Stem Cells Translational Medicine最新文献

{"title":"Ghrelin and relamorelin counteract hypoglycemia in mice engrafted with congenital hyperinsulinism stem cell-derived islets.","authors":"Väinö Lithovius, Hossam Montaser, Jonna Saarimäki-Vire, Hazem Ibrahim, Tom Barsby, Diego Balboa, Timo Otonkoski","doi":"10.1093/stcltm/szag055","DOIUrl":"10.1093/stcltm/szag055","url":null,"abstract":"<p><strong>Introduction: </strong>KATP-channel-related hyperinsulinism (KATPHI) is a rare genetic disorder of the pancreatic beta cells, manifesting as life-threatening hypoglycemia in neonates due to excessive insulin secretion. Management of the severe diffuse form of KATPHI currently lacks treatment options, as the first-line therapy octreotide is often insufficiently effective, necessitating radical pancreatectomy in many patients.</p><p><strong>Methods: </strong>In this study, we differentiated stem cells carrying the KATPHI-causing mutation KCNJ11-/- to stem cell-derived islets (SC-islets) to develop new pharmaceutical therapies for KATPHI. We tested seven candidate molecules in vitro and the most effective ones in vivo in immunocompromised mice that were transplanted with the human KCNJ11-/- SC-islets.</p><p><strong>Results: </strong>KCNJ11 -/- SC-islets inappropriately secreted 3.9 times more insulin in low glucose than KCNJ11+/+ controls. Transplanted KCNJ11-/- SC-islets caused persistent hyperinsulinemia and hypoglycemia to the recipient mice. We tested acyl-ghrelin identified in our in vitro experiments and its long-acting analogue relamorelin in these mice. Acyl-ghrelin and relamorelin alone increased fasting blood glucose. Combining relamorelin with octreotide increased blood glucose synergistically, ie, more than the sum of each drug alone, reverting hypoglycemia to normoglycemia while reducing the excessive insulin secretion.</p><p><strong>Conclusions: </strong>We show that ghrelin-receptor agonists have acute anti-hypoglycemic effects in a humanized mouse model of KATPHI, especially when combined with octreotide. Relamorelin has been tested in >650 diabetic adults with little side effects, leading us to propose relamorelin-octreotide combination for further development as a therapeutic candidate for severe KATPHI patients.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 8","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13441175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148679820","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":"Impact of infectious disease outbreaks and regulatory policies on cord blood banking: a two-decade single-center analysis in Korea.","authors":"Sue Shin, Nam-Hee Kim, Hye Ryun Lee, Jong Hyun Yoon, Byoung Jae Kim, Hyun-Woong Park, Eun Youn Roh","doi":"10.1093/stcltm/szag059","DOIUrl":"10.1093/stcltm/szag059","url":null,"abstract":"<p><p>Public cord blood (CB) banks face declining inventories worldwide, but the relative contributions of regulatory changes, declining birth rates, and infectious disease outbreaks remain unclear. We performed a retrospective analysis of 73 925 CB units submitted to a Korean public cord blood bank from 2006 to 2025, encompassing two regulatory transitions in total nucleated cell (TNC) criteria and three major outbreaks (H1N1, MERS, and COVID-19), using interrupted time series, correlation, and multivariable analyses. Of 73 925 submissions, 27 684 (37.4%) were banked. The 2011 TNC ≥ 8 × 108 criterion produced a moderate reduction in banking rate from 37.7% to 33.6%, while the 2021 TNC ≥ 11 × 108 revision caused an abrupt decline from 52.6% to 24.4%. H1N1 and MERS had minimal effects, whereas the COVID-19 period showed a sustained decline coinciding with the 2021 TNC revision. Birth decline correlated strongly with submissions (R2 = 0.94). Regulatory criteria changes were the primary driver of banking rate fluctuations, while declining births affected submission volume. Among three outbreaks, only the COVID-19 period overlapped with a sustained decline, likely reflecting concurrent regulatory change rather than the pandemic itself. CB quality and safety were maintained throughout all disruptions. These findings have direct translational implications for sustaining the global CB inventory as a critical source of hematopoietic stem cells for transplantation.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 8","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13441184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148679874","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":"Stem cell-based therapies for neuroretinal degeneration: current landscape and future perspectives.","authors":"Sarah Saietz, Filippo Locri, Helena Isla-Magrané, Brandon Mills, Fredrik Lanner, Anders Kvanta","doi":"10.1093/stcltm/szag046","DOIUrl":"10.1093/stcltm/szag046","url":null,"abstract":"<p><p>Retinal degenerations, comprising a heterogeneous group of disorders culminating in neuroretinal dysfunction, such as inherited retinal dystrophies (IRDs) and age-related retinal degeneration, are among the leading causes of irreversible vision loss worldwide. Restoring visual function through cell replacement therapy represents an attractive, yet challenging, strategy. Candidate retinal cell sources include retinal progenitor cells (RPCs), Müller glia, human neuroretinal stem-like cells (hNRSCs), and pluripotent stem cells (PSCs). In this review, we discuss their translational advantages and limitations, which in turn influence clinical implementation. We analyze critical manufacturing challenges, including GMP scalability, quality assurance, and ethical considerations in donor material sourcing. Experimental criteria for assessing cellular products' integration into host circuitry and their capacity to restore visual function in preclinical retinal degeneration models must account for donor maturity, host retina architecture, and immune modulation, which determine survival, synapse connectivity, and delivery requirements. Ongoing clinical trials highlight the diversity of cell replacement strategies-from fetal-derived and allogenic progenitor suspensions to laminated PSC-derived retinal sheets-with each approach presenting distinct implications for survival, true integration, and logistical complexity.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 8","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13405246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148607600","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":"Weekend-free and robotics-compatible protocols for high-throughput human-induced pluripotent stem cell maintenance, amplification, and differentiation.","authors":"Mariam Jouni, Sakina Petiwala, Divya Desai, Grzegorz Gawlak, Emily Y Chen, Alexandra Griffiths, Christopher Hogan, Venus E Thomanetz, Cecilia Heyne Lee, Joseph Tamm, Lamiaa Bahnassawy, Elke Käfer, Anja Finck, Sabina Bopp, Kari Barlan, Emma L Wambeke, Daniel Verduzco, Jacob D Painter, Jarel Gandhi, Peter Reinhardt, Anneke I Den Hollander","doi":"10.1093/stcltm/szag060","DOIUrl":"10.1093/stcltm/szag060","url":null,"abstract":"<p><strong>Background: </strong>Human induced pluripotent stem cells (hiPSCs) are essential tools for disease modeling, drug testing, and regenerative medicine. These applications require differentiation of multiple cell lines in parallel, synchronized production of large numbers of hiPSCs and differentiated cells, and assessment of differentiation efficiency before proceeding to in-depth characterization through molecular and cellular assays. However, hiPSC culture protocols are often laborious manual processes, which affects reproducibility and makes high-throughput applications challenging.</p><p><strong>Methods: </strong>We describe high-throughput hiPSC maintenance and amplification protocols that are weekend-free, scalable, and can be performed manually or automated. These optimized protocols enable scale-up of hiPSC production and differentiation to multiple cell types, including endothelial cells, microglia, and retinal pigment epithelial cells.</p><p><strong>Results: </strong>We characterized the differentiated cells using molecular and cellular assays and demonstrated that cells generated with this approach represent accurate cell identities.</p><p><strong>Conclusion: </strong>The approaches described here enable high-throughput hiPSC applications and improve reproducibility and scalability.If you want, I can also tighten this further to better fit a strict 350-word journal limit or adapt the heading style to a specific journal.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 8","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13445976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148679940","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":"From elective protocols to emergency reality: rethinking adipose tissue harvesting for stromal vascular fraction applications.","authors":"Caroline Nonnarath, Nicolas Serratrice","doi":"10.1093/stcltm/szag050","DOIUrl":"10.1093/stcltm/szag050","url":null,"abstract":"<p><strong>Background: </strong>Adipose tissue is a readily accessible source of stromal vascular fraction (SVF) and adipose-derived stem/stromal cells, widely used in regenerative medicine. Current harvesting and processing standards are derived almost exclusively from elective surgical settings performed under controlled physiological conditions. However, expanding applications in trauma and neurosurgery increasingly require adipose tissue procurement in emergency settings, where systemic inflammation, hypoperfusion, and time constraints may alter tissue biology. The biological impact of emergency harvesting remains insufficiently characterized, yet this knowledge is critical for optimizing SVF-based regenerative medicine strategies in emergency surgical environments.</p><p><strong>Objectives: </strong>To evaluate how emergency adipose procurement may influence SVF quality, cellular yield, viability, and translational feasibility, and to propose an acute-care-adapted framework for clinical integration.</p><p><strong>Methods: </strong>A comprehensive search of PubMed, EMBASE, and Scopus (inception-January 2026) identified studies addressing harvesting techniques, donor-site variability, enzymatic vs mechanical isolation, time-to-processing effects, cryopreservation, contamination risk, and clinical outcomes. Data were synthesized narratively with emphasis on variables relevant to emergency settings.</p><p><strong>Results: </strong>Harvesting parameters-including cannula diameter and negative pressure-influence total nucleated cell yield and viability. Enzymatic digestion increases cell recovery by approximately 1.5- to 3-fold compared with mechanical fractionation but requires laboratory infrastructure and a longer processing time. Mechanical techniques enable rapid point-of-care application yet produce stromal vascular tissue with greater heterogeneity. Processing delays reduce viable cell counts. Emergency physiology introduces additional upstream modifiers, including cytokine activation and microvascular perturbation, that remain largely unstudied in SVF research.</p><p><strong>Conclusions: </strong>Emergency adipose harvesting challenges elective-based assumptions underlying current SVF standards. Context-specific comparative studies and standardized emergency-adapted protocols are required to ensure biological robustness and clinical safety in acute surgical environments.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 8","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13415463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148607566","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":"PPARβ/δ priming enhances mesenchymal stromal cell anti-apoptotic properties on chondrocytes via ANGPTL4 and improves their therapeutic effects in osteoarthritis.","authors":"Claudia Terraza-Aguirre, Rafael Contreras-López, Clara Bernard, Carolina Pradenas, Jholy De la Cruz, Audrey Barthelaix, Catalina Asencio, Gautier Tejedor, Cécile Boyer, Stéphanie Barrère-Lemaire, Christian Jorgensen, Mingxing Wei, Jerome Guicheux, Claire Vinatier, Farida Djouad","doi":"10.1093/stcltm/szag053","DOIUrl":"10.1093/stcltm/szag053","url":null,"abstract":"<p><strong>Background: </strong>Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation, chondrocyte apoptosis, and inflammation. Mesenchymal stromal cells (MSCs) offer therapeutic potential, but their efficacy is hindered by oxidative stress and functional heterogeneity. We investigated whether PPARβ/δ priming enhances MSC therapeutic properties and explored the underlying mechanisms.</p><p><strong>Methods: </strong>MSCs were primed with the PPARβ/δ agonist GW501516. In a collagenase-induced OA mouse model, we assessed cartilage integrity by confocal laser scanning microscopy and histological grading. In vitro, we evaluated the effects of primed MSCs on oxidative stress resistance, chondrocyte apoptosis, and immunomodulation using DNA fragmentation, co-culture assays, and RNA sequencing.</p><p><strong>Results: </strong>PPARβ/δ priming significantly enhanced MSC resistance to oxidative stress, preserving their survival under H2O2-induced conditions. In co-culture experiments, primed MSCs exhibited a superior chondroprotective effect, reducing apoptosis in stressed chondrocytes. In vivo, primed MSCs improved cartilage volume, thickness, and integrity, lowering OA severity scores. RNA sequencing identified ANGPTL4 as a key mediator of these effects, as its silencing abolished MSC-mediated chondroprotection.</p><p><strong>Conclusion: </strong>PPARβ/δ priming enhances the therapeutic potential of MSCs by increasing their resistance to oxidative stress and anti-apoptotic effects on chondrocytes, mediated by ANGPTL4. These findings suggest a promising strategy for optimizing MSC-based therapies for OA.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 8","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13441182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148679922","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":"Synergistic regulation of hDPSC-iPSCs by tetrahedral DNA nanostructures for dentin-pulp complex regeneration.","authors":"Qiong Rong, Yu Guo, Tingting Wang, Xiaobing Tan","doi":"10.1093/stcltm/szag052","DOIUrl":"10.1093/stcltm/szag052","url":null,"abstract":"<p><p>The regeneration of a functional dentin-pulp complex represents a paramount objective in regenerative endodontics. However, current strategies reliant on scaffolds and growth factors are constrained by imprecise biological signaling and inefficient stem cell guidance. To address these limitations, this study aimed to develop a precise nanomaterial-based strategy. We investigated tetrahedral DNA nanostructures (TDNs) as bioactive nanocarriers to enhance the odontogenic differentiation of human dental pulp stem cell-derived induced pluripotent stem cells (hDPSC-iPSCs) within a gelatin methacryloyl (GelMA) hydrogel system. hDPSCs were isolated from young patients' teeth, reprogrammed into iPSCs, and characterized. TDNs were synthesized, characterized, and shown to be efficiently internalized by cells. In vitro, TDN treatment significantly upregulated key odontogenic markers (DSPP and DMP-1), promoted proliferation, and enhanced migration of hDPSC-iPSCs. For in vivo assessment, TDN-pretreated hDPSC-iPSCs encapsulated in GelMA were implanted into a tooth root canal regeneration model in nude mice. The TDN group regenerated well-structured, dentin-pulp-like tissues exhibiting strong dentin sialophosphoprotein (DSPP) expression, indicative of odontogenic differentiation. Collectively, these findings demonstrate that TDNs potently direct hDPSC-iPSCs toward an odontogenic lineage and support pulp-like tissue formation within a hydrogel niche. The integrated TDN-cell-GelMA platform presents a novel, precise, and minimally invasive strategy for early-stage pulp-like regeneration, with promising potential for clinical translation in regenerative endodontics.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 8","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13441177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148679957","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":"Long-term safety of intravenous human umbilical cord blood-derived mesenchymal stem cell therapy in rheumatoid arthritis: a 5-year follow-up study.","authors":"Eun Hye Park, Min Jung Kim, Kyung-Sun Kang, Kichul Shin","doi":"10.1093/stcltm/szag062","DOIUrl":"10.1093/stcltm/szag062","url":null,"abstract":"<p><strong>Background/purpose: </strong>Mesenchymal stem cell (MSC) therapy offers promise for treating autoimmune diseases due to its strong immunomodulatory effects. We investigated the long-term safety of a single intravenous injection with human umbilical cord blood-derived (hUCB)-MSCs in patients with rheumatoid arthritis (RA).</p><p><strong>Methods: </strong>Patients with RA who met the 2010 ACR/EULAR classification criteria and received a single intravenous infusion of hUCB-MSCs (2.5 × 107, 5.0 × 107, 1.0 × 108 cells) in a phase I trial (NCT02221258) entered this 5-year observational pilot study. Safety assessments were performed at 3, 6, and 12 months after infusion and annually thereafter. Safety endpoints included overall adverse events (AEs), serious adverse events (SAEs), and AEs of special interest.</p><p><strong>Results: </strong>Nine patients were treated. The most common AEs were osteoarthritis (44.4%) and nasopharyngitis (44.4%). SAEs occurred in 5 patients (55.6%); a serious infection (cellulitis) occurred in 1 patient in the 1.0 × 108 group and resolved after treatment. Benign ovarian and breast tumors were reported in 2 patients 3 years post-infusion. No deaths, thromboembolism, or malignancies occurred during the follow-up period. Laboratory findings remained stable except for 1 case each of transient hypertriglyceridemia and mild eosinophilia. While DAS28 improved markedly by 3-6 months, disease activity gradually increased over 5 years, suggesting waning efficacy after a single infusion.</p><p><strong>Conclusion: </strong>The long-term safety profile of a single dose of intravenous hUCB-MSC in patients with RA appears acceptable; however, repeated-dose regimens may be needed for sustained disease control and further safety evaluation.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 8","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13441169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148679960","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":"A Phase 1 clinical trial to evaluate the safety and tolerability of CLZ-2002 for the treatment of patients with Charcot-Marie-Tooth disease type 1.","authors":"Hyesun Kim, Byung-Ok Choi, Hyunju Lee, Saeyoung Park, Jaeseung Lim, Sung-Chul Jung","doi":"10.1093/stcltm/szag048","DOIUrl":"10.1093/stcltm/szag048","url":null,"abstract":"<p><strong>Background: </strong>Charcot-Marie-Tooth disease type 1 (CMT1) is a rare, genetically diverse condition and represents the most prevalent form of inherited peripheral neuropathy, characterized by Schwann cell dysfunction resulting in progressive demyelination and muscle wasting. CLZ-2002, an allogeneic Schwann cell-like product derived from human tonsillar mesenchymal stem cells, has been developed as a regenerative therapy and investigated in CMT1 patients.</p><p><strong>Methods: </strong>A Phase 1, open-label, dose-escalation clinical trial was performed in nine patients with genetically diagnosed CMT1 (five with CMT1A, four with CMT1B). Participants were allocated to three dosing cohorts: 6 million (G1), 12 million (G2), or 24 million cells (G3). CLZ-2002 was delivered as a single intramuscular injection into the lower limbs. The primary objective was to assess safety and tolerability. Exploratory endpoints included Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNSv2), Overall Neuropathy Limitation Score-leg (ONLS-leg), Functional Disability Score (FDS), electrophysiology, MRI, and circulating biomarkers.</p><p><strong>Results: </strong>No drug-related adverse reactions, serious adverse events, or dose-limiting toxicities occurred. Four participants experienced a total of five grade 1-2 treatment-emergent adverse events. By Week 24, improvements relative to baseline were noted in CMTNSv2 and ONLS-leg. Biomarker levels of NCAM1 and GDF15 declined at Week 4 but returned toward baseline by Week 24, reflecting the observed clinical trends.</p><p><strong>Conclusions: </strong>A single intramuscular dose of CLZ-2002 of up to 24 million cells was safe and well-tolerated in CMT1 patients. Exploratory efficacy assessments suggested possible clinical benefit, warranting continued investigation of CLZ-2002 in larger, controlled study populations.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 8","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13415455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148607597","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":"Histone acetylation promotes FKBP5 to increase reparative dentin formation in pulp repair.","authors":"Shaoying Duan, Qianqian Su, Hui Yang, Xinlei Hu, Aopeng Zhang, Tao Hu, Dan Xie, Ran Cheng","doi":"10.1093/stcltm/szag047","DOIUrl":"10.1093/stcltm/szag047","url":null,"abstract":"<p><strong>Importance: </strong>A well-formed dentin bridge isolates irritants and prevents bacterial penetration into the remaining pulp tissue, which is essential for pulp regeneration. The existing literature on promoting reparative dentin formation mostly focuses on the effects of pulp-capping materials but lacks investigations into the underlying mechanisms.</p><p><strong>Objective: </strong>To identify potential targets for enhancing reparative dentin formation as well as the epigenetic mechanisms underlying these effects.</p><p><strong>Design: </strong>Laboratory-based study combining multi-omics sequencing, epigenetic assays, in vitro FK506-binding protein 51 (FKBP5) knockdown or overexpression experiments, and in vivo validation using rat pulp injury models and nude mouse subcutaneous transplantation models.</p><p><strong>Setting: </strong>Laboratory-based in vitro and in vivo study.</p><p><strong>Participants: </strong>N/A.</p><p><strong>Intervention(s) or exposure(s): </strong>Dental pulp stem cells (DPSCs) were exposed to odontogenic differentiation induction or Lipopolysaccharide (LPS) stimulation. FKBP5 knockdown and overexpression were conducted using lentiviral vectors. In vivo validation was performed using a rat dental pulp injury model and a nude mouse subcutaneous transplantation model combining FKBP5 knockdown or overexpressed DPSCs with treated dentin matrix. Histone acetylation was modulated using dCas9-p300 targeting or pharmacological treatment with suberoylanilide hydroxamic acid (SAHA) or C646.</p><p><strong>Main outcome(s) and measure(s): </strong>FKBP5 expression, mineralized nodule formation, alkaline phosphatase (ALP) activity, odontogenic marker expression, inflammatory cytokine expression, FKBP5 promoter chromatin accessibility, promoter methylation, H3K9ac/H3K27ac enrichment, reparative dentin formation and collagen formation were assessed.</p><p><strong>Results: </strong>FKBP5 was upregulated during odontogenic differentiation induction and highly expressed in human pulpitis tissues and injured rat pulps. Overexpression of FKBP5 promoting reparative dentin formation, collagen synthesis and mineralization (dentin sialophosphoprotein and dentin matrix protein 1 expressions). Down-regulation of inflammatory factors Interleukin-1β and Interleukin-8 also contributed to the process of pulp repair. H3K9ac and H3K27ac, rather than DNA methylation, were enriched at the FKBP5 promoter, enhancing chromatin accessibility and FKBP5 transcription. SAHA enhanced H3K9ac and H3K27ac and the expression of FKBP5 near the injury site. The newly-formed reparative dentin was upregulated and pulp inflammation was suppressed with the application of SAHA.</p><p><strong>Conclusions and relevance: </strong>FKBP5 facilitated reparative dentin and neoplastic collagen synthesis at the injury site while mitigating inflammation. Histone acetylation H3K9 and H3K27 were the mechanism that modulated differentiation effects of FKBP5.</p>","PeriodicalId":21986,"journal":{"name":"Stem Cells Translational Medicine","volume":"15 8","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13415464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148607527","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}