Inflammation and regeneration最新文献

{"title":"Lysophosphatidic acid promotes cutaneous wound healing through vascular maturation and fibroblast activation in a murine model.","authors":"Kazuhiro Takara, Aika Yamamoto, Naoi Hosoe, Miku Aoki, Takenao Chino, Takayuki Sonoda, Shintaro Yamada, Yumiko Hayashi, Lamri Lynda, Minoru Hasegawa, Junko Yotsuya, Hiroyasu Kidoya","doi":"10.1186/s41232-026-00441-5","DOIUrl":"10.1186/s41232-026-00441-5","url":null,"abstract":"<p><strong>Background: </strong>Impaired cutaneous wound healing is a major clinical burden, particularly among older individuals and patients with diabetes. Lysophosphatidic acid (LPA) is a bioactive phospholipid with known roles in cell proliferation, migration, and vascular formation; however, its mechanistic contribution in wound repair has not been systematically characterized. Therefore, this study aimed to determine whether topical LPA accelerates wound closure in a murine full-thickness excisional wound model and to elucidate the underlying cellular and molecular mechanisms.</p><p><strong>Methods: </strong>Full-thickness excisional wounds were created on the dorsal skin of mice, and LPA or vehicle was applied once daily. Wound closure was assessed over 13 days using digital planimetry. Bulk RNA sequencing, quantitative reverse transcription polymerase chain reaction, immunofluorescence, flow cytometry, vascular permeability, and tissue hypoxia assays were employed to delineate the underlying mechanisms. Published single-cell RNA sequencing data from mouse skin were re-analyzed to map LPA receptor expression.</p><p><strong>Results: </strong>Topical LPA accelerated the closure of full-thickness excisional skin wounds. Transcriptomic analysis identified upregulation of gene programs associated with vasculature development and extracellular matrix organization. LPA markedly increased endothelial cell numbers and vessel density. Critically, the vessels formed in LPA-treated wounds subsequently displayed elevated pericyte coverage, reduced permeability, and decreased tissue hypoxia, indicating functional vascular maturation. Concurrently, fibroblast-associated matrix genes were upregulated, collagen deposition was accelerated, and lymphangiogenesis was promoted at the wound site. Single-cell analysis implicated LPAR1 in fibroblasts and LPAR4/LPAR6 in endothelial cells as candidate mediators of these effects.</p><p><strong>Conclusions: </strong>LPA promotes both vascular maturation and fibroblast activation during wound repair, distinguishing it from classical pro-angiogenic factors. These findings establish LPA as a mechanistically distinct therapeutic candidate and suggest a novel approach for targeting vascular maturation in cutaneous wound care.</p>","PeriodicalId":94041,"journal":{"name":"Inflammation and regeneration","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13523234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148842598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Allogeneic skin transplantation induces transient fibrosis that undergoes spontaneous regression in newts.","authors":"Kento Hosomi, Maya Nagata, Mika Okada, Kodai Hirano, Eishin Yamada, Toshinori Nakagawa, Kazuaki Maruyama, Chihena Hansini Banda, Makoto Shiraishi, Kanako Danno, Chikafumi Chiba, Mitsunaga Narushima","doi":"10.1186/s41232-026-00438-0","DOIUrl":"10.1186/s41232-026-00438-0","url":null,"abstract":"<p><strong>Background: </strong>In humans, large skin defects require tissue transplantation because adult skin lacks full regenerative capacity. However, allogeneic grafts are typically rejected due to strong immune responses, whereas autologous grafts often result in severe fibrosis and permanent scarring. In contrast, regenerative vertebrates such as newts can restore tissues with minimal scarring, suggesting the presence of distinct mechanisms regulating tissue repair. How such organisms respond to immune activation induced by non-self tissue transplantation remains unclear. In this study, we aimed to determine how adult newts respond to allogeneic skin transplantation and to examine whether fibrosis induced under such conditions is sustained or resolved.</p><p><strong>Methods: </strong>We established an allogeneic skin graft model in adult Japanese fire-bellied newts and compared it with autologous grafting. Graft fate, tissue morphology, fibrosis, and immune cell dynamics were analyzed histologically over time. To assess the contribution of macrophage-lineage cells, animals were treated with clodronate liposomes prior to transplantation.</p><p><strong>Results: </strong>In contrast to mammals, allogeneic grafts did not exhibit typical features of acute rejection and did not show apparent graft loss. Following transplantation, grafts exhibited a characteristic sequence of changes: initial vascular integration, subsequent loss of detectable perfusion, and progressive remodeling of graft appearance. At the donor-host interface, a distinct collagen-rich fibrotic tissue formed, accompanied by marked leukocyte infiltration. This tissue appeared at 2 weeks, reached maximal thickness at 4 weeks, and regressed by 8 weeks. During this period, the graft surface gradually acquired host-like pigmentation, while structural elements of donor tissue remained detectable histologically. Iba1-positive macrophage-lineage cells accumulated within the graft during the fibrotic phase and decreased as the tissue regressed. Depletion of these cells did not prevent fibrosis formation but delayed its regression and prolonged graft thickening.</p><p><strong>Conclusions: </strong>Allogeneic skin transplantation in adult newts induces a distinct response in which non-self tissue is not completely lost and a collagen-rich fibrotic tissue forms transiently and subsequently undergoes resolution. These findings suggest that fibrosis induced under non-self immune activation is not necessarily a terminal state but may represent a dynamically regulated process capable of resolution.</p>","PeriodicalId":94041,"journal":{"name":"Inflammation and regeneration","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13430897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148671725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autoreactive B cells in systemic lupus erythematosus: insights from integrative multi-omics analyses.","authors":"Toshiyuki Shiki Ushijima, Tomohisa Okamura, Keishi Fujio","doi":"10.1186/s41232-026-00432-6","DOIUrl":"10.1186/s41232-026-00432-6","url":null,"abstract":"<p><p>Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the emergence of autoantibodies and deposition of immune complexes. SLE presents with heterogeneous multi-organ involvement that varies among patients and its mechanisms have been investigated to facilitate appropriate stratification and treatment selection. Bulk RNA-seq and bulk ATAC-seq have provided important insights into the pathogenesis of SLE; however, these approaches are inherently limited by their reliance on predefined cell subsets and known markers, which can introduce bias and restrict their ability to fully resolve cellular heterogeneity. Recent advances in multi-omics analyses have enabled the investigation of multi-layered information beyond single-cell RNA sequencing (scRNA-seq) alone and have contributed substantially to elucidating the pathogenesis of SLE. Although the emergence of autoreactive B cells and the production of autoantibodies in SLE are well established, the mechanisms of evasion from negative selection remain unclear. Multi-omics analyses have revealed key aspects of SLE pathogenesis, particularly the expansion of atypical B cells (ABCs), an autoreactive population driven by extrafollicular pathways. Furthermore, beyond transcriptional profiling, multi-omics analysis has emerged as an additional investigative method, which combines scRNA-seq with other modalities. Spatial analyses, for instance, have provided critical insights into the tissue localization and persistence of autoreactive B cells within inflammatory niches in lupus nephritis, suggesting that local microenvironments contribute to treatment resistance. Additionally, B cell receptor (BCR) sequencing has revealed distinctive BCR features in SLE, such as reduced somatic hypermutation, increased repertoire naiveness, and increased immunoglobulin variable region heavy chain gene (IGHV4-34) usage in B cells in bone marrow and affected organs (not only in peripheral blood). Furthermore, emerging multimodal approaches integrating spatial, transcriptomic, and epigenomic information further highlight pathogenic cell-cell interactions and inflammatory circuits that cannot be captured by scRNA-seq alone. In this review, we summarize recent multi-omics studies that elucidate the origin, differentiation, and tissue localization of pathogenic B cells in SLE. We provide an overview of the multi-omics analyses focusing on B cells so far, especially at single-cell resolution, and discuss their possible applications in precision medicine.</p>","PeriodicalId":94041,"journal":{"name":"Inflammation and regeneration","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13383539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148474862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of tissue-state plasticity: a conceptual framework for age-associated regenerative failure.","authors":"Takayoshi Otsuka, Hideaki Matsui","doi":"10.1186/s41232-026-00435-3","DOIUrl":"10.1186/s41232-026-00435-3","url":null,"abstract":"<p><p>Tissue regeneration depends on the activation of resident stem and progenitor cells, dynamic interactions with the extracellular matrix (ECM), and tightly regulated growth factor signaling, including fibroblast growth factors (FGFs) and transforming growth factor-β (TGF-β). Numerous therapeutic strategies have aimed to enhance repair through exogenous growth factor delivery or stem cell transplantation. However, despite the presence of abundant regenerative signals, including those derived from the senescence-associated secretory phenotype (SASP), regenerative capacity declines with age across multiple organs. This discrepancy suggests that age-related regenerative decline reflects not a reduction in signal availability, but a profound alteration in how tissues interpret and respond to those signals. Here, we propose a conceptual framework centered on the concept of \"tissue state\"-a metastable, tissue-wide organizational mode that determines how incoming signals are interpreted and executed. Tissue state is shaped by the integration of cellular composition, ECM properties, inflammatory context, and intracellular stress responses. Within this framework, exogenous signals are interpreted as context-dependent inputs, and their biological outcomes are determined by the pre-existing tissue state. We further discuss how this perspective reshapes our understanding of regenerative medicine, suggesting that restoring tissue-state flexibility may be a more effective therapeutic goal than simply augmenting signal availability.</p>","PeriodicalId":94041,"journal":{"name":"Inflammation and regeneration","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148427511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alveolar type II cell therapy ameliorates pulmonary fibrosis by reprogramming macrophage activation.","authors":"Raquel Guillamat-Prats, Gemma Gay-Jordi, Paula Duch, Sabrina Gea-Sorlí, Luis Ignacio Sanchez-Lopez, Victor Ivo Peinado, Anna Serrano-Mollar","doi":"10.1186/s41232-026-00434-4","DOIUrl":"10.1186/s41232-026-00434-4","url":null,"abstract":"<p><strong>Background: </strong>Alveolar type II (ATII) cell transplantation is a promising therapeutic strategy for idiopathic pulmonary fibrosis, although its underlying cellular mechanisms remain incompletely understood. Given that macrophage profibrotic activation is a key driver of fibrosis, we hypothesized that ATII cell therapy exerts antifibrotic effects by reprogramming macrophage activation states during the established fibrotic phase.</p><p><strong>Methods: </strong>In a rat model of bleomycin-induced pulmonary fibrosis, we characterized alveolar and interstitial macrophage profiles in control animals, in fibrotic animals, and after intratracheal transplantation of ATII cells performed on day 15 after bleomycin once fibrosis was established. Gene expression analyses were used to define macrophage activation profiles, while in vitro co-cultures of macrophages with ATII cells or fibroblasts assessed paracrine interactions and macrophage activation-state modulation. The CXCL12/CXCR4 signalling axis was further examined to explore potential mechanisms linking macrophage reprogramming to CXCR4⁺ cell dynamics, including recruitment of circulating CXCR4⁺ cells.</p><p><strong>Results: </strong>Disease progression promoted a prominent profibrotic activation profile enriched in M2-associated markers in both alveolar and interstitial macrophages. ATII cell transplantation markedly reduced macrophage infiltration and shifted their activation toward a less profibrotic, more homeostatic profile. In vitro, soluble mediators released by healthy ATII cells contributed to modulation of macrophage activation states, restoring a less profibrotic activation profile. Reciprocal crosstalk between macrophages and fibroblasts was observed: fibrotic macrophages enhanced fibroblast activation, whereas macrophages from control lungs exerted antifibrotic effects. Notably, ATII cell transplantation normalised CXCL12/CXCR4 axis expression and reduced the number of circulating CXCR4⁺ cells, suggesting that modulation of this axis may limit the recruitment of circulating CXCR4⁺ cells and attenuate profibrotic signalling.</p><p><strong>Conclusions: </strong>ATII cell transplantation ameliorates pulmonary fibrosis by restoring a less profibrotic immune microenvironment and modulating macrophage-fibroblast crosstalk. These effects are associated with reduced fibroblast activation and decreased accumulation of circulating CXCR4⁺ cells, consistent with attenuation of fibrotic responses.</p>","PeriodicalId":94041,"journal":{"name":"Inflammation and regeneration","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13647792/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148427560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toll-like receptor 4 signaling links cytoskeletal remodeling to lipid accumulation in macrophages.","authors":"En Wang, Hamizah Shahirah Hamezah, Rongchun Han, Xiaohui Tong","doi":"10.1186/s41232-026-00433-5","DOIUrl":"10.1186/s41232-026-00433-5","url":null,"abstract":"<p><strong>Background: </strong>Macrophage lipid accumulation is a hallmark of atherosclerosis and other metabolic diseases. Toll-like receptor 4 (TLR4) signaling and cytoskeletal remodeling have each been implicated in this process, yet the mechanistic connections among these three elements remain incompletely defined.</p><p><strong>Main body: </strong>This review synthesizes current evidence for pathways in which TLR4 activation, via bifurcated signaling through MyD88/TRAM, SYK/Src, and integrins, engages small GTPases (Rac, Cdc42, Rho) and downstream effectors including cofilin and paxillin to drive cytoskeletal remodeling. These cytoskeletal changes facilitate lipid internalization through multiple routes, including macropinocytosis, receptor redistribution, and lysosomal synapse formation, and regulate lipid droplet dynamics, ultimately promoting foam cell formation. We also discuss the therapeutic potential and safety challenges of targeting cytoskeletal regulators in diseases such as atherosclerosis.</p><p><strong>Short conclusion: </strong>The convergence of TLR4 signaling, cytoskeletal remodeling, and lipid metabolism represents a compelling mechanistic nexus for understanding foam cell formation. Elucidating the molecular details of this pathway-particularly the SYK/Src-cytoskeleton axis-may reveal macrophage-selective therapeutic targets that suppress pathological lipid accumulation while preserving host defense functions.</p>","PeriodicalId":94041,"journal":{"name":"Inflammation and regeneration","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148388369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial-derived peptide MOTS-c activates metabolic signaling but blunts reparative function in human mesenchymal stromal cells.","authors":"Li Xing, Bo Lu, Xiangyang Zhu, Mina Al Saeedi, Amir Lerman, Alfonso Eirin, Pinchas Cohen, Lilach O Lerman","doi":"10.1186/s41232-026-00431-7","DOIUrl":"10.1186/s41232-026-00431-7","url":null,"abstract":"<p><strong>Background: </strong>Mesenchymal stromal cells (MSCs) possess therapeutic potential largely reliant on intact mitochondrial function to maintain reparative function. However, obesity compromises MSC metabolism and reparative capacity. MOTS-c, a mitochondria-derived peptide, is known to regulate cellular metabolism, but its role in human MSC biology remains unclear. We hypothesized that restoring MOTS-c signaling rescues the impaired functionality of adipose-derived MSCs from individuals with obesity.</p><p><strong>Methods: </strong>MSCs isolated from abdominal fat of patients with obesity (BMI ≥ 30 kg/m²) and lean donors (BMI < 30 kg/m²) (n = 6/group) were assessed in vitro for changes in proliferation, senescence (p16, p21) TNF-α, and antioxidant gene expression following MOTS-c co-incubation. In vivo, the effects of MOTS-c pre-treatment on the reparative capacity of obese MSC were tested in stenotic mouse kidneys.</p><p><strong>Results: </strong>Basal MOTS-c expression was lower in obese vs. lean MSCs. Nevertheless, although exogenous MOTS-c restored intracellular levels and activated AMPK signaling in obese MSCs, it reduced proliferation, increased expression of senescence-associated genes (p16, p21), and upregulated TNF-α. In vivo, in a murine model of renal artery stenosis, MOTS-c-pretreated MSCs failed to improve renal perfusion, fibrosis, or tubular injury, while pretreatment also blunted the reparative efficacy of lean MSCs. These findings reveal that restoration of mitochondrial metabolic signaling is insufficient to reverse obesity-induced MSC dysfunction and may paradoxically exacerbate senescence and inflammation.</p><p><strong>Conclusion: </strong>These results suggest a dissociation between metabolic activation and functional stemness, underscoring context-dependent effects of mitochondrial-derived peptides in MSC biology.</p>","PeriodicalId":94041,"journal":{"name":"Inflammation and regeneration","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13536784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148298112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: A novel cell-free intrathecal approach with PRP for the treatment of spinal cord multiple sclerosis in cats.","authors":"Mariam F Farid, Yara S Abouelela, Noha A E Yasin, Mohamed R Mousa, Marwa A Ibrahim, Abdelbary Prince, Hamdy Rizk","doi":"10.1186/s41232-026-00430-8","DOIUrl":"10.1186/s41232-026-00430-8","url":null,"abstract":"","PeriodicalId":94041,"journal":{"name":"Inflammation and regeneration","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13285420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148298135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring cartilage development and disease models: applications of cartilage organoids.","authors":"Chenhao Xu, Qiu Dong, Pengling Zhao, Yuting Lei, Vincent Kam Wai Wong, Manseng Tam, Zhenyan Li, Zhengang Zha, Jinzhu Pang, Huan-Tian Zhang","doi":"10.1186/s41232-026-00429-1","DOIUrl":"10.1186/s41232-026-00429-1","url":null,"abstract":"<p><p>Cartilage is an avascular and aneural connective tissue vital for joint function, yet its limited intrinsic regenerative capacity poses significant challenges for treating injuries and degenerative diseases such as osteoarthritis (OA). Conventional models-including animal studies, cell lines, and primary chondrocyte cultures-exhibit considerable limitations in accurately replicating the native cartilage microenvironment, species-specific relevance, and differentiation potential. Recently, cartilage organoids have emerged as transformative tools that closely emulate the architecture, cellular heterogeneity, and extracellular matrix (ECM) properties of native cartilage, thereby offering a physiologically relevant platform for investigation. This review systematically examines the mechanisms governing chondrogenesis, including chondrocyte differentiation and matrix synthesis, as well as the construction of cartilage disease models. We focus on recent advances in cartilage organoid research, covering cultivation techniques, structural and functional characteristics, and diverse characterization methodologies. Furthermore, we highlight their applications in simulating pathological features of cartilage diseases, drug screening, toxicity testing, and gene therapy exploration. Current technological limitations-such as challenges in vascularization and mechanical strength-are discussed, together with future directions for developing multifunctional organoids and associated ethical and clinical considerations. This review aims to provide insights into the translational potential of cartilage organoids in regenerative medicine and disease modeling.</p>","PeriodicalId":94041,"journal":{"name":"Inflammation and regeneration","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13520458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148274401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling striatal development and disease with human pluripotent stem cells.","authors":"Sopak Supakul, Yuya Sasaki, Kosuke Karasawa, Yoshitaka Kase, Mitsuru Ishikawa, Hideyuki Okano","doi":"10.1186/s41232-026-00428-2","DOIUrl":"10.1186/s41232-026-00428-2","url":null,"abstract":"<p><p>The striatum plays a central role in motor control, cognition, reward processing, and habit formation, and its dysfunction is implicated in a broad spectrum of neurological and psychiatric disorders. Although animal models have provided important insights into striatal development and disease mechanisms, species-specific differences in cellular composition, developmental timing, and circuit organization limit their translational relevance to the human brain. In this context, human pluripotent stem cells (PSCs), including embryonic stem cells and induced pluripotent stem cells, have emerged as valuable platforms for modeling human striatal development and pathology in vitro. In this review, we summarize current approaches for generating striatal cell types from PSCs, with a particular focus on medium spiny neurons (MSNs), the principal projection neurons of the striatum. We discuss key developmental principles underlying dorsal and ventral striatal specification and highlight the protracted maturation of human MSNs, which may contribute to human-specific disease vulnerability. Advances in differentiation strategies, including small molecule-based patterning, transcription factor-driven induction, and three-dimensional organoid and assembloid systems, have progressively improved the efficiency, reproducibility, and cellular complexity of PSC-derived striatal models. We further review applications of PSC-derived striatal systems in disease modeling, noting that most studies to date have focused on Huntington's disease, where these models have revealed early developmental, transcriptional, synaptic, and network-level abnormalities. More recent studies have begun to extend these approaches to other neurological conditions and to incorporate circuit-level analyses using cortico-striatal assembloids. In parallel, the growing availability of single-cell and single-nucleus transcriptomic datasets from the human striatum provides powerful reference frameworks for benchmarking the identity and maturation state of PSC-derived striatal cells. Finally, we discuss current challenges and limitations of PSC-based striatal models, including incomplete maturation, limited representation of non-neuronal cell types, and restricted applicability to psychiatric disorders. We propose that continued integration of developmental biology, public multi-omics resources, and advanced in vitro modeling strategies will be essential for advancing human striatal models and expanding their utility in translational neuroscience.</p>","PeriodicalId":94041,"journal":{"name":"Inflammation and regeneration","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148260973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}