Stem Cells Translational Medicine最新文献

{"title":"Histone acetylation facilitates multidirectional pulp repair through Neuregulin-1 mobilization.","authors":"Zhiwu Wu, Hui Yang, Shaoying Duan, Qianqian Su, Ran Cheng, Tao Hu","doi":"10.1093/stcltm/szaf022","DOIUrl":"10.1093/stcltm/szaf022","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"14 7","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mesenchymal stem/stromal cell therapy improves immune recovery in a feline model of severe coronavirus infection.","authors":"Patrawin Wanakumjorn, Kazuto Kimura, Diego Castillo, Ehren McLarty, Rachel Formaker, Rachel Qiao, Katherine Farrell, Terza Brostoff, Raneesh Ramarapu, Jully Pires, Tamar Cohen-Davidyan, Jennifer Cassano, Brian Murphy, Krystle Reagan, Amir Kol","doi":"10.1093/stcltm/szaf025","DOIUrl":"10.1093/stcltm/szaf025","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"14 7","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144638128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bone mesenchymal stem cells attenuate hepatic stellate cell activation and liver fibrosis through REDD1/autophagy pathway.","authors":"Tingjuan Huang, Lina Nie, Haichao Diao, Ziyi Shang, Qizhi Shuai, Jun Xu, Jun Xie","doi":"10.1093/stcltm/szaf023","DOIUrl":"10.1093/stcltm/szaf023","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"14 7","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mesenchymal stem cells enhance selective ER-phagy to promote α-synuclein clearance in Parkinson's disease.","authors":"Ji Eun Lee, Kyu Won Oh, Jin Young Shin, Yeon Ju Kim, Seung-Jae Lee, Phil Hyu Lee","doi":"10.1093/stcltm/szaf019","DOIUrl":"10.1093/stcltm/szaf019","url":null,"abstract":"<p><p>Ample evidence suggests that α-synuclein (αSyn) accumulation in the endoplasmic reticulum (ER) leads to ER stress, resulting in neurodegeneration in Parkinson's disease (PD). Selective degradation of accumulated αSyn through ER-phagy can alleviate ER stress and rescue neurodegeneration. In the present study, we investigated whether mesenchymal stem cells (MSCs) exert neuroprotective effects against PD by modulating ER-phagy. In a cellular model overexpressing αSyn specifically in the ER (ER-αSyn), co-culture with MSCs promoted ER-αSyn clearance through selective ER-phagy and also recovered cell viability. Injection of MSCs to an animal model using adeno-associated virus vectors to overexpress αSyn in the ER (AAV-ER- αSyn), also decreased the expression of aSyn in the ER and attenuated the dopaminergic neuronal loss in substantia nigra (SN) and denervation in striatum (ST), followed by functional improvement of motor deficits. In vitro screening identified that MSCs promoted family with sequence similarity 134 member B (FAM134B)-mediated ER-phagy via regulating transcription factor of nuclear subfamily 4 group A member 1 (NR4A1), and it underwent in vivo validation. This study suggests that MSCs modulate FAM134B-mediated ER-phagy under the regulation of NR4A1, promoting the clearance of ER-accumulated αSyn in PD cellular and murine models.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"14 6","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12150288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Mesenchymal stromal cells pretreated with pro-inflammatory cytokines promote skin wound healing through VEGFC-mediated angiogenesis.","authors":"","doi":"10.1093/stcltm/szaf029","DOIUrl":"10.1093/stcltm/szaf029","url":null,"abstract":"","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"14 6","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12166521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-viral CD8 central memory veto cells as a new platform for CAR T cell therapy.","authors":"Wei-Hsin Liu, Anat Globerson Levin, Assaf Lask, Galit Horn, Tova Waks, Bar Nathansohn Levi, Irit Milman Krentsis, Einav Shoshan, Xiaohua Su, Maksim Mamonkin, Richard E Champlin, Yair Reisner, Esther Bachar Lustig","doi":"10.1093/stcltm/szaf020","DOIUrl":"10.1093/stcltm/szaf020","url":null,"abstract":"<p><p>Central memory CD8 T cells exhibit marked veto activity enhancing engraftment in several mouse models of T cell-depleted bone marrow (TDBM) allografting. Graft-versus-host disease (GVHD) can be prevented by stimulation of mouse or human memory CD8 T cells against their cognate antigens under cytokine deprivation, in the early phase of culture followed by further expansion with IL21, IL15, and IL7. Thus, human anti-viral CD8 central memory veto T cells generated from CMV and EBV-positive donors are currently evaluated in a clinical trial at MD Anderson Cancer Centre (MDACC). Results in 15 patients indicate a low risk of GVHD. Considering that these cells could offer an attractive platform for CAR cell therapy, we evaluated methodologies for their effective transduction with 2 retroviral vectors. Initially, a vector directed against Her2 was tested and optimal transduction was attained at day 5 of culture. The transduced cells were expanded for an additional 7 days and exhibited marked anti-tumor reactivity ex-vivo while retaining their veto activity. Transduction with a vector directed at CD19 was effectively attained at days 4-5 allowing for substantial harvest of transduced cells at day 12 of culture. These Veto-CD19CAR central memory CD8 T cells exhibited marked anti-tumor reactivity in-vitro and in-vivo without GVHD, measured following transplantation into immune-deficient mice. These results strongly suggest that Veto-CAR T cells offer an attractive platform for CAR T cell therapy without gene editing for addressing the risk of GVHD or graft rejection.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"14 6","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12126084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Initial or continuous coculture with umbilical cord-derived mesenchymal stromal cells facilitates in vitro expansion of human regulatory T-cell subpopulations.","authors":"Qifeng Ou, Sarah Cormican, Rachael Power, Sarah Hontz, Shirley A Hanley, Md Nahidul Islam, Georgina Shaw, Laura M Deedigan, Emma Horan, Stephen J Elliman, Barbara Fazekas, Janusz Krawczyk, Neema Negi, Matthew D Griffin","doi":"10.1093/stcltm/szaf012","DOIUrl":"10.1093/stcltm/szaf012","url":null,"abstract":"<p><p>Clinical trials have demonstrated the safety and potential efficacy of ex vivo expanded regulatory T cells (Tregs) for immune-mediated diseases. Nonetheless, achieving consistent and timely Treg yield and purity remains challenging. We aimed to evaluate the potential to enhance culture expansion of primary human total Treg (CD4+/CD25+/CD127lo) and Treg subpopulations through coculture with human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs). In 14- to 21-day anti-CD3/anti-CD28-, interleukin-2-, and rapamycin-containing cultures, fluorescence-activated cell sorting (FACS)-purified total Treg underwent 4-fold greater expansion following hUC-MSC coculture. Potency to suppress T effector cell (Teff) proliferation was equivalent for hUC-MSC-cocultured and control Tregs and correlated with the expression of HLA-DR, CD39, and inducible costimulator (ICOS). The impact of hUC-MSC coculture on ex vivo expansion of 3 FACS-purified Treg subpopulations [CD45RA+ (Subtype I), CD45RA-HLA-DR+ (Subtype II), and CD45RA-HLA-DR- (Subtype III)] was then investigated. Both initial and continuous hUC-MSC coculture yielded significantly higher fold expansion of each Treg subpopulation compared to control. However, the magnitude of enhancement was substantially greater for non-naive (Subtypes II and III) than for naive (Subtype I) Treg. Coculture with hUC-MSC increased HLA-DR expression of all 3 expanded Treg subpopulations while maintaining comparable Teff suppressive potency. For non-naive Treg (Subtypes II and III), both initial and continuous hUC-MSC coculture also increased the final %Foxp3+ and %Helios+. Thus, coculture with clinical-grade hUC-MSC substantially enhances the ex vivo yield, preserves the suppressive potency, and modulates HLA-DR expression of FACS-purified Treg subpopulations with greatest effect on non-naive (CD45RA-) Treg. The findings have potential to facilitate identification, functional characterization, and manufacturing of Treg subpopulations with distinct therapeutic benefits.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"14 6","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12166524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Mesenchymal stromal cells-derived small extracellular vesicles protect against UV-induced photoaging via regulating pregnancy zone protein.","authors":"","doi":"10.1093/stcltm/szaf028","DOIUrl":"10.1093/stcltm/szaf028","url":null,"abstract":"","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"14 6","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12166517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DLK1-expressing neural progenitor cells promote tissue repair and functional recovery after cervical spinal cord injury.","authors":"Nader Hejrati, Zijian Lou, Sogolie Kouhzaei, Oliver Zhang, Jian Wang, Mohamad Khazaei, Michael G Fehlings","doi":"10.1093/stcltm/szaf014","DOIUrl":"10.1093/stcltm/szaf014","url":null,"abstract":"<p><p>Spinal cord injury (SCI) elicits a hostile microenvironment characterized by inflammation, gliosis, and disrupted signaling pathways that collectively impede neural repair. Neural progenitor cells (NPCs) represent a promising regenerative approach, yet their survival and differentiation are often compromised in this setting. Here, we investigated whether engineering NPCs to overexpress the Notch pathway modulator Delta-like non-canonical Notch ligand 1 (DLK1) could overcome these limitations and improve functional outcomes after cervical SCI in rats. NPCs were engineered to express DLK1 under a Pax6 promoter-driven expression system, ensuring elevated DLK1 levels during the progenitor state. Following transplantation of DLK1-overexpressing NPCs or control NPCs, we assessed graft survival, lineage differentiation, behavioral performance, and electrophysiological integration over 12 weeks. DLK1-expressing NPCs exhibited significantly greater retention in the injured spinal cord and showed enhanced neuronal differentiation alongside reduced astrocytic commitment compared to controls. Behavioral tests-including forelimb grip strength and CatWalk gait assessments-demonstrated that DLK1-modified NPCs conferred robust improvements in forelimb motor coordination and overall locomotion. Concordantly, electrophysiological recordings revealed increased motor-evoked potential amplitudes and area-under-the-curve values in animals receiving DLK1-transduced NPC grafts, indicative of strengthened synaptic integration within the host motor circuitry.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"14 6","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12126085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Upregulating CXCR4 in Human Fetal Mesenchymal Stem Cells Enhances Engraftment and Bone Mechanics in a Mouse Model of Osteogenesis Imperfecta.","authors":"","doi":"10.1093/stcltm/szaf027","DOIUrl":"10.1093/stcltm/szaf027","url":null,"abstract":"","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"14 6","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12166519/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}