Umbilical Cord-derived Mesenchymal Stem Cells Research Articles

In vivo SPECT imaging of Tc-99m radiolabeled exosomes from human umbilical-cord derived mesenchymal stem cells in small animals

Extracellular vesicles derived from human umbilical cord-derived mesenchymal stem cells (UCMSC-EVs) have been postulated to have therapeutic potential for various diseases. However, the biodistribution and pharmacokinetics of these vesicles are still unclear. For a better understanding of the in vivo properties of UCMSC-EVs, in the present study, these vesicles were first radiolabeled with Technetium-99m (99mTc-UCMSC-EVs) and evaluated using in vivo single photon emission computed tomography (SPECT) imaging and biodistribution experiments. SPECT images demonstrated that the liver and spleen tissues mainly took up the 99mTc-UCMSC-EVs. The biodistribution study observed slight uptake in the thyroid and stomach, indicating that 99mTc-UCMSC-EVs was stable at 24 h in vivo. The pharmacokinetic analyses of the blood half-life demonstrated the quick distribution phase (0.85 ± 0.28 min) and elimination phase (25.22 ± 20.76 min) in mice. This study provides a convenient and efficient method for 99mTc-UCMSC-EVs preparation without disturbing their properties. In conclusion, the biodistribution, quick elimination, and suitable stability in vivo of 99mTc-UCMSC-EVs were quantified by the noninvasive imaging and pharmacokinetic analyses, which provides useful information for indication selection, dosage protocol design, and toxicity assessment in future applications.

Safety and potential efficacy of expanded mesenchymal stromal cells of bone marrow and umbilical cord origins in patients with chronic spinal cord injuries: a phase I/II study

Background aimsSpinal cord injury (SCI) affects patients' physical, psychological, and social well-being. Presently, treatment modalities for chronic SCI have restricted clinical effectiveness. Mesenchymal stromal cells (MSCs) demonstrate promise in addressing nervous tissue damage. This single-center, open-label, parallel-group randomized clinical trial aimed to assess the safety and efficacy of intraoperative perilesional administration of expanded autologous bone marrow-derived MSCs (BMMSCs), followed by monthly intrathecal injections, in comparison to monthly intrathecal administration of expanded allogeneic umbilical cord-derived MSCs (UCMSCs) for individuals with chronic SCI. MethodsTwenty participants, who had a minimum of 1 year of SCI duration, were enrolled. Each participant in Group A received perilesional BMMSCs, followed by monthly intrathecal BMMSCs for three injections, while Group B received monthly intrathecal UCMSCs for three injections. Safety and efficacy were evaluated using the American Spinal Cord Injury Association (ASIA) score for at least 1 year post the final injection. Statistical analysis was conducted using the Wilcoxon signed-rank test. ResultsGroup A comprised 11 participants, while Group B included 9. The mean follow-up duration was 22.65 months. Mild short-term adverse events encompassed headaches and back pain, with no instances of long-term adverse events. Both groups demonstrated significant improvements in total ASIA scores, with Group A displaying more pronounced motor improvements. ConclusionsOur findings indicate that perilesional administration of expanded autologous BMMSCs, followed by monthly intrathecal BMMSCs for three injections, or monthly intrathecal UCMSCs for three injections appear to be safe and hold promise for individuals with chronic SCI. Nonetheless, larger-scale clinical trials are imperative to validate these observations.

The mechanisms of MicroRNA 21 in premature ovarian insufficiency mice with mesenchymal stem cells transplantation

Umbilical cord-derived mesenchymal stem cell (UCMSC) transplantation has been deeply explored for premature ovarian insufficiency (POI) disease. However, the associated mechanism remains to be researched. To explore whether and how the microRNA 21 (miR-21) functions in POI mice with UCMSCs transplantation, the autoimmune-induced POI mice model was built up, transplanted with or without UCMSCs transfect with the LV-hsa-miR-21-5p/LV-hsa-miR-21-5p-inhibition, with the transfection efficiency analyzed by QRT-PCR. Mice hormone secretion and the anti-Zona pellucida antibody (AZPAb) levels were analyzed, the ovarian morphological changes and folliculogenesis were observed, and the ovarian apoptosis cells were detected to evaluate ovarian function. The expression and localization of the PTEN/Akt/FOXO3a signal pathway-related cytokines were analyzed in mice ovaries.Additionally, the spleen levels of CD8 + CD28-T cells were tested and qualified with its significant secretory factor, interleukin 10 (IL-10). We found that with the LV-hsa-miR-21-5p-inhibition-UCMSCs transplantation, the mice ovarian function can be hardly recovered than mice with LV-NC-UCMSCs transplantation, and the PTEN/Akt/FOXO3a signal pathway was activated. The expression levels of the CD8 + CD28-T cells were decreased, with the decreased levels of the IL-10 expression. In contrast, in mice with the LV-hsa-miR-21-5p-UCMSCs transplantation, the injured ovarian function can be reversed, and the PTEN/AKT/FOXO3a signal pathway was detected activated, with the increased levels of the CD8 + CD28-T cells, and the increased serum levels of IL-10. In conclusion, miR-21 improves the ovarian function recovery of POI mice with UCMSCs transplantation, and the mechanisms may be through suppressing the PTEN/AKT/FOXO3a signal pathway and up-regulating the circulating of the CD8 + CD28-T cells.

Efficacy and safety of mesenchymal stem cell therapy for ovarian ageing in a mouse model

BackgroundOvarian ageing is one of the major issues that impacts female fertility. Mesenchymal stem cell (MSC)-based therapy has made impressive progress in recent years. However, the efficacy and safety of MSCs, as nonautologous components, remain to be further verified.MethodsTwo common sources of MSCs, umbilical cord-derived MSCs (UC-MSCs) and adipose tissue-derived MSCs (AD-MSCs), were orthotopically transplanted into a mouse model of ovarian ageing to evaluate their therapeutic effects. The safety of the treatment was further evaluated, and RNA sequencing was performed to explore the underlying mechanisms involved.ResultsAfter orthotopic transplantation of MSCs into the ovary, the oestrous cycle, ovarian weight, number and proportion of primary follicles, granulosa cell proliferation, and angiogenesis were improved. The effects of AD-MSCs were superior to those of UC-MSCs in several indices, such as post-transplant granulosa cell proliferation, ovarian weight and angiogenesis. Moreover, the tumorigenesis, acute toxicity, immunogenicity and biodistribution of MSCs were evaluated, and both AD-MSCs and UC-MSCs were found to possess high safety profiles. Through RNA sequencing analysis, enhancement of the MAPK cascade was observed, and long-term effects were mainly linked to the activation of immune function.ConclusionsOrthotopic transplantation of MSCs displays significant efficacy and high safety for the treatment of ovarian ageing in mice.

Single-Cell RNA Sequencing Reveals Repair Features of Human Umbilical Cord Mesenchymal Stromal Cells.

Rationale: The chronic lung disease bronchopulmonary dysplasia (BPD) is the most severe complication of extreme prematurity. BPD results in impaired lung alveolar and vascular development and long-term respiratory morbidity, for which only supportive therapies exist. Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) improve lung structure and function in experimental BPD. Results of clinical trials with MSCs for many disorders do not yet match the promising preclinical studies. A lack of specific criteria to define functionally distinct MSCs persists. Objectives: To determine and correlate single-cell UC-MSC transcriptomic profiles with therapeutic potential. Methods: UC-MSCs from five term donors and human neonatal dermal fibroblasts (HNDFs; control cells of mesenchymal origin) transcriptomes were investigated using single-cell RNA sequencing (scRNA-seq) analysis. The lung-protective effect of UC-MSCs with a distinct transcriptome and control HNDFs was tested invivo in hyperoxia-induced neonatal lung injury in rats. Measurements and Main Results: UC-MSCs showed limited transcriptomic heterogeneity but were different from HNDFs. Gene Ontology enrichment analysis revealed distinct (progenitor-like and fibroblast-like) UC-MSC subpopulations. Only treatment with progenitor-like UC-MSCs improved lung function and structure and attenuated pulmonary hypertension in hyperoxia-exposed rat pups. Moreover, scRNA-seq identified major histocompatibility complex class I as a molecular marker of nontherapeutic cells and associated with decreased lung retention. Conclusions: UC-MSCs with a progenitor-like transcriptome, but not with a fibroblast-like transcriptome, provide lung protection in experimental BPD. High expression of major histocompatibility complex class I is associated with reduced therapeutic benefit. scRNA-seq may be useful to identify subsets of MSCs with superior repair capacity for clinical application.

Human umbilical cord-derived mesenchymal stem cells and auto-crosslinked hyaluronic acid gel complex for treatment of intrauterine adhesion.

The purpose of this study was to explore the therapeutic characteristics of mesenchymal stem cells generated from human umbilical cord (hUC-MSCs) when utilized in conjunction with auto-crosslinked hyaluronic acid gel (HA-gel) for the management of intrauterine adhesion (IUA). The goal was to see how this novel therapy could enhance healing and improve outcomes for IUA patients. In this study, models of intrauterine adhesion (IUA) were established in Sprague-Dawley (SD) rats, which were then organized and divided into hUC-MSCs groups. The groups involved: hUC-MSCs/HA-gel group, control group, and HA-gel group. Following treatment, the researchers examined the uterine cavities and performed detailed analyses of the endometrial tissues to determine the effectiveness of the interventions. The results indicated that in comparison with to the control group, both HA-gel, hUC-MSCs, and hUC-MSCs/HA-gel groups showed partial repair of IUA. However, in a more notable fashion transplantation of hUC-MSCs/HA-gel complex demonstrated significant dual repair effects. Significant outcomes were observed in the group treated with hUC-MSCs and HA-gel, they showed thicker endometrial layers, less fibrotic tissue, and a higher number of endometrial glands. This treatment strategy also resulted in a significant improvement in fertility restoration, indicating a profound therapeutic effect. The findings of this study suggest that both HA-gel, hUC-MSCs, and hUC-MSCs/HA-gel complexes have the potential for partial repair of IUA and fertility restoration caused by endometrium mechanical injury. Nonetheless, the transplantation of the hUC-MSCs/HA-gel complex displayed exceptional dual healing effects, combining effective anti-adhesive properties with endometrial regeneration stimuli.

Isolation, Biological Characterization, and Quality Inspection of Human Umbilical Cord-derived Mesenchymal Stem Cells for Clinical Research

Background: Human umbilical cord mesenchymal stem cells (hUCMSCs) represent a valuable and versatile cell type derived from the umbilical cord tissue of newborns. These cells exhibit diverse characteristics, including multipotent differentiation potential and low immunogenicity. hUCMSCs hold promise for clinical applications, yet concerns persist regarding their chromosomal stability. This study employs short tandem repeat (STR) analysis to assess genomic integrity. By focusing on chromosomal stability, the study aims to enhance confidence in the clinical viability of hUCMSCs, contributing to their safe and effective use in regenerative medicine. hUCMSCs were extracted from healthy newborn umbilical cords using tissue block adherence and enzyme digestion. The third generation of hUCMSCs undergoes biological characterization and quality checks, including examinations of cell morphology, viability, growth curves, surface markers, cell cycle, and multi-lineage differentiation potential. The result of the present study shows that hUCMSCs exhibit mesenchymal stem cell characteristics, with robust growth and high viability. Positive surface markers are expressed at rates exceeding 95%, while negative markers are ≤2%. Cell karyotyping analysis, STR spectrum identification, and chromosomal microarray analysis confirm genetic stability. Microbial testing shows the absence of contaminants, and immunological studies demonstrate the immunomodulatory capabilities of hUCMSCs. Specific residues, such as trypsin, were not detected. In conclusion, hUCMSCs produced under strict GLP and GMP conditions meet the quality guidelines for clinical application in various stem cell therapies. The findings support the clinical application of hUCMSCs in various medical contexts.

Superior migration ability of umbilical cord-derived mesenchymal stromal cells (MSCs) toward activated lymphocytes in comparison with those of bone marrow and adipose-derived MSCs.

Introduction: Mesenchymal stromal cells (MSCs) are activated upon inflammation and/or tissue damage and migrate to suppress inflammation and repair tissues. Migration is the first important step for MSCs to become functional; however, the migration potency of umbilical cord-derived MSCs (UC-MSCs) remains poorly understood. Thus, we aimed to assess the migration potency of UC-MSCs in comparison with those of bone marrow-derived MSCs (BM-MSCs) and adipose tissue-derived MSCs (AD-MSCs) and investigate the influence of chemotactic factors on the migration of these cells. Methods: We compared the migration potencies of UC-, BM-, and AD-MSCs toward allogeneic stimulated mononuclear cells (MNCs) in mixed lymphocyte reaction (MLR). The number of MSCs in the upper chamber that migrated toward the MLR in the lower chamber was counted using transwell migration assay. Results and discussion: UC-MSCs showed significantly faster and higher proliferation potencies and higher migration potency toward unstimulated MNCs and MLR than BM- and AD-MSCs, although the migration potencies of the three types of MSCs were comparable when cultured in the presence of fetal bovine serum. The amounts of CCL2, CCL7, and CXCL2 in the supernatants were significantly higher in UC-MSCs co-cultured with MLR than in MLR alone and in BM- and AD-MSCs co-cultured with MLR, although they did not induce the autologous migration of UC-MSCs. The amount of CCL8 was higher in BM- and AD-MSCs than in UC-MSCs, and the amount of IP-10 was higher in AD-MSCs co-cultured with MLR than in UC- and BM-MSCs. The migration of UC-MSCs toward the MLR was partially attenuated by platelet-derived growth factor, insulin-like growth factor 1, and matrix metalloproteinase inhibitors in a dose-dependent manner. Conclusion: UC-MSCs showed faster proliferation and higher migration potency toward activated or non-activated lymphocytes than BM- and AD-MSCs. The functional chemotactic factors may vary among MSCs derived from different tissue sources, although the roles of specific chemokines in the different sources of MSCs remain to be resolved.

Repeated intravenous doses of human umbilical cord-derived mesenchymal stromal cells for bronchopulmonary dysplasia: results of a phase 1 clinical trial with 2-year follow-up

BackgroundCurrently, there is a lack of effective treatments or preventive strategies for bronchopulmonary dysplasia (BPD). Pre-clinical studies with mesenchymal stromal cells (MSCs) have yielded encouraging results. The safety of administering repeated intravenous doses of umbilical cord tissue-derived mesenchymal stromal cells (UC-MSCs) has not yet been tested in extremely-low-gestational-age newborns (ELGANs). Aimsto test the safety and feasibility of administering three sequential intravenous doses of UC-MSCs every 7 days to ELGANs at risk of developing BPD. Methods: In this phase 1 clinical trial, we recruited ELGANs (birth weight ≤1250 g and ≤28 weeks in gestational age [GA]) who were on invasive mechanical ventilation (IMV) with FiO2 ≥ 0.3 at postnatal days 7–14. Three doses of 5 × 106/kg of UC-MSCs were intravenously administered at weekly intervals. Adverse effects and prematurity-related morbidities were recorded. ResultsFrom April 2019 to July 2020, 10 patients were recruited with a mean GA of 25.2 ± 0.8 weeks and a mean birth weight of 659.8 ± 153.8 g. All patients received three intravenous UC-MSC doses. The first dose was administered at a mean of 16.6 ± 2.9 postnatal days. All patients were diagnosed with BPD. All patients were discharged from the hospital. No deaths or any serious adverse events related to the infusion of UC-MSCs were observed during administration, hospital stays or at 2-year follow-up. ConclusionsThe administration of repeated intravenous infusion of UC-MSCs in ELGANs at a high risk of developing BPD was feasible and safe in the short- and mid-term follow-up.

Comparative analysis of effects of conditioned mediums obtained from 2D or 3D cultured mesenchymal stem cells on kidney functions of diabetic rats: Early intervention could potentiate transdifferentiation of parietal epithelial cell into podocyte precursors

AimThe secretome of mesenchymal stem cells (MSCs) could be a potential therapeutic intervention for diabetes and associated complications like nephropathy. This study aims to evaluate the effects of conditioned mediums (CMs) collected from umbilical cord-derived MSCs incubated under 2-dimensional (2D) or 3D culture conditions on kidney functions of rats with type-I diabetes (T1D). Main methodsSprague-Dawley rats were treated with 20 mg/kg streptozocin for 5 consecutive days to induce T1D, and 12 doses of CMs were applied intraperitoneally for 4 weeks. The therapeutic effects of CMs were comparatively investigated by biochemical, physical, histopathological, and immunohistochemical analysis. Key findings3D-CM had significantly higher total protein concentration than the 2D-CM Albumin/creatinine ratios of both treatment groups were significantly improved in comparison to diabetes. Light microscopic evaluations showed that glomerular and cortical tubular damages were significantly ameliorated in only the 3D-CM applied group compared to the diabetes group, which were correlated with transmission electron microscopic observations. The nephrin and synaptopodin expressions increased in both treatment groups compared to diabetes. The WT1, Ki-67, and active caspase-3 expressions in glomeruli and parietal layers of the treatment groups suggest that both types of CMs suppress apoptosis and promote possible parietal epithelial cells' (PECs') transdifferentiation towards podocyte precursor cells by switching on WT1 expression in parietal layer rather than inducing new cell proliferation. Significance3D-CM was found to be more effective in improving kidney functions than 2D-CM by ameliorating glomerular damage through the possible mechanism of transdifferentiation of PECs into podocyte precursors and suppressing glomerular apoptosis.

Transplantation of the LRP1high subpopulation of human umbilical cord-derived mesenchymal stem cells improves ovarian function in mice with premature ovarian failure and aged mice

BackgroundPremature ovarian failure (POF) has a profound impact on female reproductive and psychological health. In recent years, the transplantation of umbilical cord-derived mesenchymal stem cells (UC-MSCs) has demonstrated unprecedented potential in the treatment of POF. However, the heterogeneity of human UC-MSCs remains a challenge for their large-scale clinical application. Therefore, it is imperative to identify specific subpopulations within UC-MSCs that possess the capability to improve ovarian function, with the aim of reducing the uncertainty arising from the heterogeneity while achieving more effective treatment of POF.Methods10 × Genomics was performed to investigate the heterogeneity of human UC-MSCs. We used LRP1 as a marker and distinguished the potential therapeutic subpopulation by flow cytometry, and determined its secretory functions. Unsorted UC-MSCs, LRP1high and LRP1low subpopulation was transplanted under the ovarian capsules of aged mice and CTX-induced POF mice, and therapeutic effects was evaluated by assessing hormone levels, estrous cycles, follicle counts, and embryo numbers. RNA sequencing on mouse oocytes and granulosa cells after transplantation was performed to explore the mechanism of LRP1high subpopulation on mouse oocytes and granulosa cells.ResultsWe identified three distinct functional subtypes, including mesenchymal stem cells, multilymphoid progenitor cells and trophoblasts. Additionally, we identified the LRP1high subpopulation, which improved ovarian function in aged and POF mice. We elucidated the unique secretory functions of the LRP1high subpopulation, capable of secreting various chemokines, cytokines, and growth factors. Furthermore, LRP1 plays a crucial role in regulating the ovarian microenvironment, including tissue repair and extracellular matrix remodeling. Consistent with its functions, the transcriptomes of oocytes and granulosa cells after transplantation revealed that the LRP1high subpopulation improves ovarian function by modulating the extracellular matrix of oocytes, NAD metabolism, and mitochondrial function in granulosa cells.ConclusionThrough exploration of the heterogeneity of UC-MSCs, we identified the LRP1high subpopulation capable of improving ovarian function in aged and POF mice by secreting various factors and remodeling the extracellular matrix. This study provides new insights into the targeted exploration of human UC-MSCs in the precise treatment of POF.Graphical abstract

Amelioration of diabetic nephropathy in mice by a single intravenous injection of human mesenchymal stromal cells at early and later disease stages is associated with restoration of autophagy

Background and aimsMesenchymal stromal cells (MSCs) a potentially effective disease-modulating therapy for diabetic nephropathy (DN) but their clinical translation has been hampered by incomplete understanding of the optimal timing of administration and in vivo mechanisms of action. This study aimed to elucidate the reno-protective potency and associated mechanisms of single intravenous injections of human umbilical cord-derived MSCs (hUC-MSCs) following shorter and longer durations of diabetes.MethodsA streptozotocin (STZ)-induced model of diabetes and DN was established in C57BL/6 mice. In groups of diabetic animals, human (h)UC-MSCs or vehicle were injected intravenously at 8 or 16 weeks after STZ along with vehicle-injected non-diabetic animals. Diabetes-related kidney abnormalities was analyzed 2 weeks later by urine and serum biochemical assays, histology, transmission electron microscopy and immunohistochemistry. Serum concentrations of pro-inflammatory and pro-fibrotic cytokines were quantified by ELISA. The expression of autophagy-related proteins within the renal cortices was investigated by immunoblotting. Bio-distribution of hUC-MSCs in kidney and other organs was evaluated in diabetic mice by injection of fluorescent-labelled cells.ResultsCompared to non-diabetic controls, diabetic mice had increases in urine albumin creatinine ratio (uACR), mesangial matrix deposition, podocyte foot process effacement, glomerular basement membrane thickening and interstitial fibrosis as well as reduced podocyte numbers at both 10 and 18 weeks after STZ. Early (8 weeks) hUC-MSC injection was associated with reduced uACR and improvements in multiple glomerular and renal interstitial abnormalities as well as reduced serum IL-6, TNF-α, and TGF-β1 compared to vehicle-injected animals. Later (16 weeks) hUC-MSC injection also resulted in reduction of diabetes-associated renal abnormalities and serum TGF-β1 but not of serum IL-6 and TNF-α. At both time-points, the kidneys of vehicle-injected diabetic mice had higher ratio of p-mTOR to mTOR, increased abundance of p62, lower abundance of ULK1 and Atg12, and reduced ratio of LC3B to LC3A compared to non-diabetic animals, consistent with diabetes-associated suppression of autophagy. These changes were largely reversed in the kidneys of hUC-MSC-injected mice. In contrast, neither early nor later hUC-MSC injection had effects on blood glucose and body weight of diabetic animals. Small numbers of CM-Dil-labeled hUC-MSCs remained detectable in kidneys, lungs and liver of diabetic mice at 14 days after intravenous injection.ConclusionsSingle intravenous injections of hUC-MSCs ameliorated glomerular abnormalities and interstitial fibrosis in a mouse model of STZ-induced diabetes without affecting hyperglycemia, whether administered at relatively short or longer duration of diabetes. At both time-points, the reno-protective effects of hUC-MSCs were associated with reduced circulating TGF-β1 and restoration of intra-renal autophagy.Graphical abstract

Human umbilical cord mesenchymal stem cell therapy for renal dysfunction in Alport syndrome: protocol for an open-label, single-arm trial in China

IntroductionAlport syndrome (AS) is one of the most common fatal hereditary renal diseases in human, with a high risk of progressing to end-stage renal disease without effective treatments. Mesenchymal stem...

Therapeutic utility of human umbilical cord-derived mesenchymal stem cells-based approaches in pulmonary diseases: Recent advancements and prospects.

Pulmonary diseases across all ages threaten millions of people and have emerged as one of the major public health issues worldwide. For diverse disease conditions, the currently available approaches are focused on alleviating clinical symptoms and delaying disease progression but have not shown significant therapeutic effects in patients with lung diseases. Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) isolated from the human UC have the capacity for self-renewal and multilineage differentiation. Moreover, in recent years, these cells have been demonstrated to have unique advantages in the treatment of lung diseases. We searched the Public Clinical Trial Database and found 55 clinical trials involving UC-MSC therapy for pulmonary diseases, including coronavirus disease 2019, acute respiratory distress syndrome, bronchopulmonary dysplasia, chronic obstructive pulmonary disease, and pulmonary fibrosis. In this review, we summarize the characteristics of these registered clinical trials and relevant published results and explore in depth the challenges and opportunitiesfaced in clinical application. Moreover, the underlying molecular mechanisms involved in UC-MSC-based therapy for pulmonary diseases are also analyzed in depth. In brief, this comprehensive review and detailed analysis of these clinical trials can be expected to provide a scientific reference for future large-scale clinical application.

Efficacy and Safety of Umbilical Cord-Derived Mesenchymal Stromal Cell Therapy in Preclinical Models of Sepsis: A Systematic Review and Meta-analysis.

In preclinical studies, mesenchymal stromal cells (MSCs), including umbilical cord-derived MSCs (UC-MSCs), demonstrate the ability to modulate numerous pathophysiological processes related to sepsis; however, a systematic synthesis of the literature is needed to assess the efficacy of UC-MSCs for treating sepsis. To examine the effects of UC-MSCs on overall mortality (primary outcome) as well as on organ dysfunction, coagulopathy, endothelial permeability, pathogen clearance, and systemic inflammation (secondary outcomes) at prespecified time intervals in preclinical models of sepsis. A systematic search was conducted on Embase, Ovid MEDLINE, and Web of Science up to June 20, 2023. Preclinical controlled studies using in vivo sepsis models with systemic UC-MSC administration were included. Meta-analyses were conducted and expressed as odds ratios (OR) and ratios of the weighted means with 95% CI for categorical and continuous data, respectively. Risk of bias was assessed with the SYRCLE tool. Twenty-six studies (34 experiments, n = 1258 animals) were included in this review. Overall mortality was significantly reduced with UC-MSC treatment as compared to controls (OR: 0.26, 95% CI: 0.18-0.36). At various prespecified time intervals, UC-MSCs reduced surrogate measures of organ dysfunction related to the kidney, liver, and lung; reduced coagulopathy and endothelial permeability; and enhanced pathogen clearance from multiple sites. UC-MSCs also modulated systemic inflammatory mediators. No studies were rated as low risk across all SYCLE domains. These results demonstrate the efficacy of UC-MSC treatment in preclinical sepsis models and highlight their potential as a therapeutic intervention for septic shock.

Assessment of the proteome profile of decellularized human amniotic membrane and its biocompatibility with umbilical cord-derived mesenchymal stem cells.

Extracellular matrix-based bio-scaffolds are useful for tissue engineering as they retain the unique structural, mechanical, and physiological microenvironment of the tissue thus facilitating cellular attachment and matrix activities. However, considering its potential, a comprehensive understanding of the protein profile remains elusive. Herein, we evaluate the impact of decellularization on the human amniotic membrane (hAM) based on its proteome profile, physicochemical features, as well as the attachment, viability, and proliferation of umbilical cord-derived mesenchymal stem cells (hUC-MSC). Proteome profiles of decellularized hAM (D-hAM) were compared with hAM, and gene ontology (GO) enrichment analysis was performed. Proteomic data revealed that D-hAM retained a total of 249 proteins, predominantly comprised of extracellular matrix proteins including collagens (collagen I, collagen IV, collagen VI, collagen VII, and collagen XII), proteoglycans (biglycan, decorin, lumican, mimecan, and versican), glycoproteins (dermatopontin, fibrinogen, fibrillin, laminin, and vitronectin), and growth factors including transforming growth factor beta (TGF-β) and fibroblast growth factor (FGF) while eliminated most of the intracellular proteins. Scanning electron microscopy was used to analyze the epithelial and basal surfaces of D-hAM. The D-hAM displayed variability in fibril morphology and porosity as compared with hAM, showing loosely packed collagen fibers and prominent large pore areas on the basal side of D-hAM. Both sides of D-hAM supported the growth and proliferation of hUC-MSC. Comparative investigations, however, demonstrated that the basal side of D-hAM displayed higher hUC-MSC proliferation than the epithelial side. These findings highlight the importance of understanding the micro-environmental differences between the two sides of D-hAM while optimizing cell-based therapeutic applications.

The Role of the Notch Signaling Pathway in the Differentiation of Human Umbilical Cord-Derived Mesenchymal Stem Cells.

Human umbilical cord mesenchymal stem cells (hUCMSCs) exhibit potent self-renewal and multilineage differentiation characteristics. They have garnered substantial attention within the domain of regenerative medicine owing to their therapeutic potential, such as in tissue repair, regeneration, immunomodulation, anti-inflammation, angiogenesis, wound healing, neuroprotection, and neuroregeneration. The process of fate determination is initiated by multiple signaling molecules. During development and tissue homeostasis, the Notch signaling pathway assumes a pivotal function in cell differentiation and the renewal of stem cells. A growing body of research has revealed that the Notch signaling pathwayplays a pivotal role in hUCMSC proliferation and differentiation. The latest progress concerning the crucial functions of the Notch signaling pathway in maintaining homeostasis and determining the cell fate of hUCMSCs is summarized. Furthermore, the authors also summarized the mediators related to the Notch signaling pathway in hUCMSC differentiation, as well as the pathway alterations and mechanisms involved in hUCMSC therapy.

Comparison of the Efficacy of Human Umbilical Cord-Derived and Bone Marrow Aspirate Concentrate Mesenchymal Stem Cells for Cartilage Repair Defects of the Knee via Arthroscopic Implementation on Scaffolds in a Retrospective Study.

Injuries to the articular cartilage of the human knee joint, commonly resulting from trauma, inflammation, or age- and activity-related wear and tear, have significant implications, primarily leading to osteoarthritis (OA). Conservative treatments for such injuries often yield suboptimal clinical outcomes. Surgical interventions using current methods may not consistently provide satisfactory results, largely due to the formation of low-quality scar tissue lacking the biomechanical properties of hyaline cartilage. In this retrospective study, we compared the results of two promising methods for regenerating cartilage defects in the knee joints using scaffolds soaked with stem cells of different origins: bone marrow aspirate concentrate mesenchymal stem cells (BMAC-MSCs) and human umbilical cord-derived mesenchymal stem cells (hUCB-MSCs). We evaluated 39 patients (39 knees, hUCB-MSCs: 20 knees, BMAC: 19 knees) at the 12-month follow-up using VAS, KOOS, Lysholm scales and radiologically with M-MOCART 2.0 score. The analysis demonstrated substantial overall improvement in both groups, notably reflected in enhanced quality of life for the patients. Interestingly, the final scores in the hUCB-MSCs group were comparable to those in the BMAC-MSCs group, with no statistically significant differences observed, despite variations in preoperative age and lesion size. Notably, the hUCB-MSCs group consisted of significantly older individuals with larger lesion sizes. Both procedures were found to be safe, and improvement was observed in both groups, which holds promise for future clinical investigations.

TC14012 enhances the anti-fibrosis effects of UC-MSCs on the liver by reducing collagen accumulation and ameliorating inflammation

BackgroundMesenchymal stem cells (MSCs) are attracting attention as a promising cell-based therapy for the treatment of liver fibrosis or cirrhosis. However, the strategies and potential mechanisms of MSCs therapy need further investigation. The CXCL12/CXCR4/CXCR7 chemokine axis is well known to regulate cell migration and is involved in the regulation of liver fibrosis. This study aims to treat MSCs with a CXCR7-specific agonist to evaluate its therapeutic effects on hepatic fibrosis and potential mechanisms.MethodsTC14012, a potent agonist of CXCR7, has been used to pretreat human umbilical cord-derived MSCs (UC-MSCs) and assess its effect on proliferation, apoptosis, migration, immunoregulation, and gene regulatory network. Then, CCl4-induced liver fibrosis mice models were used to evaluate the therapeutic effect and mechanism of TC14012-treated UC-MSCs for treating hepatic fibrosis.ResultsTC14012 increased CXCR7 expression in UC-MSCs. Notably, co-culture of liver sinusoidal endothelial cells (LSEC) with TC14012-pretreated UC-MSCs increased CXCR7 expression in LSEC. Additionally, TC14012 promoted cell migration and mediated the immunoregulation of UC-MSCs. Compared to UC-MSCs without TC14012 pretreatment, UC-MSCs treated with TC14012 ameliorated live fibrosis by restoring CXCR7 expression, reducing collagen fibril accumulation, inhibiting hepatic stellate cells activation, and attenuating the inflammatory response.ConclusionThis study suggests that TC14012 pretreatment can enhance the therapeutic effects of UC-MSCs on liver fibrosis, mainly by promoting the migration and immunoregulation of MSCs.

A Phase I Dose-Escalation Clinical Trial to Assess the Safety and Efficacy of Umbilical Cord-Derived Mesenchymal Stromal Cells in Knee Osteoarthritis.

Osteoarthritis (OA) is the most common degenerative joint disease. Mesenchymal stromal cells (MSC) are promising cell-based therapy for OA. However, there is still a need for additional randomized, dose-dependent studies to determine the optimal dose and tissue source of MSC for improved clinical outcomes. Here, we performed a dose-dependant evaluation of umbilical cord (UC)-derived MSC (Celllistem) in a murine model and in knee OA patients. For the preclinical study, a classical dose (200.000 cells) and a lower dose (50.000 cells) of Cellistem were intra-articularly injected into the mice knee joints. The results showed a dose efficacy response effect of Cellistem associated with a decreased inflammatory and degenerative response according to the Pritzker OARSI score. Following the same approach, the dose-escalation phase I clinical trial design included 3 sequential cohorts: low-dose group (2 × 106 cells), medium-dose group (20 × 106), and high-dose group (80 × 106). All the doses were safe, and no serious adverse events were reported. Nonetheless, 100% of the patients injected with the high-dose experienced injection-related swelling in the knee joint. According to WOMAC total outcomes, patients treated with all doses reported significant improvements in pain and function compared with baseline after 3 and 6 months. However, the improvements were higher in patients treated with both medium and low dose as compared to high dose. Therefore, our data demonstrate that the intra-articular injection of different doses of Cellistem is both safe and efficient, making it an interesting therapeutic alternative to treat mild and symptomatic knee OA patients. Trial registration ClinicalTrials.gov NCT03810521.