Stem Cells Translational Medicine最新文献

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized as a biphasic T-lymphocyte-mediated disease involving T-helper cells. Dupilumab is a human monoclonal antibody that inhibits Th2-related cytokines and has recently been approved for patients with AD. However, the effects of dupilumab are relatively narrow in scope, primarily targeting cytokine-driven inflammatory pathways, with few reported systemic effects. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) could serve as an alternative therapeutic strategy for AD. This study aims to compare the effects of a single subcutaneous injection of EVs and biweekly subcutaneous injection of dupilumab on the skin and spleen in a house dust mite-induced model of AD. Clinical and histological analyses, including H&E and toluidine blue staining, showed that both EVs and dupilumab ameliorated AD in an animal model. Biodistribution analysis through live animal imaging revealed that subcutaneously injected EVs can migrate to the spleen, and flow cytometry analysis showed that EVs restored the splenic ratio of CD4+/CD8 + and spleen enlargement. Cytokine analysis of the skin and spleen showed that EVs effectively regulated both Th2 and Th1 responses, while dupilumab had limited effects on Th1 response. Further, mechanistic analyses revealed that both EVs and dupilumab ameliorated AD via the JAK/STAT signaling pathway. Thus, a single subcutaneous injection of EVs was equally effective as a biweekly subcutaneous injection of dupilumab in ameliorating AD. While dupilumab specifically targets and inhibits the Th2 immune response, clinical-scale EV therapeutics can regulate a broad spectrum of immune responses.

Background: The objective of this study was to assess the long-term effectiveness and safety of implanting mesenchymal stem cells derived from umbilical cord tissue (UC-MSC) in patients diagnosed with retinitis pigmentosa (RP).

Methods: In this single-center study with a retrospective design, 669 eyes received suprachoroidal implantation of 5 million UC-MSCs. Postoperative assessments were conducted on the first day, third month, and every 6 months thereafter. At each visit, evaluations included best-corrected visual acuity (BCVA), anterior segment and fundus examinations, fundus photography, optical coherence tomography, and visual field (VF) tests. Multifocal electroretinography (mfERG) and full-field stimulus threshold (FST) testing were performed at baseline and every 6 months post-therapy. Procedure-related ocular and systemic complications were methodically documented.

Results: A total of 669 eyes from 429 patients underwent surgical intervention. Bilateral procedures were performed in 240 patients, while 189 patients received surgery in only 1 eye. All 669 eyes completed the 12-month follow-up, while 265 eyes completed 2 years, 128 eyes completed 3 years, and 19 eyes completed 4 years of follow-up. No notable ocular or systemic complications were reported during the study duration. Statistically significant improvements in BCVA, VF, and mfERG central rings amplitude measurements were observed over time. FST testing revealed significant improvements in visual sensitivity in 27 patients.

Conclusions: This investigation confirms the long-term benefits and safety profile of suprachoroidal UC-MSC therapy in cases of RP, demonstrating significant improvements in BCVA, VF, mfERG, and FST test outcomes. The data support the feasibility and potential of cell-based therapies as a promising and effective strategy for managing degenerative retinal diseases.

Importance:  Amniotic fluid is a promising source of autologous cells for disease modeling, drug screening, and regenerative medicine applications. However, current methods of collecting amniotic fluid are invasive, and samples are limited to pregnancies that require amniocentesis or cesarean section.

Objective:  The purpose of this study was to determine whether amniotic fluid cells could be isolated and cultured from amniotic fluid collected during vaginal deliveries.

Intervention:  Amniotic fluid samples were obtained during delivery of 4 neonates, 3 of which had been prenatally diagnosed with hypoplastic left heart syndrome (HLHS) in utero. Adherent amniotic fluid cells were assessed for maternal cell contamination, proliferation rate, surface marker expression, and differentiation potential. Amniotic fluid cells were also reprogrammed to induced pluripotent stem cells (iPSCs) and differentiated into functional cardiomyocytes.

Results: Amniotic fluid cells collected from vaginal deliveries showed similar surface marker phenotype and differentiation characteristics to amniotic fluid-derived mesenchymal stem cells collected from amniocentesis and cesarean section. Amniotic fluid cells collected during vaginal births of both neonates with HLHS and one neonate with typical heart geometry could be reprogrammed to iPSCs and differentiated to a cardiac lineage with high efficiency. Conclusions and Relevence: These findings suggest that amniotic fluid collected from vaginal births is a readily available source of patient-specific stem cells for banking, in vitro disease modeling, and regenerative medicine applications.

Organoids, which are tiny, lab-grown 3D structures that mimic some organizational and functional properties of human organs, are slowly transforming the face of systems and developmental biology, biomedical research, pharmaceutical testing, environmental toxin testing, and healthcare. Significant investments are essential for the mass production, preservation, and distribution of organoids, with the aim to accelerate innovation and progress across multiple fields-much like the investments made in cell and biologics manufacturing over the past 2 decades.

This study explores the potential for adipocyte-derived stem cells (ASCs) to be used in bladder reconstruction. Current methods, such as enterocystoplasty, have significant limitations, making new approaches necessary. Tissue engineering, specifically using acellular scaffolds such as the bladder acellular matrix, offers a promising basis for this development. For this study, ASCs were isolated from adipose tissue derived from liposuction and co-cultured with urothelial cells (UC; SV-HUC) to induce transdifferentiation. Results indicate successful isolation and characterization of ASCs, displaying positive markers for stem cells. The co-culture of ASCs with SV-HUC cells resulted in changes resembling epithelial cells, indicating a potential transdifferentiation process, and is corroborated by the mRNA and protein levels. For the functional assay, urothelial-like cells were seeded onto decellularized bladder tissues. These findings demonstrate the successful transdifferentiation of ASCs into functional UC, presenting a promising strategy for bladder reconstruction and a potential alternative to current approaches.

Regardless of the source of injury or metabolic dysfunction, fibrosis is a frequent driver of liver pathology. Excessive liver fibrosis is caused by persistent activation of hepatic stellate cells (HSCs), which is defined by myofibroblast activation (MFA) and the epithelial-mesenchymal transition (EMT). Strategies to prevent or reverse this HSC phenotype will be critical for successful treatment of liver fibrosis. We have previously shown that full-term, cell-free human amniotic fluid (cfAF) inhibits MFA and EMT in fibroblasts in vitro. We hypothesize that cfAF treatment can attenuate HSC activation and limit liver fibrosis. We tested if cfAF could prevent liver fibrosis or HSC activation in murine models of liver damage, 3-dimensional hepatic spheroids, and HSC cultures. Administering cfAF prevented weight loss and the extent of fibrosis in mice with chronic liver damage without stimulating deleterious immune responses. Gene expression profiling and immunostaining indicated that cfAF administration in carbon tetrachloride-treated mice reduced EMT- and MFA-related biomarker abundance and modulated transcript levels associated with liver metabolism, immune regulatory pathways, and cell signaling. cfAF treatment lowered MFA biomarker levels in a dose-dependent manner in ex vivo hepatic spheroids. Treating HSCs with cfAF in vitro strongly repressed EMT. Multiomics analyses revealed that it also attenuates TGFβ-induced MFA and inflammation-associated processes. Thus, cfAF treatment prevents liver fibrosis by safeguarding against persistent HSC activation. These findings suggest that cfAF may be a safe and effective therapy for reducing liver fibrosis and preventing the development of cirrhosis and/or hepatocellular carcinoma.

Postmenopausal osteoporosis, a prevalent metabolic bone disease, elevates susceptibility to fragility fractures while imposing substantial healthcare costs and public health challenges. The profound interplay between BMSCs and surrounding extracellular matrix (ECM) proteins, which are highly rich in O-GlcNAcylation, play pivotal roles in the process of osteoporosis. M6A methylation plays a crucial regulatory role in the development of osteoporosis, while the crosstalk between m6A methylation and ECM O-GlcNAcylation remains mechanistically undefined. Here we found Mettl7a overexpression improved the impaired osteogenic capability of OVX-mBMSCs in vitro. Conditional knockout of Mettl7a in the mesenchyme (Prx1-cre;Mettl7af/f) accelerated bone loss of OVX mice. Mechanistically, Mettl7a promoted mBMSCs osteogenic differentiation by targeting the O-GlcNAcylation of Bsp, an ECM protein. Mettl7a regulated the expression and O-GlcNAcylation of Bsp through m6A methylation of Oga. We further demonstrated that Mettl7a-AAV treatment alleviated bone loss phenotype in osteoporosis mice via the O-GlcNAcylation of Bsp. Collectively, our findings reveal novel mechanistic intersections between ECM protein O-GlcNAcylation and m6A methylation, advancing the understanding of osteoporotic regulation.

Appropriate dental pulp repair is based on effective control of inflammation and involves the regeneration of dental pulp nerves, blood vessels (soft tissue), and dentin (hard tissue). Limited evidence has shown how to modulate the uncertainty due to individual variability in dental pulp repair. NRG1, a cytokine modulating nerve injury and repair, was intricately associated with the outcome of pulp repair. Yet, its mobilization in spontaneous pulp repair had individual variability. The study further explored the role of NRG1 during pulp repair as well as an epigenetic way to modulate NRG1 through histone acetylation to enhance pulp repair. Overexpression of NRG1 exhibited the effects of anti-inflammation and integrated regeneration of soft and hard tissue, by inhibiting pro-inflammatory factors IL-1β, IL-8, and promoting the expressions of DSPP, DMP1 (dentin regeneration), and nestin (nerve regeneration). Moreover, restricted H3K9 and H3K27 acetylation correlated with NRG1 expression in pulp repair both temporally and spatially, showing individual variability as well. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor, enhanced H3K9ac and H3K27ac, which dramatically activated NRG1, suppressed pulp inflammation, and facilitated soft and hard tissue regeneration. In summary, targeting histone acetylation with HDAC inhibitors may be an effective approach to promote pulp repair by activating NRG1.

Severe coronavirus infections, including SARS-CoV-2, are marked by systemic inflammation, T-cell exhaustion, lymphopenia, and chronic immune dysfunction, with limited therapeutic options for recovery. Feline infectious peritonitis (FIP), a naturally occurring feline coronavirus infection, mirrors these immune pathologies, providing a valuable translational model. This study evaluated the safety and efficacy of allogeneic mesenchymal stem/stromal cell (MSC) therapy combined with antiviral treatment in cats with effusive FIP. Hematologic, virologic, and immunologic analyses were conducted over 12 weeks. Antiviral therapy reduced cytotoxic T-cell exhaustion by downregulating inhibitory receptors PD-1, TIM-3, and LAG-3. MSC-treated cats demonstrated enhanced immune recovery, evidenced by reduced expression of exhaustion-related transcription factors (IKZF2, ZEB2, PRDM1) and increased regulatory T-cell populations, promoting immune homeostasis. Single-cell RNA sequencing of mesenteric lymph nodes revealed transcriptomic shifts indicative of immune rejuvenation, including elevated memory T-cell markers (IKZF1, GZMK, IL7R) and reduced hyperproliferative lymphocyte subsets. Serum cytokine analysis revealed 3 distinct inflammatory mediator patterns using principal component analysis. Both treatment groups showed transitions toward cytokine profiles resembling those of healthy controls. Notably, residual cytokine elevations persisted at the study's end, mirroring features of chronic immune dysregulation. PDGF-bb, a marker of tissue repair, was uniquely associated with higher lymphocyte counts, suggesting its role in lymphoid recovery. This study highlights the potential of MSC therapy to modulate immune dysfunction and support durable immune recovery. The findings underscore its translational relevance for addressing severe viral diseases characterized by chronic inflammation and immune dysregulation, advancing both veterinary and human medicine.

Background: Bone mesenchymal stem cells (BMSCs) have demonstrated therapeutic potential in attenuating liver fibrosis. However, the precise molecular targets through which BMSCs regulate hepatic stellate cells (HSCs) activation, as well as liver fibrosis remains unclear.

Methods: BMSCs were isolated from rat bone marrow, cultured, and characterized. BMSCs were administered via tail vein injection into bile duct ligation (BDL)-induced liver fibrosis mice. The downstream target of BMSCs was analyzed using RNA-sequencing (RNA-seq) and detected in liver tissues of Primary Biliary Cholangitis (PBC) patients and mice liver fibrosis. Mechanistic evaluations were employed using immunofluorescence, Western blot, RT-qPCR, transmission electron microscope (TEM), and histological analyses.

Results: BMSCs transplantation markedly attenuated liver fibrosis. RNA-seq revealed Regulated in Development and DNA Damage Response 1 (REDD1) is a novel regulator of BMSCs-based antifibrotic liver fibrosis therapy and upregulated in liver tissues of PBC patients and mice liver fibrosis. Mechanistically, REDD1 overexpression suppressed HSCs activation by impairing HSCs autophagy, thereby potentiating BMSCs therapeutic efficacy. More importantly, the in vivo experiments revealed REDD1 treatment ameliorated liver function, alleviated liver injury, and attenuated liver fibrosis, and PI3K/AKT/mTOR and TGFβ/Smad3 pathway were involved in the regulation.

Conclusions: Our results provide preliminary evidence for the protective roles of BMSCs in liver fibrosis through REDD1/autophagy pathway and suggest that REDD1 may be a promising therapeutic target for treating liver fibrosis.