapies.

Advances in combined application of dental stem cells and small-molecule drugs in regenerative medicine.

Teeth are a kind of masticatory organs of special histological origin, unique to vertebrates, playing an important role in chewing, esthetics, and auxiliary pronunciation. In the past decades, with the development of tissue engineering and regenerative medicine, the studies of mesenchymal stem cells (MSCs) gradually attracted the interest of researchers. Accordingly, several types of MSCs have been successively isolated in teeth or teeth-related tissues, including dental pulp stem cells, periodontal ligament stem cells, stem cells from human exfoliated deciduous teeth, dental follicle stem cells, stem cells from apical papilla and gingival mesenchymal stem cells. These dental stem cells (DSCs) are easily accessible, possess excellent stem cell characteristics, such as high proliferation rates and profound immunomodulatory properties. Small-molecule drugs are widely used and show great advantages in clinical practice. As research progressed, small-molecule drugs are found to have various complex effects on the characteristics of DSCs, especially the enhancement of biological characteristics of DSCs, which has gradually become a hot issue in the field of DSCs research. This review summarizes the background, current status, existing problems, future research directions, and prospects of the combination of DSCs with three common small-molecule drugs: aspirin, metformin, and berberine.

857-P: Quiescence Recovers Adipose Tissue–Derived Stromal Cells from Senescence-Associated Secretory Phenotype, Leading to Enhanced Angiogenesis and Diabetic Wound Healing

Although a number of studies have shown that mesenchymal stem cells (MSCs) promote diabetic wound healing, their clinical applications are still limited. One of the reasons is that MSCs exhibit a senescence-associated secretory phenotype (SASP) in diabetes, which results in attenuation of their anti-inflammatory functions. We previously reported that adipose tissue-derived stromal cells (ADSCs), one type of MSCs used in multiple clinical trials, are able to exhibit their anti-inflammatory functions when they become quiescent in gels with a stiffness mimicking that of adipose tissue. We also showed that transplants containing quiescent ADSCs enhanced diabetic wound healing more than those containing non-quiescent ADSCs. Here, we investigated the effect of inducing quiescence in ADSCs on their angiogenic functions in a high glucose environment both in vitro and in vivo. High glucose-induced attenuated migration and tubular formation of HUVECs, an endothelial cell line, were ameliorated more significantly by conditioned medium from quiescent ADSCs cultured under high glucose than by that from non-quiescent ADSCs cultured under high glucose. Furthermore, ADSCs cultured at a high glucose level in vitro enhanced angiogenesis and wound healing in STZ-induced diabetic mice similarly to ADSCs cultured at a normal glucose level in vitro, when they were made quiescent in gels and subcutaneously injected into the mice. These results suggest that quiescence restores ADSCs from SASP and enhances angiogenesis even under diabetic conditions, which may be crucial for MSC-based cell therapies against diabetic microangiopathy. Disclosure M.Funaki: Board Member; Mechanogenic, Inc. H.Ogawa: None. T.Oya: None. A.Hata: None. M.Yoshida: None. N.Miyamoto: None. T.Ikuta: None. Y.Uemura: None. M.Akizuki: None. A.Tangoku: None. H.Yumoto: None.

Comparison of Biological Properties and Clinical Application of Mesenchymal Stem Cells from the Mesoderm and Ectoderm.

Since the discovery of mesenchymal stem cells (MSCs) in the 1970s, they have been widely used in the treatment of a variety of diseases because of their wide sources, strong differentiation potential, rapid expansion in vitro, low immunogenicity, and so on. At present, most of the related research is on mesoderm-derived MSCs (M-MSCs) such as bone marrow MSCs and adipose-derived MSCs. As a type of MSC, ectoderm-derived MSCs (E-MSCs) have a stronger potential for self-renewal, multidirectional differentiation, and immunomodulation and have more advantages than M-MSCs in some specific conditions. This paper analyzes the relevant research development of E-MSCs compared with that of M-MSCs; summarizes the extraction, discrimination and culture, biological characteristics, and clinical application of E-MSCs; and discusses the application prospects of E-MSCs. This summary provides a theoretical basis for the better application of MSCs from both ectoderm and mesoderm in the future.

Molecules Inducing Dental Stem Cells Differentiation and Bone Regeneration: State of the Art.

Teeth include mesenchymal stem cells (MSCs), which are multipotent cells that promote tooth growth and repair. Dental tissues, specifically the dental pulp and the dental bud, constitute a relevant source of multipotent stem cells, known as dental-derived stem cells (d-DSCs): dental pulp stem cells (DPSCs) and dental bud stem cells (DBSCs). Cell treatment with bone-associated factors and stimulation with small molecule compounds are, among the available methods, the ones who show excellent advantages promoting stem cell differentiation and osteogenesis. Recently, attention has been paid to studies on natural and non-natural compounds. Many fruits, vegetables, and some drugs contain molecules that can enhance MSC osteogenic differentiation and therefore bone formation. The purpose of this review is to examine research work over the past 10 years that has investigated two different types of MSCs from dental tissues that are attractive targets for bone tissue engineering: DPSCs and DBSCs. The reconstruction of bone defects, in fact, is still a challenge and therefore more research is needed; the articles reviewed are meant to identify compounds useful to stimulate d-DSC proliferation and osteogenic differentiation. We only consider the results of the research which is encouraging, assuming that the mentioned compounds are of some importance for bone regeneration.

Conditioned medium of human menstrual blood-derived endometrial stem cells protects against cell inflammation and apoptosis of Npc1KO N2a cells.

Niemann-Pick disease type C1 (NPC1) is a hereditary neurodegenerative disorder caused by a mutation in the NPC1 gene. This gene encodes a transmembrane protein found in lysosomes. This disease characterized by hepatosplenomegaly, neurological impairments and premature death. Recent preclinical studies have shown promising results in using mesenchymal stem cells (MSCs) to alleviate the symptoms of NPC1. One type of MSCs, known as human menstrual blood-derived endometrial stem cells (MenSCs), has attracted attention due to its accessibility, abundant supply, and strong proliferation and regeneration capabilities. However, it remains uncertain whether the conditioned medium of MenSCs (MenSCs-CM) can effectively relieve the symptoms of NPC1. To investigate this further, we employed the CRISPR-Cas9 technique to successfully create a Npc1 gene knockout N2a cell line (Npc1KO N2a). Sanger sequencing confirmed the occurrence of Npc1 gene mutation in these cells, while western blotting revealed a lack of NPC1 protein expression. Filipin staining provided visual evidence of unesterified cholesterol accumulation in Npc1KO N2a cells. Moreover, Npc1KO N2a cells exhibited significantly decreased viability, increased inflammation, and heightened cell apoptosis. Notably, our study demonstrated that the viability of Npc1KO N2a cells was most significantly improved after being cultured by 36h-collected MenSCs-CM for 0.5 days. Additionally, MenSCs-CM exhibited the ability to effectively reduce inflammation, counteract cell apoptosis, and ameliorate unesterified cholesterol accumulation in Npc1KO N2a cells. This groundbreaking finding establishes, for the first time, the protective effect of MenSCs-CM on N2a cells with Npc1 gene deletion. These findings suggest that the potential of MenSCs-CM as a beneficial therapeutic approach for NPC1 and other neurodegenerative diseases.

Effect of Composition of Lung Biomimetic Niche on the Mesenchymal Stem Cell Differentiation toward Alveolar Type II Pneumocytes.

Pulmonary niche dynamically orchestrates the signals, such as proliferation or differentiation of mesenchymal stem cells (MSCs), which allows inducing tissue repair. Lung niche includes extracellular matrix (ECM), comprising hyaluronic acid (HA) and collagen (COLL), and several types of MSCs. Impaired ECM, in lung pathologies, makes the promising therapies based on MSCs ineffective, as it results in a reduced attachment and homing of MSCs, precluding their differentiation and viability. To overcome this problem, in this study a pulmonary biomimetic niche based on HA and COLL hydrogel is developed, with the specific aim to elucidate the role of COLL and HA/COLL semi-interpenetrating polymer networks (SIPNs) in directing the differentiation of MSCs into Alveolar Type II (ATII) cells. The effect of low (L), medium (M), and high (H) molecular weight (MW) HA is investigated, both like structural component of the SIPNs hydrogel and like trophic factor in cell culture media solution. HA in the culture media significantly improves surfactant protein (SP)-C expression (≈2ng mL-1 ), without showing difference in the MW tested, compared to control only (≈1ng mL-1 ). Furthermore, LMWHA/COLL hydrogel promotes the SPC expression (approximately two times) compared to COLL, MMWHA/COLL, and HMWHA/COLL hydrogels.