Stem Cell Research & Therapy最新文献

Background: The clinical application of mesenchymal stem cells (MSCs) in myocardial infarction (MI) is severely hampered by their poor survival. Pretreatment is a key strategy that has been adopted to promote their therapeutic efficacy. This study aimed to investigate the benefit of growth differentiation factor 15-pretreated MSCs (GDF15-MSCs) in enhancing cardiac repair following MI and to determine the underlying mechanisms.

Methods: MSCs with or without GDF15 pretreatment were exposed to serum deprivation and hypoxia (SD/H) challenge. Apoptosis of MSCs was assessed by TUNEL staining. The conditioned media (CM) of MSCs and GDF15-MSCs was collected by centrifugation. MSCs and GDF15-MSCs were transplanted into the peri-infarct region in a mouse model of MI. Cardiac function, fibrosis and MSC survival were examined 4 weeks after MSC transplantation.

Results: Pretreatment with GDF15 greatly reduced SD/H-induced apoptosis of MSCs via inhibition of reactive oxygen species (ROS) generation by attenuating mitochondrial fission. Mechanistically, GDF15 pretreatment ameliorated mitochondrial fission of MSCs under SD/H challenge by activating the AMPK pathway. These effects were partially abrogated by AMPK inhibitor. Pretreatment with GDF15 also promoted paracrine effects of MSCs in vitro, evidenced by improving tube formation of HUVECs, and inhibited the apoptosis of cardiomyocytes induced by SD/H. At 4 weeks after transplantation, compared with MSCs, GDF15 pretreatment strongly promoted the survival of MSCs in the ischemic heart with consequent enhanced cardiac function, reduced cardiac fibrosis and increased angiogenesis.

Conclusions: Our study showed that pretreatment with GDF15 promoted the cardioprotective effects of MSCs in MI via regulation of pro-survival signaling and paracrine actions. GDF15 pretreatment is an effective approach to enhance the therapeutic efficacy of MSCs in ischemic heart disease.

Background: Defects in the ataxin-2 (ATXN-2) protein and CAG trinucleotide repeat expansion in its coding gene, Atxn-2, cause the neurodegenerative disorder spinocerebellar ataxia type 2 (SCA2). While clinical studies suggest potential benefits of human-derived mesenchymal stem cells (hMSCs) for treating various ataxias, the exact mechanisms underlying their therapeutic effects and interaction with host tissue to stimulate neurotrophin expression remain unclear specifically in the context of SCA2.

Methods: Human bone marrow-derived MSCs (hMSCs) were injected into the cisterna magna of 26-week-old wild-type and SCA2 mice. Mice were assessed for impaired motor coordination using the accelerating rotarod, open field test, and composite phenotype scoring. At 50 weeks, the cerebellum vermis was harvested for protein assessment and immunohistochemical analysis.

Results: Significant loss of NeuN and calbindin was observed in 25-week-old SCA2 mice. However, after receiving multiple injections of hMSCs starting at 26 weeks of age, these mice exhibited a significant improvement in abnormal motor performance and a protective effect on Purkinje cells. This beneficial effect persisted until the mice reached 50 weeks of age, at which point they were sacrificed to study further mechanistic events triggered by the administration of hMSCs. Calbindin-positive cells in the Purkinje cell layer expressed bone-derived neurotrophic factor after hMSC administration, contributing to the protection of cerebellar neurons from cell death.

Conclusion: In conclusion, repeated administration of hMSCs shows promise in alleviating SCA2 symptoms by preserving Purkinje cells, improving neurotrophic support, and reducing inflammation, ultimately leading to the preservation of locomotor function in SCA2 mice.

Background: Standard approaches to the treatment of chronic post-radiation proctitis are associated with a high risk of complications and a high percentage of unsatisfactory results due to the reduced regenerative potential of irradiated tissues. Regenerative surgery techniques using the stromal-vascular cell fraction (SVF) based on the patient's autologous adipose tissue are a promising direction for study.

Clinical case description: A 76-year-old patient suffering from chronic post-radiation erosive-ulcerative proctitis, grade 4 according to RTOG-EORTC, complicated by recurrent profuse rectal bleeding, underwent local autotransplantation of SVF into the submucosal layer of the rectum and pararectal connective tissue. The follow-up colonoscopies 1 and 6 months after the surgery and histological examination showed the complete epithelialization of ulcerative defects and a decrease in proctitis activity. There were no bleeding episodes during the 12-month postoperative observation period.

Conclusion: The proangiogenic, wound-healing, and anti-apoptotic effects of the SVF cell suspension provided reduction of inflammation activity, epithelialization of ulcers, and elimination of defecation-associated hemorrhage, following the SVF injection into the submucosal layer of the rectal wall and pararectal connective tissue in a patient with post-radiation proctitis with ulcers and recurrent bleeding.

Background: Type 1 diabetes, an autoimmune disorder leading to the destruction of pancreatic β-cells, requires lifelong insulin therapy. Islet transplantation offers a promising solution but faces challenges such as limited availability and the need for immunosuppression. Induced pluripotent stem cells (iPSCs) provide a potential alternative source of functional β-cells and have the capability for large-scale production. However, current differentiation protocols, predominantly conducted in hybrid or 2D settings, lack scalability and optimal conditions for suspension culture.

Methods: We examined a range of bioreactor scaleup process parameters and quality target product profiles that might affect the differentiation process. This investigation was conducted using an optimized High Dimensional Design of Experiments (HD-DoE) protocol designed for scalability and implemented in 0.5L (PBS-0.5 Mini) vertical wheel bioreactors.

Results: A three stage suspension manufacturing process is developed, transitioning from adherent to suspension culture, with TB2 media supporting iPSC growth during scaling. Stage-wise optimization approaches and extended differentiation times are used to enhance marker expression and maturation of iPSC-derived islet-like clusters. Continuous bioreactor runs were used to study nutrient and growth limitations and impact on differentiation. The continuous bioreactors were compared to a Control media change bioreactor showing metabolic shifts and a more β-cell-like differentiation profile. Cryopreserved aggregates harvested from the runs were recovered and showed maintenance of viability and insulin secretion capacity post-recovery, indicating their potential for storage and future transplantation therapies.

Conclusion: This study demonstrated that stage time increase and limited media replenishing with lactate accumulation can increase the differentiation capacity of insulin producing cells cultured in a large-scale suspension environment.

Background: Inflammatory bowel disease (IBD) poses a significant and growing global health challenge, affecting both humans and domestic cats. Research on feline IBD has not kept pace with its widespread prevalence in human populations. This study aimed to develop a model of feline IBD by incorporating dextran sulfate sodium (DSS) to evaluate the therapeutic potential of MSCs and to elucidate the mechanisms that enhance their action.

Methods: We conducted a comprehensive clinical assessment, including magnetic resonance imaging (MRI), endoscopy, and histopathological examination. Additionally, alterations in intestinal microbiota were characterized by 16 S rDNA sequencing, and the influence of MSCs on IBD-related gene expression was investigated through transcriptome analysis.

Results: According to our findings, MSC treatment significantly mitigated DSS-induced clinical manifestations, reduced inflammatory cell infiltration, decreased the production of inflammatory mediators, and promoted mucosal repair. Regarding the intestinal microbiota, MSC intervention effectively corrected the DSS-induced dysbiosis, increasing the presence of beneficial bacteria and suppressing the proliferation of harmful bacteria. Transcriptome analysis revealed the ability of MSCs to modulate various inflammatory and immune-related signaling pathways, including cytokine-cytokine receptor interactions, TLR signaling pathways, and NF-κB pathways.

Conclusion: The collective findings indicate that MSCs exert multifaceted therapeutic effects on IBD, including the regulation of intestinal microbiota balance, suppression of inflammatory responses, enhancement of intestinal barrier repair, and modulation of immune responses. These insights provide a solid scientific foundation for employing MSCs as an innovative therapeutic strategy for IBD and pave the way for future clinical explorations.

Bone regeneration is a complex biological process that relies on the orchestrated interplay of various cellular and molecular events. Bone tissue engineering is currently the most promising method for treating bone regeneration. However, the immunogenicity, stable and cell quantity of seed cells limited their application. Recently, exosomes, which are small extracellular vesicles released by cells, have been found to effectively address these problems and better induce bone regeneration. Meanwhile, a growing line of research has shown the cargos of exosomes may provide effective therapeutic and biomarker tools for bone repair, including miRNA, lncRNA, and proteins. Moreover, engineered scaffolds loaded with exosomes can offer a cell-free bone repair strategy, addressing immunogenicity concerns and providing a more stable functional performance. Herein, we provide a comprehensive summary of the role played by scaffolds loaded with exosomes in bone regeneration, drawing on a systematic analysis of relevant literature available on PubMed, Scopus, and Google Scholar database.

Since wound healing is one of the most important medical challenges and common dressings have not been able to manage this challenge well today, efforts have been increased to achieve an advanced dressing. Mesenchymal stem cells and exosomes derived from them have shown high potential in healing and regenerating wounds due to their immunomodulatory, anti-inflammatory, immunosuppressive, and high regenerative capacities. However, challenges such as the short life of these cells, the low durability of these cells in the wound area, and the low stability of exosomes derived from them have resulted in limitations in their use for wound healing. Nowadays, different scaffolds are considered suitable biomaterials for wound healing. These scaffolds are made of natural or synthetic polymers and have shown promising potential for an ideal dressing that does not have the disadvantages of common dressings. One of the strategies that has attracted much attention today is using these scaffolds for seeding and delivering MSCs and their exosomes. This combined strategy has shown a high potential in enhancing the shelf life of cells and increasing the stability of exosomes. In this review, the combination of different scaffolds with different MSCs or their exosomes for wound healing has been comprehensively discussed.