Axelle Bois, Catarina Grandela, James Gallant, Christine Mummery, Philippe Menasché
{"title":"Revitalizing the heart: strategies and tools for cardiomyocyte regeneration post-myocardial infarction.","authors":"Axelle Bois, Catarina Grandela, James Gallant, Christine Mummery, Philippe Menasché","doi":"10.1038/s41536-025-00394-2","DOIUrl":"10.1038/s41536-025-00394-2","url":null,"abstract":"<p><p>Myocardial infarction (MI) causes the loss of millions of cardiomyocytes, and current treatments do not address this root issue. New therapies focus on stimulating cardiomyocyte division in the adult heart, inspired by the regenerative capacities of lower vertebrates and neonatal mice. This review explores strategies for heart regeneration, offers insights into cardiomyocyte proliferation, evaluates in vivo models, and discusses integrating in vitro human cardiac models to advance cardiac regeneration research.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"10 1","pages":"6"},"PeriodicalIF":6.4,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11754855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143025793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qianqian Guo, Guokun Zhang, Jing Ren, Jiping Li, Zhen Wang, Hengxing Ba, Zihao Ye, Ying Wang, Junjun Zheng, Chunyi Li
{"title":"Systemic factors associated with antler growth promote complete wound healing.","authors":"Qianqian Guo, Guokun Zhang, Jing Ren, Jiping Li, Zhen Wang, Hengxing Ba, Zihao Ye, Ying Wang, Junjun Zheng, Chunyi Li","doi":"10.1038/s41536-025-00391-5","DOIUrl":"10.1038/s41536-025-00391-5","url":null,"abstract":"<p><p>Deer antlers are the only mammalian appendages that can fully regenerate from periosteum of pedicles (PP). This regeneration process starts from regenerative healing of wounds. Removal of PP abolishes antler regeneration, however, the regenerative cutaneous wound healing proceeds, indicating that some factors in the circulation contribute to this healing. In this study, we produced a wound in the scalp of deer either in antler regeneration period (ARP) (n = 3) or in non-ARP (n = 3). Results showed full regeneration took place only when the wound was created during ARP. Interestingly, topical application of systemic factors from ARP (n = 9) promoted regenerative wound healing in rats. Comparative proteomics analysis (n = 3) revealed that PRG4 and IGF-1 were high during ARP, and topical application of PRG4 + IGF-1 promoted restoration in rat FTE wounds. We believe that, ultimately, incorporating systemic factors into advanced wound care modalities could offer new opportunities for regenerative healing in the clinical setting.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"10 1","pages":"4"},"PeriodicalIF":6.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11756403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143016227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fei Fang, Matthew Casserly, Julia Robbins, Stavros Thomopoulos
{"title":"Hedgehog signaling directs cell differentiation and plays a critical role in tendon enthesis healing.","authors":"Fei Fang, Matthew Casserly, Julia Robbins, Stavros Thomopoulos","doi":"10.1038/s41536-025-00392-4","DOIUrl":"10.1038/s41536-025-00392-4","url":null,"abstract":"<p><p>A high prevalence of rotator cuff tears presents a major clinical challenge. A better understanding of the molecular mechanisms underlying enthesis development and healing is needed for developing treatments. We recently identified hedgehog (Hh)-lineage cells critical for enthesis development and repair. This study revealed cell-cell communication within the Hh-lineage cell population. To further characterize the role of Hh signaling, we used mouse models to activate and inactivate the Hh pathway in enthesis progenitors. Activation of Hh target genes during enthesis development increased its mineralization and mechanical properties. Activation of Hh signaling at the injured mature enthesis promoted fibrocartilage formation, enhanced mineralization, and increased expression of chondrogenic and osteogenic markers, which implies that Hh signaling drives cell differentiation to regenerate the damaged enthesis. Conversely, deletion of Hh target genes impaired enthesis healing. In summary, this study revealed a new strategy for enthesis repair via activation of Hh signaling in endogenous cells.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"10 1","pages":"3"},"PeriodicalIF":6.4,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143016153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hung-Chih Chen, Yu-Che Cheng, Marvin L Hsieh, Po-Ju Lin, Emily F Wissel, Theodore Steward, Cindy M C Chang, Jennifer Coonen, Timothy A Hacker, Timothy J Kamp, Patrick C H Hsieh
{"title":"Gut microbiota modulation in cardiac cell therapy with immunosuppression in a nonhuman primate ischemia/reperfusion model.","authors":"Hung-Chih Chen, Yu-Che Cheng, Marvin L Hsieh, Po-Ju Lin, Emily F Wissel, Theodore Steward, Cindy M C Chang, Jennifer Coonen, Timothy A Hacker, Timothy J Kamp, Patrick C H Hsieh","doi":"10.1038/s41536-025-00390-6","DOIUrl":"10.1038/s41536-025-00390-6","url":null,"abstract":"<p><p>Gut microbiota affect transplantation outcomes; however, the influence of immunosuppression and cell therapy on the gut microbiota in cardiovascular care remains unexplored. We investigated gut microbiota dynamics in a nonhuman primate (NHP) cardiac ischemia/reperfusion model while under immunosuppression and receiving cell therapy with human induced pluripotent stem cell (hiPSC)-derived endothelial cells (EC) and cardiomyocytes (CM). Both immunosuppression and EC/CM co-treatment increased gut microbiota alpha diversity. Immunosuppression promoted anaerobes, such as Faecalibacterium, Streptococcus, Anaerovibrio and Dialister, and altered amino acid metabolism and nucleosides/nucleotides biosynthesis in host plasma. EC + CM cotreatment favors Phascolarctobacterium, Fusicatenibacter, Erysipelotrichaceae UCG-006, Veillonella and Mailhella. Remarkably, gut microbiota of the EC/CM co-treatment group resembled that of the pre-injury group, and the NHPs exhibited a metabolic shift towards amino acid and fatty acid/lipid biosynthesis in plasma following cell therapy. The interplay between shift in microbial community and host homeostasis during treatment suggests gut microbiome modulation could improve cell therapy outcomes.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"10 1","pages":"2"},"PeriodicalIF":6.4,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142985617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lynn A C Devilée, Abou Bakr M Salama, Jessica M Miller, Janice D Reid, Qinghui Ou, Nourhan M Baraka, Kamal Abou Farraj, Madiha Jamal, Yibing Nong, Todd K Rosengart, Douglas Andres, Jonathan Satin, Tamer M A Mohamed, James E Hudson, Riham R E Abouleisa
{"title":"Pharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activity.","authors":"Lynn A C Devilée, Abou Bakr M Salama, Jessica M Miller, Janice D Reid, Qinghui Ou, Nourhan M Baraka, Kamal Abou Farraj, Madiha Jamal, Yibing Nong, Todd K Rosengart, Douglas Andres, Jonathan Satin, Tamer M A Mohamed, James E Hudson, Riham R E Abouleisa","doi":"10.1038/s41536-025-00389-z","DOIUrl":"10.1038/s41536-025-00389-z","url":null,"abstract":"<p><p>Cardiomyocytes (CMs) lost during ischemic cardiac injury cannot be replaced due to their limited proliferative capacity. Calcium is an important signal transducer that regulates key cellular processes, but its role in regulating CM proliferation is incompletely understood. Here we show a robust pathway for new calcium signaling-based cardiac regenerative strategies. A drug screen targeting proteins involved in CM calcium cycling in human embryonic stem cell-derived cardiac organoids (hCOs) revealed that only the inhibition of L-Type Calcium Channel (LTCC) induced the CM cell cycle. Furthermore, overexpression of Ras-related associated with Diabetes (RRAD), an endogenous inhibitor of LTCC, induced CM cell cycle activity in vitro, in human cardiac slices, and in vivo. Mechanistically, LTCC inhibition by RRAD or nifedipine induced CM cell cycle by modulating calcineurin activity. Moreover, ectopic expression of RRAD/CDK4/CCND in combination induced CM proliferation in vitro and in vivo, improved cardiac function and reduced scar size post-myocardial infarction.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"10 1","pages":"1"},"PeriodicalIF":6.4,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11724930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142973288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Macrophage-derived extracellular vesicles transfer mitochondria to adipocytes and promote adipocyte-myofibroblast transition in epidural fibrosis.","authors":"Feng Hua, Jinpeng Sun, Mohan Shi, Rui Mei, Zeyuan Song, Jun Liu, Mingshun Zhang","doi":"10.1038/s41536-024-00388-6","DOIUrl":"10.1038/s41536-024-00388-6","url":null,"abstract":"<p><p>Epidural fibrosis post laminectomy is the leading cause of failed back surgery syndrome. Little is known about the role and mechanisms of adipose tissues in epidural fibrosis. Here, we found that obese patients were more likely to develop epidural fibrosis after spine surgery. Similarly, obesity led to more progressive epidural fibrosis in a mouse model of laminectomy. Adipocyte-myofibroblast transition (AMT) occurs in epidural scarring. Mechanistically, large extracellular vesicles (EVs) from M2-type macrophages transfer mitochondria into adipocytes and promote AMT by activating the TGF-β and PAI-1 pathways. Blocking the PAI-1 pathway significantly attenuated the transition of adipocytes into myofibroblasts. We conclude that large EVs from macrophages transfer mitochondria to promote AMT in epidural fibrosis.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"9 1","pages":"43"},"PeriodicalIF":6.4,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11685489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ning Zhao, Chang-Jun Zhang, Xiao Zhang, Wen Wang, Kangxin Jin, Zi-Bing Jin
{"title":"Transplantation of derivative retinal organoids from chemically induced pluripotent stem cells restored visual function.","authors":"Ning Zhao, Chang-Jun Zhang, Xiao Zhang, Wen Wang, Kangxin Jin, Zi-Bing Jin","doi":"10.1038/s41536-024-00387-7","DOIUrl":"10.1038/s41536-024-00387-7","url":null,"abstract":"<p><p>As an emerging type of pluripotent stem cells, chemically induced pluripotent stem cells (CiPSCs) avoid the risks of genomic disintegration by exogenous DNAs from viruses or plasmids, providing a safer stem cell source. To verify CiPSCs' capacity to differentiate into retinal organoids (ROs), we induced CiPSCs from mouse embryonic fibroblasts by defined small-molecule compounds and successfully differentiated the CiPSCs into three-dimensional ROs, in which all major retinal cell types and retinal genes were in concordance with those in vivo. We transplanted retinal photoreceptors from ROs into the subretinal space of retinal degeneration mouse models and the cells could integrate into the host retina, establish synaptic connections, and significantly improve the visual functions of the murine models. This proof-of-concept study for the first time demonstrated that CiPSCs could differentiate into ROs with a full spectrum of retinal cell types, and provided new insights into chemical approach-based retinal regeneration for degenerative diseases.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"9 1","pages":"42"},"PeriodicalIF":6.4,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11681058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142900444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Benjamin M Kidd, Justin A Varholick, Dana M Tuyn, Pradip K Kamat, Zachary D Simon, Lei Liu, Mackenzie P Mekler, Marjory Pompilus, Jodi L Bubenik, Mackenzie L Davenport, Helmut A Carter, Matteo M Grudny, W Brad Barbazuk, Sylvain Doré, Marcelo Febo, Eduardo Candelario-Jalil, Malcolm Maden, Maurice S Swanson
{"title":"Stroke-induced neuroplasticity in spiny mice in the absence of tissue regeneration.","authors":"Benjamin M Kidd, Justin A Varholick, Dana M Tuyn, Pradip K Kamat, Zachary D Simon, Lei Liu, Mackenzie P Mekler, Marjory Pompilus, Jodi L Bubenik, Mackenzie L Davenport, Helmut A Carter, Matteo M Grudny, W Brad Barbazuk, Sylvain Doré, Marcelo Febo, Eduardo Candelario-Jalil, Malcolm Maden, Maurice S Swanson","doi":"10.1038/s41536-024-00386-8","DOIUrl":"10.1038/s41536-024-00386-8","url":null,"abstract":"<p><p>Stroke is a major cause of disability for adults over 40 years of age. While research into animal models has prioritized treatments aimed at diminishing post-stroke damage, no studies have investigated the response to a severe stroke injury in a highly regenerative adult mammal. Here we investigate the effects of transient ischemia on adult spiny mice, Acomys cahirinus, due to their ability to regenerate multiple tissues without scarring. Transient middle cerebral artery occlusion was performed and Acomys showed rapid behavioral recovery post-stroke yet failed to regenerate impacted brain regions. An Acomys brain atlas in combination with functional (f)MRI demonstrated recovery coincides with neuroplasticity. The strength and quality of the global connectome are preserved post-injury with distinct contralateral and ipsilateral brain regions compensating for lost tissue. Thus, we propose Acomys recovers functionally from an ischemic stroke injury not by tissue regeneration but by altering its brain connectome.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"9 1","pages":"41"},"PeriodicalIF":6.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiao-Lin Lin, Jin-Hua Lin, Yan Cao, Han Zhang, Si-Yi He, Hai-Yan Wu, Ze-Bing Ye, Li Zheng, Xu-Feng Qi
{"title":"Cardiomyocyte proliferation and heart regeneration in adult Xenopus tropicalis evidenced by a transgenic reporter line.","authors":"Xiao-Lin Lin, Jin-Hua Lin, Yan Cao, Han Zhang, Si-Yi He, Hai-Yan Wu, Ze-Bing Ye, Li Zheng, Xu-Feng Qi","doi":"10.1038/s41536-024-00384-w","DOIUrl":"10.1038/s41536-024-00384-w","url":null,"abstract":"<p><p>Cardiomyocyte proliferation in adult Xenopus tropicalis during heart regeneration has remained largely contentious due to the absence of genetic evidence. Here, we generated a transgenic reporter line Tg(mlc2:H2C) expressing mCherry specifically in cardiomyocyte nuclei driven by the promoter of myosin light chain 2 (mlc2). Using the reporter line, we found that traditional whole-cell staining is not a rigorous way to identify cardiomyocytes in adult Xenopus tropicalis when using a cryosection with common thickness (5 μm) which leading to a high error, but this deviation could be reduced by increasing section thickness. In addition, the reporter line confirmed that apex resection injury greatly increased the proliferation of mlc2<sup>+</sup> cardiomyocytes at 3-30 days post-resection (dpr), thereby regenerating the lost cardiac muscle by 30 dpr in adult Xenopus tropicalis. Our findings from the reporter line have rigorously defined cardiomyocyte proliferation in adult heart upon injury, thereby contributing heart regeneration in adult Xenopus tropicalis.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"9 1","pages":"40"},"PeriodicalIF":6.4,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11659404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nandaraj Taye, Levon Rodriguez, James C Iatridis, Woojin M Han, Dirk Hubmacher
{"title":"Myoblast-derived ADAMTS-like 2 promotes skeletal muscle regeneration after injury.","authors":"Nandaraj Taye, Levon Rodriguez, James C Iatridis, Woojin M Han, Dirk Hubmacher","doi":"10.1038/s41536-024-00383-x","DOIUrl":"10.1038/s41536-024-00383-x","url":null,"abstract":"<p><p>Skeletal muscle regeneration and functional recovery after minor injuries requires the activation of muscle-resident myogenic muscle stem cells (i.e. satellite cells) and their subsequent differentiation into myoblasts, myocytes, and ultimately myofibers. We recently identified secreted ADAMTS-like 2 (ADAMTSL2) as a pro-myogenic regulator of muscle development, where it promoted myoblast differentiation. Since myoblast differentiation is a key process in skeletal muscle regeneration, we here examined the role of ADAMTSL2 during muscle regeneration after BaCl<sub>2</sub> injury. Specifically, we found that muscle regeneration was delayed after ablation of ADAMTSL2 in myogenic precursor cells and accelerated following injection of pro-myogenic ADAMTSL2 protein domains. Mechanistically, ADAMTSL2 regulated the number of committed myoblasts, which are the precursors for myocytes and regenerating myofibers. Collectively, our data support a role for myoblast-derived ADAMTSL2 as a positive regulator of muscle regeneration and provide a proof-of-concept for potential therapeutic applications.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"9 1","pages":"39"},"PeriodicalIF":6.4,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11659564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}