Mesenchymal Stem Cell Transplantation Research Articles

Activation of cellular antioxidative stress and migration activities by purified components from immortalized stem cells from human exfoliated deciduous teeth

Although stem cell-based regenerative medicine has been extensively studied, it remains difficult to reconstruct three dimensional tissues and organs in combination with vascular systems in vitro. One clinically successful therapy is transplantation of mesenchymal stem cells (MSC) into patients with graft versus host disease. However, transplanted cells are immediately damaged and destroyed because of innate immune reactions provoked by thrombogenic inflammation, and patients need to take immunosuppressive drugs for the immunological regulation of allogeneic cells. This reduces the benefits of stem cell transplantation. Therefore, alternative therapies are more realistic options for clinical use. In this study, we aimed to take advantage of the therapeutic efficacy of MSC and use multiple cytokines released from MSC, that is, stem cells from human exfoliated deciduous teeth (SHEDs). Here, we purified components from conditioned media of immortalized SHED (IM-SHED-CM) and evaluated the activities of intracellular dehydrogenase, cell migration, and antioxidative stress by studying the cells. The immortalization of SHED could make the stable supply of CM possible. We found that the fractionated component of 50–100 kD from IM-SHED-CM had higher efficacy than the original IM-SHED-CM in terms of intracellular dehydrogenase and cell migration in which intracellular signal transduction was activated via receptor tyrosine kinases, and the glutathione peroxidase and reductase system was highly active. Although antioxidative stress activities in the fractionated component of 50–100 kD had slightly lower than that of original IM-SHE-CM, the fraction still had the activity. Thus, the use of fractionated components of 50–100 kD from IM-SHED-CM could be an alternative choice for MSC transplantation because the purified components from CM could maintain the effect of cytokines from SHED.

The Effect of Exercise on Mesenchymal Stem Cells and their Application in Obesity Treatment.

Mesenchymal stem cells (MSCs) have demonstrated considerable potential in tissue repair and the treatment of immune-related diseases, but there are problems with homing efficiency during MSCs transplantation. Exercise, as an intervention, has been shown to have an important impact on the properties of MSCs. This review summarizes the effects of exercise on the properties (including proliferation, apoptosis, differentiation, and homing) of bone marrow-derived MSCs and adipose-derived MSCs. Studies indicated that exercise enhances bone marrow-derived MSCs proliferation, osteogenic differentiation, and homing while reducing adipogenic differentiation. For adipose-derived MSCs, exercise enhances proliferation and reduces adipogenic differentiation. In addition, studies have investigated the therapeutic effects of combined therapy of MSCs transplantation with exercise on diseases of the bone, cardiac, and nervous systems. The combined therapy improves tissue repair by increasing the homing of transplanted MSCs and cytokine secretion (such as neurotrophin 4). Furthermore, MSCs transplantation also has potential for the treatment of obesity. Although the effect is not significant in weight loss, MSCs transplantation shows effects in controlling blood glucose, improving dyslipidemia, reducing inflammation, and improving liver disease. Finally, the potential role of combined MSCs transplantation and exercise therapy in addressing obesity is discussed.

Exosome-mediated Repair of Intervertebral Disc Degeneration: The Potential Role of miRNAs.

Intervertebral disc degeneration (IVDD) is a serious condition that manifests as low back pain, intervertebral disc protrusion, and spinal canal stenosis. At present, the main treatment methods for IVDD are surgical interventions such as discectomy, total disc replacement, and spinal fusion. However, these interventions have shown limitations, such as recurrent lumbar disc herniation after discectomy, lesions in adjacent segments, and failure of fixation. To overcome these shortcomings, researchers have been exploring stem cell transplantation therapy, such as mesenchymal stem cell (MSC) transplantation, but the treatment results are still controversial. Therefore, researchers are in search of new methods that are more efficient and have better outcomes. The exosomes from stem cells contain a variety of bioactive molecules that mediate cell interactions, and these components have been investigated for their potential therapeutic role in the repair of various tissue injuries. Recent studies have shown that MSC-derived miRNAs in exosomes and vesicles have therapeutic effects on nucleus pulposus cells, annulus fibrosus, and cartilage endplate. miRNAs play a role in many cell activities, such as cell proliferation, apoptosis, and cytokine release, by acting on mRNA translation, and they may have immense therapeutic potential, especially when combined with stem cell therapy. This article reviews the current status of research on intervertebral disc repair, especially with regard to the latest research findings on the molecular biological mechanisms of miRNAs in MSC-derived exosomes in intervertebral disc repair.

Controversies regarding transplantation of mesenchymal stem cells.

Mesenchymal stem cells (MSCs) have tantalized regenerative medicine with their therapeutic potential, yet a cloud of controversies looms over their clinical transplantation. This comprehensive review navigates the intricate landscape of MSC controversies, drawing upon 15 years of clinical experience and research. We delve into the fundamental properties of MSCs, exploring their unique immunomodulatory capabilities and surface markers. The heart of our inquiry lies in the controversial applications of MSC transplantation, including the perennial debate between autologous and allogeneic sources, concerns about efficacy, and lingering safety apprehensions. Moreover, we unravel the enigmatic mechanisms surrounding MSC transplantation, such as homing, integration, and the delicate balance between differentiation and paracrine effects. We also assess the current status of clinical trials and the ever-evolving regulatory landscape. As we peer into the future, we examine emerging trends, envisioning personalized medicine and innovative delivery methods. Our review provides a balanced and informed perspective on the controversies, offering readers a clear understanding of the complexities, challenges, and potential solutions in MSC transplantation.

Intra-bone marrow mesenchymal stem cell transplantation modulates myeloid bias tendency of hematopoietic stem and progenitor cells in severe MRL/lpr lupus mice

The hematopoietic homeostasis in the bone marrow is inextricably intertwined with the immune milieu in peripheral circulation. Researches investigating the pathogenesis of systemic lupus erythematosus (SLE) have defined considerable secretion of inflammatory mediators and activation of pro-inflammatory cells. However, the impacts of “extrinsic” factors on hematopoietic stem and progenitor cells (HSPCs) remain unclear, and it is uncertain whether treatments can help coordinate the biased differentiation. In this study, we showed differences in the proportions of common myeloid progenitors (CMP) and myeloid output in the bone marrow of premorbid and morbid MRL/lpr mice using flow cytometry. RNA-seq analysis of lineage-affiliated transcriptional factors and dysregulated genes within lin- HSPCs revealed inflammation potentiation during disease progression. Further, intra-bone marrow mesenchymal stem cells transplantation (IBM-MSCT) partially coordinated myeloid generation and counteracted lupus-associated inflammation gene alterations, compared to intravenous injection. Additionally, co-culturing with umbilical cord mesenchymal stem cells (UC-MSCs) intervened in myeloid lineage tendency, as detected by RT-qPCR of myeloid-related genes. Our research demonstrated enhanced tendency toward myeloid differentiation and highlighted the feasibility of IBM-MSCT for lineage-biased HSPCs in MRL/lpr lupus model, providing novel insight into hematopoiesis and MSC-related treatments for SLE.

Development of gelatin-methacryloyl composite carriers for bone morphogenetic Protein-2 delivery: A potential strategy for spinal fusion.

To reduce the risk of nonunion after spinal fusion surgery, the in situ transplantation of bone marrow mesenchymal stem cells (BMSCs) induced toward osteogenic differentiation by bone morphogenetic protein-2 (BMP2) has been proven effective. However, the current biological agents used for transplantation have limitations, such as a short half-life and low bioavailability. To address this, our study utilized a safe and effective gelatin-methacryloyl (GelMA) as a carrier for BMP2. In vitro, experiments were conducted to observe the ability of this composite vehicle to induce osteogenic differentiation of BMSCs. The results showed that the GelMA hydrogel, with its critical properties and controlled release performance of BMP2, exhibited a slow release of BMP2 over 30 days. Moreover, the GelMA hydrogel not only enhanced the proliferation activity of BMSCs but also significantly promoted their osteogenic differentiation ability, surpassing the BMP2 effects. To investigate the potential of the GelMA-BMP2 composite vehicle, a rabbit model was employed to explore its ability to induce in situ intervertebral fusion by BMSCs. Transplantation experiments in rabbits demonstrated the effective induction of intervertebral bone fusion by the GelMA-BMP2-BMSC composite vehicle. In conclusion, the GelMA-BMP2-BMSC composite vehicle shows promising prospects in preclinical translational therapy for spinal intervertebral fusion. It addresses the limitations of current biological agents and offers a controlled release of BMP2, enhancing the proliferation and osteogenic differentiation of BMSCs.

Effectiveness of cell therapy of acute radiation syndrome in mice with intravenous and intraperitoneal administration of a cellular product

The therapeutic effect of fibroblast-like cells obtained from the stromal vascular fraction of subcutaneous adipose tissue of mice and cultured for the treatment of bone marrow form of acute radiation syndrome was studied on a mouse experimental model. The cells were identified as multipotent mesenchymal stem (stromal) cells, owing to adhesion to plastic, confluent monolayer formation during cultivation, and the fact that osteogenic differentiation in vitro resulted in osteoblast maturation and calcium deposit formation, which indicated their multipotent nature. Irradiation of laboratory rodents was conducted using theX-ray therapy unit “RUM-17”. Stromal cells were obtained from subcutaneous adipose tissue of a mouse and grown in a culture of 3–4 passages and used as a cell product. Cell transplantation was performed 24 h after uniformX-ray irradiation of mice at a dose of 7.8 Gy. This is the first study to compare the therapeutic efficacy of allogeneic transplantation of multipotent mesenchymal stem cells with the different routes (intravenous and intraperitoneal) of cell suspension administration. A significant increase was found in the survival rate of mice during the 30-day follow-up period after lethal dose irradiation, which depended on the number of injected cells and delivery method of the biomedical cell product. Thus, with intravenous administration of 30 and 60 × 103multipotent mesenchymal stem cells, the 30-day survival rate of mice after irradiation at a dose of 7.8 Gy increased by 54.5% and 40%, respectively, compared with that of untreated animals (p= 0.03). An increase in the number of cells in the cell product to 120 × 103/mouse led to a decrease in therapy effectiveness. In intraperitoneal administration, the protection of animals from death was 57% after transplantation of 30 and 60 × 103cells (p= 0.039) and 50% after application of 120 × 103cells. On day 30 after irradiation, in the introduction of a cellular product in different schemes, 70%–80% of animals showed restoration of the values of the main indicators of the hematopoiesis system to initial levels. Thus, cell therapy using multipotent mesenchymal stem cells isolated from adipose tissue with intravenous and intraperitoneal delivery routes of the cellular product to the irradiated body protects mice from death after exposure toX-ray radiation in lethal doses, decreasing the severity of radiation damage to the hematopoietic system in mice, and provides prospects for further research as an effective and safe treatment for acute radiation sickness.

Transplantation of olfactory mucosa mesenchymal stromal cells repairs spinal cord injury by inducing microglial polarization.

Animal studies OBJECTIVES: To evaluate the therapeutic effect of olfactory mucosa mesenchymal stem cell (OM-MSCs) transplantation in mice with spinal cord injury (SCI) and to explore the mechanism by which OM-MSCs inhibit neuroinflammation and improve SCI. Xiangya Hospital, Central South University; Affiliated Hospital of Guangdong Medical University. Mice (C57BL/6, female, 6-week-old) were randomly divided into sham, SCI, and SCI + OM-MSC groups. The SCI mouse model was generated using Allen's method. OM-MSCs were immediately delivered to the lateral ventricle after SCI using stereotaxic brain injections. One day prior to injury and on days 1, 5, 7, 14, 21, and 28 post-injury, the Basso Mouse Scale and Rivlin inclined plate tests were performed. Inflammation and microglial polarization were evaluated using histological staining, immunofluorescence, and qRT-PCR. OM-MSCs originating from the neuroectoderm have great potential in the management of SCI owing to their immunomodulatory effects. OM-MSCs administration improved motor function, alleviated inflammation, promoted the transformation of the M1 phenotype of microglia into the M2 phenotype, facilitated axonal regeneration, and relieved spinal cord injury in SCI mice. OM-MSCs reduced the level of inflammation in the spinal cord tissue, protected neurons, and repaired spinal cord injury by regulating the M1/M2 polarization of microglia.

Stem cell grafts enhance endogenous extracellular vesicle expression in the stroke brain

Endogenous brain repair occurs following an ischemic stroke but is transient, thus unable to fully mount a neuroprotective response against the evolving secondary cell death. Finding a treatment strategy that may render robust and long-lasting therapeutic effects stands as a clinically relevant therapy for stroke. Extracellular vesicles appear to be upregulated after stroke, which may represent a candidate target for neuroprotection. In this study, we probed whether transplanted stem cells could enhance the expression of extracellular vesicles to afford stable tissue remodeling in the ischemic stroke brain. Aged rats were initially exposed to the established ischemic stroke model of middle cerebral artery occlusion then received intravenous delivery of either bone marrow-derived mesenchymal stem cell transplantation or vehicle. A year later, the animals were assayed for brain damage, inflammation, and extracellular vesicle expression. Our findings revealed that while core infarction was not reduced, the stroke animals transplanted with stem cells displayed a significant reduction in peri-infarct cell loss that coincided with downregulated Iba1-labeled inflammatory cells and upregulated CD63-positive extracellular vesicles that appeared to be co-localized with GFAP-positive astrocytes. Interestingly, grafted stem cells were not detected at one year post-transplantation period, suggesting that the extracellular vesicles likely originated within the host brain. That long-lasting functional benefits persisted in the absence of surviving transplanted stem cells, but with upregulation of endogenous extracellular vesicles, advances the concept that transplantation of stem cells acutely after stroke propels host extracellular vesicles to the ischemic brain, altogether promoting chronic brain remodeling.

Mesenchymal Stem Cells-Conditioned Medium; An Effective Cell-Free Therapeutic Option for in vitro Maturation of Oocytes.

Infertility is a major reproductive health issue worldwide. One of the main problems in infertile women is the failure to generate or release a mature egg. Therefore, the development of new technologies for in vitro generation or induction of mature oocytes can improve various ART procedures. Recently, stem cell-based therapy has opened a new window for several pathological complications. Mesenchymal stem cells (MSCs) are multipotent stem cells with the capacity to self-renew and differentiate into the mesodermal lineage. MSCs contain various bioactive molecules which are involved in the regulation of key biological processes. They can secret multiple paracrine factors, such as VEGF, IGF, HGF, EGF, and FGF to stimulate egg maturation. Although MSCs represent a promising source for cell therapy, the potential risk of tumor development reduces their clinical applications. Recent studies have suggested that the supernatant or conditioned medium of MSCs also contains similar components and regulates the oocyte behavior. The MSC-conditioned medium can eliminate the safety concerns associated with MSC transplantation and avoid rejection problems. Although MSC and MSC-CM could improve oocyte quality, ovarian function, and fertility, these improvements have not yet been demonstrated in clinical trials in humans. Hereby, we summarized recent research findings of MSCs-derived conditioned medium in in vitro development of immature oocytes.

Molecular Prospective on Malignant Transformation of Mesenchymal Stem Cells: An Issue in Cell Therapy.

Mesenchymal stem cell (MSCs) therapy, as a rapidly developing area of medicine, holds great promise for the treatment of a variety of medical conditions. MSCs are multipotent stem cells that can be isolated from various tissues and could self-renew and differentiate. They secrete cytokines and trophic factors that create a regenerative microenvironment and have immunomodulatory properties. Although clinical trials have been conducted with MSCs in various diseases, concerns regarding the possibility of malignant transformation of these cells have been raised. The studies showed a higher rate of hematological malignancy and carcinogenesis in experimental models after MSC transplantation. The mechanisms underlying malignant transformation of MSCs are complex and not fully understood, but they are believed to involve the presence of special signaling molecules and alterations in cell behavior regulation pathways. Possible pathways that lead to MSCs' oncogenic transformation occur through two mechanisms: spontaneous and stimulated malignant transformation, including cell fusion, fusion proteins, and the tumor microenvironment. MSC-based therapies have the potential to revolutionize medicine, and addressing the issue of malignancy is crucial to ensure their safety and efficacy. Therefore, the purpose of the present review is to summarize the potential mechanisms of the malignant transformation of MSCs. [Figure: see text].

Synergistic effect of ex-vivo quality and quantity cultured mononuclear cells and mesenchymal stem cell therapy in ischemic hind limb model mice

IntroductionChronic limb-threatening ischemia (CLTI) is a condition characterized by peripheral arterial disease and tissue damage caused by reduced blood flow. New therapies using various cell types, such as mesenchymal stem cells (MSCs) and mononuclear cells (MNCs), have been developed for the patients unresponsive to conventional therapies. MSCs are promising because of their ability to secrete growth factors essential for vascularization, whereas MNCs contain endothelial progenitor cells that are important for blood vessel formation. However, conventional methods for isolating these cells have limitations, especially in patients with diabetes with dysfunctional cells. To overcome this problem, a culture method called quality and quantity cultured peripheral blood MNCs (MNC-QQ) was developed to efficiently produce high-quality cells from small amounts of peripheral blood. Combining MSCs with MNC-QQs has been hypothesized to enhance therapeutic outcomes. This study aimed to examine the angiogenic efficacy of MSCs with MNC-QQs in models with severe lower limb ischemia. MethodsMNC-QQ was manufactured from the peripheral blood of healthy volunteers, while human bone marrow derived MSCs were purchased. To verify the effects of the MSC and MNC-QQs combination in angiogenesis, we conducted the HUVEC tube formation assay. For in vivo experiments, we created an ischemic limb model using BALB/c nude mice. Saline, MSCs alone, and a combination of MSCs and MNC-QQs were administered intramuscularly into the ischemic limbs. Blood flow was measured over time using laser doppler, and the ischemic limbs were harvested 21 days later for HE staining and immunostaining for histological assessment. ResultsIn-vitro studies demonstrated increased angiogenesis when MSCs were combined with MNC-QQs compared with MSCs alone. In vivo experiments using a mouse model of severe lower limb ischemia showed that combination therapy significantly improved blood flow recovery and limb salvage compared with MSCs alone or saline treatment. Histological analysis revealed enhanced vessel density, arteriogenesis, muscle regeneration, and reduced fibrosis in the MSC + MNC-QQ group compared with those in the saline group. Although the specific interactions between MSCs and MNC-QQs have not been fully elucidated, combined therapy leverages the benefits of both cell types, resulting in improved outcomes for vascular regeneration. ConclusionsThis study highlights the potential of the simultaneous transplantation of MSCs and MNC-QQs as a promising therapeutic approach for CLTI, offering sustained long-term benefits for patients.

Human umbilical cord mesenchymal stem cell transplantation for the treatment of acute-on-chronic liver failure: protocol for a multicentre random double-blind placebo-controlled trial

IntroductionAcute-on-chronic liver failure (ACLF) is a prevalent and life-threatening liver disease with high short-term mortality. Although recent clinical trials on the use of mesenchymal stem cells (MSCs) for ACLF treatment...

Effects of Rabbit Bone Marrow Mesenchymal Stem Cell Transplantation on Anterior Cruciate Ligament Injury Repair and Related Serum Indicators

Effects of Rabbit Bone Marrow Mesenchymal Stem Cell Transplantation on Anterior Cruciate Ligament Injury Repair and Related Serum Indicators

Efficacy and safety of stem cell transplantation for multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials

Multiple sclerosis (MS) is a common autoimmune neurological disease affecting patients’ motor, sensory, and visual performance. Stem Cell Transplantation (SCT) is a medical intervention where a patient is infused with healthy stem cells with the purpose of resetting their immune system. SCT shows remyelinating and immunomodulatory functions in MS patients, representing a potential therapeutic option. We conducted this systematic review and meta-analysis that included randomized control trials (RCTs) of SCT in MS patients to investigate its clinical efficacy and safety, excluding observational and non-English studies. After systematically searching PubMed, Web of Science, Scopus, and Cochrane Library until January 7, 2024, nine RCTs, including 422 patients, were eligible. We assessed the risk of bias (ROB) in these RCTs using Cochrane ROB Tool 1. Data were synthesized using Review Manager version 5.4 and OpenMeta Analyst software. We also conducted subgroup and sensitivity analyses. SCT significantly improved patients expanded disability status scale after 2 months (N = 39, MD = − 0.57, 95% CI [− 1.08, − 0.06], p = 0.03). SCT also reduced brain lesion volume (N = 136, MD = − 7.05, 95% CI [− 10.69, − 3.4], p = 0.0002). The effect on EDSS at 6 and 12 months, timed 25-foot walk (T25-FW), and brain lesions number was nonsignificant. Significant adverse events (AEs) included local reactions at MSCs infusion site (N = 25, RR = 2.55, 95% CI [1.08, 6.03], p = 0.034) and hematological disorders in patients received immunosuppression and autologous hematopoietic SCT (AHSCT) (N = 16, RR = 2.33, 95% CI [1.23, 4.39], p = 0.009). SCT can improve the disability of MS patients and reduce their brain lesion volume. The transplantation was generally safe and tolerated, with no mortality or significant serious AEs, except for infusion site reactions after mesenchymal SCT and hematological AEs after AHSCT. However, generalizing our results is limited by the sparse number of RCTs conducted on AHSCT. Our protocol was registered on PROSPERO with a registration number: CRD42022324141.

Administration of Human-Derived Mesenchymal Stem Cells Activates Locally Stimulated Endogenous Neural Progenitors and Reduces Neurological Dysfunction in Mice after Ischemic Stroke.

Increasing evidence shows that the administration of mesenchymal stem cells (MSCs) is a promising option for various brain diseases, including ischemic stroke. Studies have demonstrated that MSC transplantation after ischemic stroke provides beneficial effects, such as neural regeneration, partially by activating endogenous neural stem/progenitor cells (NSPCs) in conventional neurogenic zones, such as the subventricular and subgranular zones. However, whether MSC transplantation regulates the fate of injury-induced NSPCs (iNSPCs) regionally activated at injured regions after ischemic stroke remains unclear. Therefore, mice were subjected to ischemic stroke, and mCherry-labeled human MSCs (h-MSCs) were transplanted around the injured sites of nestin-GFP transgenic mice. Immunohistochemistry of brain sections revealed that many GFP+ cells were observed around the grafted sites rather than in the regions in the subventricular zone, suggesting that transplanted mCherry+ h-MSCs stimulated GFP+ locally activated endogenous iNSPCs. In support of these findings, coculture studies have shown that h-MSCs promoted the proliferation and neural differentiation of iNSPCs extracted from ischemic areas. Furthermore, pathway analysis and gene ontology analysis using microarray data showed that the expression patterns of various genes related to self-renewal, neural differentiation, and synapse formation were changed in iNSPCs cocultured with h-MSCs. We also transplanted h-MSCs (5.0 × 104 cells/µL) transcranially into post-stroke mouse brains 6 weeks after middle cerebral artery occlusion. Compared with phosphate-buffered saline-injected controls, h-MSC transplantation displayed significantly improved neurological functions. These results suggest that h-MSC transplantation improves neurological function after ischemic stroke in part by regulating the fate of iNSPCs.

Endothelial cell-derived extracellular vesicles modulate the therapeutic efficacy of mesenchymal stem cells through IDH2/TET pathway in ARDS

BackgroundAcute respiratory distress syndrome (ARDS) is a severe and fatal disease. Although mesenchymal stem cell (MSC)-based therapy has shown remarkable efficacy in treating ARDS in animal experiments, clinical outcomes have been unsatisfactory, which may be attributed to the influence of the lung microenvironment during MSC administration. Extracellular vesicles (EVs) derived from endothelial cells (EC-EVs) are important components of the lung microenvironment and play a crucial role in ARDS. However, the effect of EC-EVs on MSC therapy is still unclear. In this study, we established lipopolysaccharide (LPS) - induced acute lung injury model to evaluate the impact of EC-EVs on the reparative effects of bone marrow-derived MSC (BM-MSC) transplantation on lung injury and to unravel the underlying mechanisms.MethodsEVs were isolated from bronchoalveolar lavage fluid of mice with LPS - induced acute lung injury and patients with ARDS using ultracentrifugation. and the changes of EC-EVs were analysed using nanoflow cytometry analysis. In vitro assays were performed to establish the impact of EC-EVs on MSC functions, including cell viability and migration, while in vivo studies were performed to validate the therapeutic effect of EC-EVs on MSCs. RNA-Seq analysis, small interfering RNA (siRNA), and a recombinant lentivirus were used to investigate the underlying mechanisms.ResultsCompared with that in non-ARDS patients, the quantity of EC-EVs in the lung microenvironment was significantly greater in patients with ARDS. EVs derived from lipopolysaccharide-stimulated endothelial cells (LPS-EVs) significantly decreased the viability and migration of BM-MSCs. Furthermore, engrafting BM-MSCs pretreated with LPS-EVs promoted the release of inflammatory cytokines and increased pulmonary microvascular permeability, aggravating lung injury. Mechanistically, LPS-EVs reduced the expression level of isocitrate dehydrogenase 2 (IDH2), which catalyses the formation of α-ketoglutarate (α-KG), an intermediate product of the tricarboxylic acid (TCA) cycle, in BM-MSCs. α-KG is a cofactor for ten-eleven translocation (TET) enzymes, which catalyse DNA hydroxymethylation in BM-MSCs.ConclusionsThis study revealed that EC-EVs in the lung microenvironment during ARDS can affect the therapeutic efficacy of BM-MSCs through the IDH2/TET pathway, providing potential strategies for improving the therapeutic efficacy of MSC-based therapy in the clinic.

Transplantation of Wnt5a-modified Bone Marrow Mesenchymal Stem Cells Promotes Recovery After Spinal Cord Injury via the PI3K/AKT Pathway.

Spinal cord injury (SCI) is a severe neurological condition that can lead to paralysis or even death. This study explored the potential benefits of bone marrow mesenchymal stem cell (BMSC) transplantation for repairing SCI. BMSCs also differentiate into astrocytes within damaged spinal cord tissues hindering the cell transplantation efficacy, therefore it is crucial to enhance their neuronal differentiation rate to facilitate spinal cord repair. Wnt5a, an upstream protein in the non-classical Wnt signaling pathway, has been implicated in stem cell migration, differentiation, and neurite formation but its role in the neuronal differentiation of BMSCs remains unclear. Thus, this study investigated the role and underlying mechanisms of Wnt5a in promoting neuronal differentiation of BMSCs both in vivo and in vitro. Wnt5a enhanced neuronal differentiation of BMSCs in vitro while reducing astrocyte differentiation. Additionally, high-throughput RNA sequencing revealed a correlation between Wnt5a and phosphoinositide 3-kinase (PI3K)/protein kinase B(AKT) signaling, which was confirmed by the use of the PI3K inhibitor LY294002 to reverse the effects of Wnt5a on BMSC neuronal differentiation. Furthermore, transplantation of Wnt5a-modified BMSCs into SCI rats effectively improved the histomorphology (Hematoxylin and eosin [H&E], Nissl and Luxol Fast Blue [LFB] staining), motor function scores (Footprint test and Basso-Beattie-Bresnahan [BBB]scores)and promoted neuron production, axonal formation, and remodeling of myelin sheaths (microtubule associated protein-2 [MAP-2], growth-associated protein 43 [GAP43], myelin basic protein [MBP]), while reducing astrocyte production (glial fibrillary acidic protein [GFAP]). Therefore, targeting the Wnt5a/PI3K/AKT pathway could enhance BMSC transplantation for SCI treatment.

Transplantation of Mesenchymal Stem Cells Derived from Old Rats Improves Healing and Biomechanical Properties of Vaginal Tissue Following Surgical Incision in Aged Rats.

Pelvic floor dysfunction encompasses a group of disorders that negatively affect the quality of women's lives. These include pelvic organ prolapse (POP), urinary incontinence, and sexual dysfunction. The greatest risk factors for prolapse are increased parity and older age, with the largest group requiring surgical intervention being post-menopausal women over 65. Prolapse recurrence rates following surgery were reported to be as high as 30%. This may be attributed to ineffective healing in the elderly. Autologous stem cell transplantation during surgery may improve surgical results. In our previous studies, we showed that the transplantation of bone marrow-derived mesenchymal stem cells (MSCs) from young donor rats improved the healing of full-thickness vaginal surgical incision in the vaginal wall of old rats, demonstrated by both histological and functional analysis. In order to translate these results into the clinical reality of autologous MSC transplantation in elderly women, we sought to study whether stem cells derived from old donor animals would provide the same effect. In this study, we demonstrate that MSC transplantation attenuated the inflammatory response, increased angiogenesis, and exhibited a time-dependent impact on MMP9 localization. Most importantly, transplantation improved the restoration of the biomechanical properties of the vagina, resulting in stronger healed vaginal tissue. These results may pave the way for further translational studies focusing on the potential clinical autologous adjuvant transplantation of MSCs for POP repair for the improvement of surgical outcomes.

The comparative effects of bone marrow mesenchymal stem cells and supernatant transplantation on demyelination and inflammation in cuprizone model.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) with inflammation and immune dysfunction. We compared the remyelination and immunomodulation properties of mesenchymal stem cells (MSCs) with their conditioned medium (CM) in the cuprizone model. Twenty-four C57BL/ 6 mice were divided into four groups. After cuprizone demyelination, MSCs and their CM were injected into the right lateral ventricle of mice. The expression level of IL-1β, TNF-α, and BDNF genes was evaluated using the qRT-PCR. APC antibody was used to assess the oligodendrocyte population using the immunofluorescent method. The remyelination and axonal repair were studied by specific staining of the LFB and electron microscopy techniques. Transplantation of MSCs and CM increased the expression of the BDNF gene and decreased the expression of IL-1β and TNF-α genes compared to the cuprizone group, and these effects in the cell group were more than CM. Furthermore, cell transplantation resulted in a significant improvement in myelination and axonal repair, which was measured by luxol fast blue and transmission electron microscope images. The cell group had a higher number of oligodendrocytes than other groups. According to the findings, injecting MSCs intraventricularly versus cell-conditioned medium can be a more effective approach to improving chronic demyelination in degenerative diseases like MS.