Mahmoud Farahat, Sophie Brosset, Yufei Chen, Ayesha Aijaz, Graham Rix, Bhavishya Challagundla, Margarita Elloso, Maria Fernanda Hutter, Ian M Rogers, Marc G Jeschke
{"title":"Human iPSCs-derived mesenchymal stem cells promote skin regeneration and burn wound healing.","authors":"Mahmoud Farahat, Sophie Brosset, Yufei Chen, Ayesha Aijaz, Graham Rix, Bhavishya Challagundla, Margarita Elloso, Maria Fernanda Hutter, Ian M Rogers, Marc G Jeschke","doi":"10.1038/s41536-025-00427-w","DOIUrl":"10.1038/s41536-025-00427-w","url":null,"abstract":"<p><p>The key to surviving severe burns is rapid burn wound excision and closure, yet extensive wounds often surpass natural healing capacity. Alternative treatments, such as synthetic skin substitutes, have not emerged as a standard, optimal solution. Stem cell therapies, especially using allogenic sources, show promise in enhancing wound repair. Induced mesenchymal stem cells (iMSCs) have demonstrated vast possibilities to overcome traditional stem cell therapy limitations. This study utilized Cord tissue-derived iMSCs (CT-iMSCs) incorporated into well-established epidermal-dermal substitutes Integra® Dermal Regeneration Template (DRT) at 5000-20,000 cells/cm<sup>2</sup> in a porcine full-thickness burn model to test their regenerative capabilities. We evaluated healing outcomes, inflammation, neovascularization, collagen levels, and fibrosis markers. Wounds treated with CT-iMSCs showed notable improvements, including faster wound healing, better epithelialization, and marked improvements in healing markers compared to controls. These data support the potential of iMSCs as an ideal cell source for autologous skin regeneration.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"10 1","pages":"40"},"PeriodicalIF":6.5,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12398485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144978493","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}
Siavash Rahimi, William V J Hariton, Fattaneh Khalaj, Ralf J Ludwig, Luca Borradori, Eliane J Müller
{"title":"Desmoglein-driven dynamic signaling in pemphigus vulgaris: a systematic review of pathogenic pathways.","authors":"Siavash Rahimi, William V J Hariton, Fattaneh Khalaj, Ralf J Ludwig, Luca Borradori, Eliane J Müller","doi":"10.1038/s41536-025-00426-x","DOIUrl":"10.1038/s41536-025-00426-x","url":null,"abstract":"<p><p>Epithelial tissue integrity is maintained through specialized intercellular junctions known to coordinate homeostatic processes. In this context, outside-in signaling and mechanotransduction through desmosomal cadherins, the building blocks of desmosomes and main stress bearers in epithelial tissue, are only starting to emerge. To better understand the dual function of desmosomal cadherins in structural integrity and cellular signaling, we here performed a systematic, unbiased review on pathogenic signaling effectors identified in models and patients with pemphigus vulgaris (PV). PV is an autoimmune blistering disorder characterized by disruption of desmosomal transadhesion through autoantibodies mainly targeting the desmosomal cadherins desmoglein (Dsg) 3 or Dsg1 and Dsg3. The survey of functionally validated pathogenic pathways published since inception in 1977 up to mid-2024 identifies 128 studies and 128 signaling molecules, highlighting a coherent network of biomechanical, bioelectrical, and biochemical signaling events. This in-depth analysis will stimulate future research as well as development of potential therapeutic applications beyond PV.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"10 1","pages":"39"},"PeriodicalIF":6.5,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373888/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144978486","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}
Christina L Jablonski, Dora Modrcin, John Cobb, Donna-Marie McCafferty, Paul T Salo, Roman J Krawetz
{"title":"Prx1<sup>+</sup> progenitors give rise to new articular cartilage when conditions are permissive for endogenous regeneration.","authors":"Christina L Jablonski, Dora Modrcin, John Cobb, Donna-Marie McCafferty, Paul T Salo, Roman J Krawetz","doi":"10.1038/s41536-025-00425-y","DOIUrl":"10.1038/s41536-025-00425-y","url":null,"abstract":"<p><p>It is widely acknowledged that articular cartilage lacks the ability to regenerate. However, if such regeneration were possible, which cell type would generate new tissue? The p21<sup>-/-</sup> mouse provides an excellent platform to explore this question, hence, we conducted lineage tracing on Paired related homeobox 1 (Prrx1/Prx1) cells post-injury to determine whether endogenous Prx1<sup>+</sup> cells contribute to regenerated tissues post-injury. p21<sup>-/-</sup> mice displayed enhanced endogenous cartilage regeneration, accompanied by notable differences in the number and kinetics of Prx1<sup>+</sup> cells within and around the injury site. In p21<sup>-/-</sup> mice, Prx1<sup>+</sup> cells underwent chondrogenesis, ultimately contributing to the regenerated articular cartilage layer. These findings underscore the impact of tissue-resident cells on cartilage regeneration, albeit under abnormal conditions. If the conditions within the joint could be manipulated to favor such a regenerative environment, these endogenous cell types might be recruited to facilitate the formation of a new articular cartilage surface post-injury.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"10 1","pages":"38"},"PeriodicalIF":6.5,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12335530/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812666","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}
Oscar A Carballo-Molina, Alexandra N Kolberg-Edelbrock, Matías Alvarez-Saavedra, Zaida Álvarez, Timmy Fyrner, Tamara Perez-Rosello, Zois Syrgiannis, Stacey M Chin, Nozomu Takata, Madison Strong, Liam C Palmer, D James Surmeier, Samuel I Stupp
{"title":"Supramolecular nanostructure mimics GDNF trophic effects in vitro on human dopaminergic neurons.","authors":"Oscar A Carballo-Molina, Alexandra N Kolberg-Edelbrock, Matías Alvarez-Saavedra, Zaida Álvarez, Timmy Fyrner, Tamara Perez-Rosello, Zois Syrgiannis, Stacey M Chin, Nozomu Takata, Madison Strong, Liam C Palmer, D James Surmeier, Samuel I Stupp","doi":"10.1038/s41536-025-00424-z","DOIUrl":"10.1038/s41536-025-00424-z","url":null,"abstract":"<p><p>Peptide-based supramolecular nanostructures offer a versatile platform with substantial promise for clinical translation in regenerative medicine. These systems allow for the incorporation of biologically active sequences and can be engineered to modulate tissue-specific parameters such as stiffness, diffusivity, and biodegradability. We developed here a bioactive supramolecular nanostructure containing a peptide designed based on glial cell-derived neurotrophic factor. These nanostructures form scaffolds that mimic important trophic effects provided by this growth factor on iPSC-derived human dopaminergic neurons. Our in vitro data show that the nanostructures promote cell viability, confer neuroprotection against 6-hydroxydopamine toxicity, enhance neuronal morphology, facilitate electrophysiological maturation, and induce genes involved in neuronal survival. We also found that the scaffold promoted axonal extension in midbrain human organoids. These findings suggest that the supramolecular system could be useful to improve outcomes in cell-based therapies for Parkinson's disease, where progressive dopaminergic degeneration is a hallmark.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"10 1","pages":"37"},"PeriodicalIF":6.5,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12334742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805317","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":"From fragment to form: whole-body regeneration in a model urochordate.","authors":"Yuval Rinkevich, Baruch Rinkevich","doi":"10.1038/s41536-025-00423-0","DOIUrl":"10.1038/s41536-025-00423-0","url":null,"abstract":"<p><p>Tissue and organ regeneration are common among aquatic invertebrates, yet these taxa and their potential as model organisms remain underexplored. We present evidence of extensive regenerative capabilities in aquatic invertebrates, highlighting examples of whole-body regeneration (WBR), a peak form of regeneration, where entire organisms regenerate from minute body fragments. Among the many examples of WBR, we focus on botryllid ascidians, an intriguing group of invertebrate chordates that display chordate tissue complexity while demonstrating WBR from small fragments of blood vessels. Centering on WBR in the model species Botrylloides leachi, we outline shared characteristics of WBR across botryllid ascidians including the presence of circulating multipotent stem cells, systemic induction processes, and ensuing competition among regeneration sites, culminating in the restoration of a complete organism. This regeneration mode is distinct from those in mammals and humans. Further research may offer valuable insights into mechanisms by which tissue fragments reinstate new organisms.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"10 1","pages":"36"},"PeriodicalIF":6.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12316915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765787","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":"Exogenous melatonin alleviates premature ovarian failure by regulating granulosa cell autophagy.","authors":"Guang-Hu Zhou, Ye-Fei He, Hai-Ling Wang, Yi-Bo Lv, Yi-Mei Cong, Zhen-Long Sun, Xiao-Wen Jiang, Wen-Hui Yu","doi":"10.1038/s41536-025-00422-1","DOIUrl":"10.1038/s41536-025-00422-1","url":null,"abstract":"<p><p>Premature ovarian failure (POF) is a disease closely related to the apoptosis of granulosa cells (GCs) in the follicle. In this study, exogenous melatonin (Mel) was used to interfere with POF model mice, so as to provide reference for Mel prevention and treatment of POF. Mel could promote estrogen secretion and improve ovarian physiological function in mice. In GCs, mitochondrial membrane potential increases and ATP content increases, LC3/LC3-LL and Beclin1 expression increases, p62 expression decreases, which promoted the occurrence of autophagy. Intersecting target screening, GO and KEGG enrichment analysis of Mel and POF revealed that estrogen receptor 1 (ESR1) was the most compatible target for Mel action; meanwhile, Mel had a high enrichment value in the PI3K-AKT-mTOR pathway. It was detected that Mel could increase the expression of ESR1 and inhibit the phosphorylation levels of PI3K, AKT, and mTOR to promote autophagy and reduce apoptosis of GCs.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"10 1","pages":"35"},"PeriodicalIF":6.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12287420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144700285","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}
Mackenzie E Turner, Jingru Che, Joseph T Leland, Delaney J Villarreal, Sahana Rajesh, Sugath Suravarapu, Kan N Hor, Matthew G Wiet, Bryce A Kerlin, Tai Yi, Cameron A Best, James W Reinhardt, Christopher K Breuer
{"title":"Modulating the platelet-mediated innate foreign body response to affect in situ vascular tissue engineering outcomes.","authors":"Mackenzie E Turner, Jingru Che, Joseph T Leland, Delaney J Villarreal, Sahana Rajesh, Sugath Suravarapu, Kan N Hor, Matthew G Wiet, Bryce A Kerlin, Tai Yi, Cameron A Best, James W Reinhardt, Christopher K Breuer","doi":"10.1038/s41536-025-00419-w","DOIUrl":"10.1038/s41536-025-00419-w","url":null,"abstract":"<p><p>The success of implanted tissue-engineered vascular grafts (TEVGs) relies on the coordinated inflammation and wound healing processes that simultaneously degrade the scaffold and guide the formation of a neovessel. Dysregulated responses can lead to aberrant remodeling (e.g., stenosis), impacting the long-term outcome and functionality of the TEVG. We developed a TEVG that, despite demonstrating growth capacity in the clinic, exhibited an unexpectedly high incidence of stenosis, or narrowing of the graft lumen. This study identified platelet-mediated immune signaling via the lysosomal trafficking regulator (Lyst) as a key driver of stenosis. Lyst mutations significantly impaired platelet dense granule exocytosis yet preserved alpha granule secretion and adhesion to the biomaterial. Uncontrolled platelet aggregation, potentiated by dense granule signaling, results in the formation of a mural thrombus that remodels into occlusive neotissue. Importantly, inhibiting sustained platelet aggregation using the P2Y12 antagonist, prasugrel, is a successful strategy for optimizing neotissue formation and improving overall TEVG performance.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"10 1","pages":"34"},"PeriodicalIF":6.4,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12279924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683547","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}
Ni Su, Heena Saqib, Cassandra Villicana, Sungwon Kim, Thomas H Ambrosi, Peyton Freeman, Tayne Kim, Xinming Tong, Manish Ayushman, Charles K F Chan, Fan Yang
{"title":"Modulating immune-stem cell crosstalk enables robust bone regeneration via tuning compositions of macroporous scaffolds.","authors":"Ni Su, Heena Saqib, Cassandra Villicana, Sungwon Kim, Thomas H Ambrosi, Peyton Freeman, Tayne Kim, Xinming Tong, Manish Ayushman, Charles K F Chan, Fan Yang","doi":"10.1038/s41536-025-00421-2","DOIUrl":"10.1038/s41536-025-00421-2","url":null,"abstract":"<p><p>Following bone injury, macrophages (Mφ) initiate the immune response by secreting signals that recruit mesenchymal stem cells (MSC) and other niche cells to shape healing. Despite its importance, the potential of enhancing bone regeneration by modulating immune-stem cell crosstalk is largely unexplored. Here, we report a macroporous microribbon (µRB) scaffold with tunable ratios of gelatin (Gel) and chondroitin sulfate (CS), achieving rapid endogenous bone regeneration in a critical-sized defect model without exogenous growth factors or cells. The 3D MSC/Mφ co-culture model, but not the mono-culture model, effectively identified Gel50_CS50 as the leading ratio for accelerating bone regeneration in vivo. Single-cell sequencing (scRNAseq) and CellChat analysis revealed that Gel50_CS50 significantly enhanced the cellular crosstalk among Mφ and other bone niche cell types, with signaling pathways linked to anti-inflammation, angiogenesis, and osteogenesis. This study demonstrates Gel50_CS50 µRB as a promising biomaterial-based therapy for treating critical-sized bone defects by modulating cellular crosstalk.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"10 1","pages":"33"},"PeriodicalIF":6.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12219738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546161","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":"Bioengineered chondrocyte-products from human induced pluripotent stem cells are useful for repairing articular cartilage injury in minipig model.","authors":"Shota Takihira, Tomoka Takao, Yuki Fujisawa, Daisuke Yamada, Shojiro Hanaki, Tomohiro Inoue, Shigeo Otake, Aki Yoshida, Kazuki Yamada, Shinichi Miyazawa, Eiji Nakata, Toshifumi Ozaki, Takeshi Takarada","doi":"10.1038/s41536-025-00420-3","DOIUrl":"10.1038/s41536-025-00420-3","url":null,"abstract":"<p><p>The capacity of articular cartilage for self-repair is limited. Therefore, wide-ranging cartilage damage rarely resolves spontaneously, leading to the development of osteoarthritis. Previously, we developed human-induced pluripotent stem cell (hiPSC)-derived expandable human limb-bud-like mesenchymal (ExpLBM) cells with stable expansion and high chondrogenic capacity. In this study, various forms of articular cartilage-like tissue were fabricated using ExpLBM technology and evaluated to examine their potential as biomaterials. ExpLBM cells derived from hiPSCs were used to produce particle-like cartilage tissue and plate-like cartilage tissue. The cartilaginous particles and cartilaginous plates were transplanted into a minipig osteochondral defect model, and cartilage engraftment was histologically evaluated. For both transplanted cartilaginous particles and cartilaginous plates, good Safranin O staining and integration with the surrounding tissue were observed. Cartilaginous particles and cartilaginous plates made using hiPSCs-derived ExpLBM cells are effective for the regeneration of cartilage after injury.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"10 1","pages":"31"},"PeriodicalIF":6.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12219148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546160","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}
Marije Koning, Sébastien J Dumas, Elda Meta, Ellen Lievers, Annemarie M A de Graaf, Mila Borri, Lynn J Nai Chung Tong, Xue Liang, Ping Liu, Fang Chen, Lin Lin, Yonglun Luo, Peter Carmeliet, Cathelijne W van den Berg, Ton J Rabelink
{"title":"Single cell transcriptomics of human kidney organoid endothelium reveals vessel growth processes and arterial maturation upon transplantation.","authors":"Marije Koning, Sébastien J Dumas, Elda Meta, Ellen Lievers, Annemarie M A de Graaf, Mila Borri, Lynn J Nai Chung Tong, Xue Liang, Ping Liu, Fang Chen, Lin Lin, Yonglun Luo, Peter Carmeliet, Cathelijne W van den Berg, Ton J Rabelink","doi":"10.1038/s41536-025-00418-x","DOIUrl":"10.1038/s41536-025-00418-x","url":null,"abstract":"<p><p>Kidney organoids derived from human induced pluripotent stem cells lack a proper vasculature, hampering their applicability. Transplantation prevents the loss of organoid endothelial cells (ECs) observed in vitro, and promotes vascularization. In this study, we transplanted kidney organoids in chicken embryos and deployed single-cell RNA sequencing of ~12,000 organoid ECs to delineate their molecular landscape and identify key changes associated with transplantation. Transplantation significantly altered EC phenotypic composition. Consistent with angiogenesis, proliferating EC populations expanded 8 days after transplantation. Importantly, ECs underwent a major vein-to-arterial phenotypic shift. One of the transplantation-specific arterial EC populations, characterized by laminar shear stress response and Notch signalling, showed a similar transcriptome as human fetal kidney arterial/afferent arteriolar ECs. Consistently, transplantation-induced transcriptional changes involved proangiogenic and arteriogenic SOX7 transcription factor upregulation and regulon enrichment. These findings point to blood flow and candidate transcription factors such as SOX7 as possible targets to enhance kidney organoid vascularization.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"10 1","pages":"32"},"PeriodicalIF":6.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12216864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546162","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}