Regenerative Therapy最新文献

{"title":"Cholangiocyte-derived exosomal miR-381-3p promotes hepatic stellate cell activation and cholestatic liver fibrosis via targeting Klf6","authors":"Yang Gao,&nbsp;Yonglin Chen,&nbsp;Yuanyi Mang,&nbsp;Xibing Zhang,&nbsp;Xiaoshan Li,&nbsp;Shengning Zhang","doi":"10.1016/j.reth.2025.09.008","DOIUrl":"10.1016/j.reth.2025.09.008","url":null,"abstract":"<div><h3>Introduction</h3><div>The activation of hepatic stellate cells (HSCs) is a central mechanism driving the progression of chronic cholestatic liver diseases (CCLD). MicroRNAs (miRNAs) have been increasingly recognized for their regulatory roles in various liver pathologies. This study aimed to identify specific miRNAs involved in the progression of CCLD and elucidate their underlying molecular mechanisms.</div></div><div><h3>Methods</h3><div>A bile duct ligation (BDL) mouse model was established to mimic cholestatic liver injury. Exosomes were isolated from mouse large cholangiocytes (MLE) and co-cultured with HSCs to investigate their functional effects. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was employed to assess the expression levels of fibrotic marker genes. Exosomal miRNA microarray assay was used to screen differentially expressed miRNAs. Furthermore, dual-luciferase reporter assays and RNA pull-down experiments were conducted to validate the interaction between miR-381-3p and its putative target gene, kinesin family member 6 (Klf6).</div></div><div><h3>Results</h3><div>The results confirmed the successful isolation of exosomes from MLE. Furthermore, exosomes derived from BDL-MLE were shown to promote the activation of HSCs and exacerbate hepatic fibrosis. Dicer knockout reduced the mRNA expression of key fibrotic markers. In addition, miR-381-3p was found to be upregulated both in BDL-MLE–derived exosomes and in HSCs treated with transforming growth factor (TGF)-β and BDL-MLE–exosomes. Mechanistic investigations identified Klf6 as a direct target gene of miR-381-3p. Rescue experiments further revealed that overexpression of Klf6 alleviated the pro-fibrotic effects caused by miR-381-3p overexpression, thereby attenuating HSC activation and mitigating cholestatic liver fibrosis.</div></div><div><h3>Conclusion</h3><div>This study highlighted the role of MLE-derived exosomal miR-381-3p in promoting HSC activation and cholestatic liver fibrosis through the regulation of Klf6. These findings provide novel insights into the molecular mechanisms underlying CCLD.</div></div>","PeriodicalId":20895,"journal":{"name":"Regenerative Therapy","volume":"30 ","pages":"Pages 769-777"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145157155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subretinal suspensions of hiPSC-derived retinal pigment epithelium cells form functional monolayers in NOD-SCID mice facilitating treatment of advanced retinal diseases","authors":"Xiaojing Song ,&nbsp;Guanjie Gao ,&nbsp;Ke Ye,&nbsp;Ping Xu,&nbsp;Yuan Wang,&nbsp;Suai Zhang,&nbsp;Dandan Zheng,&nbsp;Jian Ge,&nbsp;Xiufeng Zhong","doi":"10.1016/j.reth.2025.06.021","DOIUrl":"10.1016/j.reth.2025.06.021","url":null,"abstract":"<div><h3>Introduction</h3><div>Transplantation of human induced pluripotent stem cells derived retinal pigment epithelium (hiPSC-RPE) is regarded as one of the most promising strategies for advanced retinal degenerative diseases leading to blindness, such as age-related macular degeneration. Despite its therapeutic potential, this approach is encumbered by critical challenges, notably the survival of donor RPE cells post-transplantation and the successful reconstruction of a functional RPE layer.</div></div><div><h3>Methods</h3><div>With our previously reported strategy, abundant hiPSC-RPEs were generated from human induced pluripotent stem cells. These cells were characterized <em>in vitro</em> by morphology, marker expression and function. Further, hiPSC-RPE cell suspensions were injected into the eyes of NOD-SCID mice. Animals were monitored by optical coherence tomography screening and color fundus imaging to evaluate the survival of hiPSC-RPEs. Polarity, maturity, integration and phagocytosis of hiPSC-RPEs were analyzed histologically.</div></div><div><h3>Results</h3><div>hiPSC-RPE cells exhibited a cobblestone morphology with abundant microvilli and tight junctions, expressed RPE specific molecular markers, and possessed ability to phagocytize photoreceptor outer segments (POS), thereby resembling the characteristics of the native human RPE cells. Following transplantation into NOD-SCID mice, the cells survived for the 8-week testing period and formed a highly organized monolayer in regions with an intact Bruch's membrane (BM) in the host retina. The reconstructed RPE layer expressed both human-specific and RPE-specific markers with POS phagocytic function. No severe adverse effects, such as malignant tumors or infections, were observed.</div></div><div><h3>Conclusions</h3><div>These findings demonstrate that hiPSC-RPE suspensions can survive and form RPE monolayers with morphological and functional features analogous to those of native human RPE cells in the host retina with a healthy BM. Our study may facilitate the development of cell-based therapies for treatment of advanced retinal degenerations.</div></div>","PeriodicalId":20895,"journal":{"name":"Regenerative Therapy","volume":"30 ","pages":"Pages 503-514"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144772685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tracking adipose-derived mesenchymal stromal cells in the eye: Integrating IVIS imaging and Alu PCR for enhanced detection of human cells","authors":"Robert M. Rusch ,&nbsp;Emi Inagaki ,&nbsp;Kentaro Ago ,&nbsp;Tetsu Yoshida ,&nbsp;Yui Ueno ,&nbsp;Hidenori Nonaka ,&nbsp;Hideyuki Okano ,&nbsp;Masaya Nakamura ,&nbsp;Shigeto Shimmura","doi":"10.1016/j.reth.2025.06.018","DOIUrl":"10.1016/j.reth.2025.06.018","url":null,"abstract":"<div><h3>Introduction</h3><div>Cell transplantation finds broad applications in medical science, with applications ranging from stem cell therapies to cancer research. Despite its widespread use, inherent risks such as tumor formation and immune rejection necessitate a comprehensive understanding of transplanted cell dynamics. Thus, tracing cellular behavior is a critical aspect of medical research, particularly in the context of cell transplantation. The capacity to precisely monitor and evaluate the behavior of transplanted cells over time is essential for evaluating therapeutic effectiveness, safety profiles, and long-term consequences.</div><div>Traditional imaging approaches, like Z-stack and overlay images, present challenges due to limitations in sample size, determining cell location and migration, and only observing the one moment of the therapeutical application. However, recent advancements in imaging technologies have significantly improved our ability to trace cellular behavior in vivo. Bioluminescence imaging (BLI) has emerged as a powerful tool for non-invasive, real-time monitoring of cell survival, proliferation, and distribution in animal models. The in vivo imaging system (IVIS) for instance, focuses on its non-invasive nature and versatile applications in real-time investigations. Genetically modified cells express luciferase, allowing for the detection of light emission when luciferin is administered. BLI offers high sensitivity and the ability to track cells over extended periods, providing crucial information about cell engraftment and persistence.</div></div><div><h3>Method</h3><div>Transfecting human adipose mesenchymal stem cells (adMSCs) with a lentiviral vector encoding firefly luciferase under the CAG promoter (CAG-ffLuc-cp156), which allows to establish a comprehensive understanding of adMSC behavior, distribution, and therapeutic safety, addressing a critical obstacle in the clinical evaluation of stem cell applications. The study tracked transfected adMSCs over seven days, with subsequent analysis of human DNA distribution by Alu-PCR.</div></div><div><h3>Result</h3><div>Data indicates adMSCs disappear from the recipient by day 7, corroborated by the absence of human DNA in tested organs. The primary objective is to present a methodology for subconjunctival delivery, investigating the biodistribution and migration of adMSCs post-injection, with potential implications for various cell therapies.</div></div><div><h3>Conclusion</h3><div>This study provides a valuable methodology for investigating cell behavior post-injection, contributing to the optimization of cell therapies for clinical applications. Furthermore, it highlights the safety of applying adMSCs with relatively low potential of tumorgenicity.</div></div>","PeriodicalId":20895,"journal":{"name":"Regenerative Therapy","volume":"30 ","pages":"Pages 333-338"},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From an Antimicrobial Agent to a constituent of 3D Printed Heterogenous Scaffolds Stimulating Bone Characteristics: An In-vitro and Animal model evaluation","authors":"Shahad Ahmed Daood ,&nbsp;Martha Then Xin Yi ,&nbsp;Nicole Wen Ce Mun ,&nbsp;Sharjeel Ilyas ,&nbsp;Lee Yin Shien ,&nbsp;Oh Jia En ,&nbsp;Syed Saad Bin Qasim ,&nbsp;Yichen Dai ,&nbsp;Galvinderjeet Kaur Grewal ,&nbsp;Ng Mei Liit ,&nbsp;Gopu Sriram ,&nbsp;Malikarjuna Rao Pichika ,&nbsp;Kit-Kay Mak ,&nbsp;Ranjeet Ajit Bapat ,&nbsp;Zeeshan Sheikh ,&nbsp;Umer Daood","doi":"10.1016/j.reth.2025.08.001","DOIUrl":"10.1016/j.reth.2025.08.001","url":null,"abstract":"<div><div>This paper describes a promising candidate molecule, investigates the pattern of scaffold composition which arises and assesses the effect of the agent on its mechanical properties.</div></div><div><h3>Methods</h3><div>Scaffold samples were fabricated using a commercial extrusion bioprinter equipped with a pneumatic printhead fitted with a 21G conical nozzle. The Pore Printability Index, and the area and perimeter of the pore within the grid patterns were quantified using ImageJ software (NIH, USA). Mechanical properties of scaffolds were assessed using atomic force microscopy. The phase composition and crystal structures were analyzed using X-ray diffraction and Raman mapping. Morphologies of human gingival fibroblastic cells were examined using scanning electron microscopy. Lactobacillus biofilms were generated for cytolysin peptide cleavage. A rabbit bone defect model with scaffold implantations was used to provide histologic specimens for measuring percentages of bone trabeculae, collagen fibers and inflammatory cells along with granulation tissue. The Primeway Total RNA Extraction Kit was used for RNA extraction.</div></div><div><h3>Results</h3><div>All bioink formulations demonstrated successful printing of 3D grid and solid square patterned scaffolds achieving Pr values exceeding 0.9. _{<strong>0.1</strong> <strong>%</strong>}<strong>K21</strong> group showed the highest elastic modulus. XRD revealed a pattern producing around 90 % β-tricalcium phosphate displaying two peaks at 2θ angles. 0.1 % K21 and _{<strong>0.1</strong> <strong>%</strong>}<strong>CHX</strong> did not alter scaffold's pore size and porosity. _{<strong>0.1</strong> <strong>%</strong>}<strong>K21</strong> group exhibited highest ratio (62.5 ± 6.1 θ), significantly surpassing control. Surface morphologies of cells were also well retained. TEM image shows a sequence of structural changes in fibroblastic cell structure when exposed to K21. 0.1 % K21 proved to be critical in completely eradicating the biofilm. <strong>_0.K21</strong> group closed the openings of wound areas completely. Correlation coefficient of gene expression levels demonstrates sample variations and recurring instances among groupings.</div></div><div><h3>Conclusion</h3><div>3D-printing technologies with _{<strong>0.1</strong> <strong>%</strong>}<strong>K21</strong> represent a significant advancement over conventional regenerative medicine techniques for bone-related treatments.</div></div>","PeriodicalId":20895,"journal":{"name":"Regenerative Therapy","volume":"30 ","pages":"Pages 558-574"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144826956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mesenchymal stem cells in neurological disorders: Insights from clinical trials","authors":"Beatriz Araújo ,&nbsp;Inês Serrenho ,&nbsp;Andreia Valente da Silva ,&nbsp;Bragança Moisés Marceta ,&nbsp;Graça Baltazar","doi":"10.1016/j.reth.2025.10.020","DOIUrl":"10.1016/j.reth.2025.10.020","url":null,"abstract":"<div><div>Mesenchymal stem cells (MSCs) exhibit unique properties that make them promising candidates for cell therapy, particularly in neurological disorders. They can be derived from various tissues, with bone marrow, adipose tissue, umbilical cord, and placenta being the most common sources. Evidence suggests that the tissue of origin significantly influences MSC characteristics, including secretome composition, proliferation rate, and adhesion capacity.</div><div>Clinical trials have demonstrated the safety and therapeutic potential of MSCs in conditions such as spinal cord injury, multiple sclerosis, and stroke. MSC therapy has been associated with improvements in motor, sensory, and cognitive functions, as well as enhanced quality of life. Mechanistically, MSCs promote neuroprotection, reduce inflammation, and modulate immune responses. In spinal cord injury, intrathecal administration of adipose- and bone marrow-derived MSCs has led to significant functional recovery, with single high-dose treatments often yielding better outcomes than multiple lower doses. In amyotrophic lateral sclerosis, bone marrow-derived MSCs have shown potential in slowing disease progression, though higher doses do not always result in greater benefits. In multiple sclerosis, high doses of umbilical cord-derived MSCs improved quality of life and prevented disease progression, whereas lower doses of bone marrow-derived MSCs provided limited functional benefits.</div><div>While MSC therapy is considered safe, patient responses vary, and a definitive correlation between administered dose and therapeutic effects remains elusive. The small number of studies using comparable protocols impedes comparison of other relevant factor, limits the drawing of conclusions and underscore the importance of developing standardized protocols to optimize MSC-based treatments and maximize their clinical efficacy.</div></div>","PeriodicalId":20895,"journal":{"name":"Regenerative Therapy","volume":"30 ","pages":"Pages 1024-1035"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145464866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preface of the special issue “Mechanisms of reprogramming for cell differentiation and tissue regeneration”","authors":"Goshi Shiota (Senior Associate Editor)","doi":"10.1016/j.reth.2025.05.005","DOIUrl":"10.1016/j.reth.2025.05.005","url":null,"abstract":"","PeriodicalId":20895,"journal":{"name":"Regenerative Therapy","volume":"30 ","pages":"Page 46"},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144071544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mid-term outcomes of a bio-artificial pleura composed of autologous dermal fibroblasts used to close intraoperative pulmonary air leaks caused by intraoperative pleural injury: A case report","authors":"Masato Kanzaki ,&nbsp;Ryo Takagi ,&nbsp;Shota Mitsuboshi ,&nbsp;Tamami Isaka ,&nbsp;Masayuki Yamato","doi":"10.1016/j.reth.2025.06.001","DOIUrl":"10.1016/j.reth.2025.06.001","url":null,"abstract":"<div><h3>Introduction</h3><div>The visceral pleura is a thin, serous membrane that closely covers the surface of the lung. The pleura is injured or ruptured, causing air to accumulate in the thoracic cavity and the lung to collapse. Increased pleural pressure due to lung air leaks (LALs) from the lung can have serious effects. LALs are frequently observed due to pleural injury caused by lung resection. Postoperative LALs prolongs hospital stay and has a significant impact on patients' postoperative quality of life. Based on the above background, we developed and reported the effectiveness of dermal fibroblast sheet (DFS) as a bio-artificial pleura for closing LALs caused by intraoperative pleural injury in humans for the first time in a clinical study. There are no mid-term reports of bio-artificial pleura created using tissue engineering. In this study, we report the safety of bio-artificial pleural transplantation using cultured autologous DFS for pleural injury in two cases.</div></div><div><h3>Previous study and case presentation</h3><div>Two of the five patients who met the criteria and underwent LAL closure using a bio-artificial pleura between May 2016 and March 2018 were followed up mid-term. Although the criteria included a 6-month monitoring period after LAL closure, these two patients continued to visit our hospital beyond the monitoring period for treatment of other comorbid conditions. Case 1. A male in his 40s who was receiving long-term steroid therapy for Takayasu's disease and underwent thoracoscopic lung wedge resection for a benign lung tumor in the left anteromedial basal segment. During surgery, the minor LALs from the resection margins with an automatic stapler were closed with a bio-artificial pleura, specifically, a total of three DFSs. During the patient's 51-month follow-up, no LAL recurrence, tumor development, infiltration, and fibrogenesis were observed. Case 2. A female patient in her 70s had bullae associated with combined pulmonary fibrosis and emphysema (CPFE). Thoracoscopic bullectomy of the left lower lobe was performed, and the major LALs were closed intraoperatively with a bio-artificial pleura consisting of a total of eight DFSs. She was readmitted for contralateral pneumonia 2 months after surgery. During a follow-up period of 82 months, no LAL recurrence and tumor development was observed in the operated left lung. However, chest CT revealed slowly progressing CPFE lesions.</div></div><div><h3>Conclusions</h3><div>This report of two cases demonstrated the mid-term safety of bio-artificial pleural transplantation using cultured autologous DFS for pleural injury.</div></div>","PeriodicalId":20895,"journal":{"name":"Regenerative Therapy","volume":"30 ","pages":"Pages 234-240"},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144338775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A bibliometric analysis of the global status of platelet-rich plasma in regenerative medicine from 2004 to 2023","authors":"Siwen Zhang ,&nbsp;Xudong Zhang ,&nbsp;Haochen Zhang ,&nbsp;Shengqing Zhang ,&nbsp;Zichen Liu ,&nbsp;Shanshan Wu ,&nbsp;Yimeng Lu ,&nbsp;Chao Han ,&nbsp;Jichun Tan","doi":"10.1016/j.reth.2025.07.007","DOIUrl":"10.1016/j.reth.2025.07.007","url":null,"abstract":"<div><h3>Introduction</h3><div>Platelet-rich plasma (PRP) is a plasma product that concentrates platelets from whole blood and used widely in regenerative medicine. This study aimed to evaluate the evolution, development trend, and research highlights of research status of PRP in regenerative medicine.</div></div><div><h3>Methods</h3><div>Publications related to PRP were retrieved from the Science Citation Index Expanded (SCIE) database of the Web of Science (WoS) in February 2024. The impact factor (IF) was used to evaluate and compare the contributions of different countries. Then, the top 10 countries, top 10 productive journals, top 10 WoS categories, and top 10 most cited articles were listed. The data was processed, and the relative contributions of the top 10 productive countries in each year were presented in a line chart and a heatmap. VOSviewer software and heatmap were used to investigate the holistic trend of research highlights according to the change trends of keywords.</div></div><div><h3>Results</h3><div>A total of 9,577 publications were retrieved from SCIE database. The USA topped the list with 2,311 papers, followed by China (1,583 papers), the UK (525 papers), and Spain (512 papers). The studies of PRP in regenerative medicine have increasing trend globally. The USA had the most total citation and took the leading position for relative contributions, the UK ranked 1st in average citations and average IF. However, China's contribution had a dramatically increasing trend since 2015, and exceeded the USA in 2022. There were seven keywords of “Bone-related cluster”, “hyaluronic acid-related cluster”, “cartilage-related cluster”, “stomatology-related cluster”, “damage repair-related cluster”, “experiment-related cluster”, and “nerve-related cluster” generated in keyword co-occurrence analysis. Except for bone &amp; joint diseases, novel clinical applications of PRP have been carried out, including dental and neurological practice, reproductive medicine, dermatology, gynecology, and plastic surgery, cosmetic treatments, and the improvement of non-musculoskeletal organ function.</div></div><div><h3>Conclusion</h3><div>To summarize, the research advancements of PRP appear to be more prominent in the United States and China. Experimental research on PRP is mostly concentrated on exploring on mechanism and signal pathway. As an effective adjuvant treatment, the clinical application of PRP has expanded from initial trauma repair to multiple systemic organ disorders. Leveraging the intersection of multiple disciplines, the development of novel PRP-based medical materials tailored to specific disease characteristics may represent a promising direction for future research.</div></div>","PeriodicalId":20895,"journal":{"name":"Regenerative Therapy","volume":"30 ","pages":"Pages 456-464"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144724656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human iPSC-derived cerebral organoids reveal oxytocin-mediated protection against amyloid-β pathology","authors":"Tomoki Asaba,&nbsp;Sayuri Hamano,&nbsp;Ayaka Nanmo,&nbsp;Jieun Seo,&nbsp;Tatsuto Kageyama,&nbsp;Junji Fukuda","doi":"10.1016/j.reth.2025.06.013","DOIUrl":"10.1016/j.reth.2025.06.013","url":null,"abstract":"<div><h3>Introduction</h3><div>Neuroinflammation is a key contributor to the pathogenesis of Alzheimer's disease (AD), and impaired clearance of amyloid-β (Aβ) by microglia is closely associated with disease progression. Oxytocin (OXT), a hypothalamic neuropeptide, has recently been reported to exert anti-inflammatory effects on microglia; however, its therapeutic potential in the human brain remains unclear.</div></div><div><h3>Methods</h3><div>We generated human cerebral organoids (hCOs) from induced pluripotent stem cells (iPSCs) to model early AD-like pathology. Aβ toxicity was induced by applying 3 μM Aβ_1–42 for 48 h. The protective effects of OXT were evaluated through immunohistochemistry, RT-qPCR, calcium imaging, and multielectrode array (MEA) recordings. The involvement of microglia in Aβ clearance was assessed by immunostaining and gene expression analysis of TREM2.</div></div><div><h3>Results</h3><div>Aβ exposure led to significant deposition of Aβ in the outer layers of hCOs, accompanied by suppressed neural activity and increased apoptotic signaling. Pretreatment with OXT attenuated Aβ deposition and caspase-3-mediated apoptosis in a concentration-dependent manner. OXT also restored calcium oscillations and neuronal network activity as measured by MEA. Notably, OXT enhanced the recruitment of microglia to Aβ deposits and upregulated the expression of TREM2, a key regulator of microglial phagocytosis. Co-expression of oxytocin receptors (OXTR) on Iba1-positive microglia suggests that OXT directly modulates microglial activation and Aβ clearance.</div></div><div><h3>Conclusions</h3><div>OXT has neuroprotective effects on human cortical organoids by preserving their neuronal activity and promoting microglial-mediated Aβ clearance. This study provides novel insights into the therapeutic potential of OXT for targeting neuroinflammation and Aβ pathology in patients with AD.</div></div>","PeriodicalId":20895,"journal":{"name":"Regenerative Therapy","volume":"30 ","pages":"Pages 259-267"},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144479962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanosecond pulsed electric field applications rejuvenate aging endothelial cells by rescuing mitochondrial-to-nuclear retrograde communication","authors":"Meifang Yin ,&nbsp;Jie Xiao ,&nbsp;Guangtao Huang ,&nbsp;Huanyu Xie ,&nbsp;Hongwei Liu ,&nbsp;Jianqiang Yuan ,&nbsp;Xiaofang Liu ,&nbsp;Anna Chiarini ,&nbsp;Ubaldo Armato ,&nbsp;Ilaria Dal Prà ,&nbsp;Shumaila Ijaz ,&nbsp;Naziat Begum ,&nbsp;Lingyun Wang ,&nbsp;Jun Wu","doi":"10.1016/j.reth.2025.06.004","DOIUrl":"10.1016/j.reth.2025.06.004","url":null,"abstract":"<div><h3>Introduction</h3><div>Endothelial cell aging is strongly associated with mitochondrial dysfunction, particularly the disruption of mitochondrial-nuclear retrograde communication (MNRC), which is essential for sustaining cellular homeostasis and regulating crucial cellular processes. Nanosecond pulsed electric fields (nsPEF) were shown to exert biological effects by targeting mitochondria. However, the nsPEF regulation of MNRC is still unclear.</div></div><div><h3>Methods</h3><div>In this study, we set up an <em>in vitro</em> model of <span>d</span>-galactose-induced senescence in human umbilical vein endothelial cells (HUVECs) to investigate the effects of nsPEF treatment on oxidative stress, cell proliferation, mitochondrial membrane potential, and markers of MNRC (MNRC), including HIF-1α and SIRT1. Moreover, we conducted <em>in vivo</em> animal experiments to evaluate nsPEF treatment's effects on HIF-1α and SIRT1 protein expression in endothelial cells (ECs) of <em>in vivo</em> rodents' aging/senescing skin tissue, as well as to examine any later changes in vascular density within the skin.</div></div><div><h3>Results</h3><div>In vitro results showed that nsPEF treatment suppressed <span>d</span>-galactose-induced senescing effects as they rescued mitochondrial membrane potential, and activated HIF-1α and SIRT1. These effects were confirmed by concurrent reductions in SA-β-Gal activity and in ROS production, and increases in EdU-positive (DNA-synthesizing) cells. Our data showed that nsPEF treatments rescued endothelial cells from <span>d</span>-galactose senescence. Interestingly, nsPEF selectively targeted senescing cells at the tested dose, with no detectable effect on otherwise untreated (normal) HUVECs. In vivo nsPEF treatments upregulated the expression of HIF-1α and SIRT1 in ECs and promoted neoangiogenesis in aged/senescent rodents' skin.</div></div><div><h3>Conclusions</h3><div>These findings suggest that nsPEF treatments rescue ECs from aging by restoring MNRC, highlighting its potential as a therapeutic strategy for age-related vascular diseases.</div></div>","PeriodicalId":20895,"journal":{"name":"Regenerative Therapy","volume":"30 ","pages":"Pages 207-216"},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144307633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}