npj Regenerative Medicine最新文献

Preclinical efficacy and safety of AAVrh10-based plakophilin-2 gene therapy (LX2020) as a treatment for arrhythmogenic cardiomyopathy.

IF 6.4 1区医学

npj Regenerative Medicine Pub Date : 2025-04-03 DOI: 10.1038/s41536-025-00401-6

Jing Zhang, Erika Joana Gutierrez-Lara, Aryanne Do, Lena Nguyen, Anju Nair, Nithya Selvan, Tim Fenn, Eric Adler, Richie Khanna, Farah Sheikh

{"title":"Preclinical efficacy and safety of AAVrh10-based plakophilin-2 gene therapy (LX2020) as a treatment for arrhythmogenic cardiomyopathy.","authors":"Jing Zhang, Erika Joana Gutierrez-Lara, Aryanne Do, Lena Nguyen, Anju Nair, Nithya Selvan, Tim Fenn, Eric Adler, Richie Khanna, Farah Sheikh","doi":"10.1038/s41536-025-00401-6","DOIUrl":"10.1038/s41536-025-00401-6","url":null,"abstract":"Plakophilin-2 (PKP2) mutations cause fatal genetic heart disease and arrhythmogenic cardiomyopathy (ACM) with primary effects on the right ventricle (RV). Adeno-associated virus (AAV)-PKP2 gene therapy shows promise as a therapeutic strategy but lacks long-term data and guidelines on minimal effective doses in animal studies for treating RV deficits, arrhythmia burden, and improving survival when administered during disease settings, which are most relevant to clinical trials. Using AAVrh10, known for its preferential cardiac gene expression at lower doses, we show minimal doses required for efficacy for AAVrh10.PKP2 (LX2020) to rescue cardiac (molecular and especially RV) deficits, arrhythmia burden and survival in PKP2 ACM mice, suggesting its potential to reverse late-stage pathology. Safety assessments in non-human primates revealed no adverse events. These data support LX2020 as a viable treatment for PKP2 ACM patients.","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"10 1","pages":"17"},"PeriodicalIF":6.4,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965304/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143774792","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}

引用次数: 0

Fibroblast-derived osteoglycin promotes epithelial cell repair.

IF 6.4 1区医学

npj Regenerative Medicine Pub Date : 2025-03-25 DOI: 10.1038/s41536-025-00404-3

Luke van der Koog, Manon E Woest, Iris C Gorter, Vicky Verschut, Robin A B Elferink, Annet B Zuidhof, Dyan F Nugraha, Maunick L Koloko Ngassie, Sophie I T Bos, Deepesh Dhakad, Justina C Wolters, Peter L Horvatovich, Y S Prakash, Wim Timens, Önder A Yildirim, Corry-Anke Brandsma, Henderik W Frijlink, Anika Nagelkerke, Reinoud Gosens

{"title":"Fibroblast-derived osteoglycin promotes epithelial cell repair.","authors":"Luke van der Koog, Manon E Woest, Iris C Gorter, Vicky Verschut, Robin A B Elferink, Annet B Zuidhof, Dyan F Nugraha, Maunick L Koloko Ngassie, Sophie I T Bos, Deepesh Dhakad, Justina C Wolters, Peter L Horvatovich, Y S Prakash, Wim Timens, Önder A Yildirim, Corry-Anke Brandsma, Henderik W Frijlink, Anika Nagelkerke, Reinoud Gosens","doi":"10.1038/s41536-025-00404-3","DOIUrl":"10.1038/s41536-025-00404-3","url":null,"abstract":"There is an urgent need for innovative therapies targeting defective epithelial repair in chronic diseases like COPD. The mesenchymal niche is a critical regulator in epithelial stem cell activation, suggesting that their secreted factors are possible potent drug targets. Utilizing a proteomics-guided drug discovery strategy, we explored the lung fibroblast secretome to uncover impactful drug targets. Our lung organoid assays identified several regenerative ligands, with osteoglycin (OGN) showing the most profound effects. Transcriptomic analyses revealed that OGN enhances alveolar progenitor differentiation, detoxifies reactive oxygen species, and strengthens fibroblast-epithelial crosstalk. OGN expression was diminished in COPD patients and smoke-exposed mice. An active fragment of OGN (leucine-rich repeat regions 4-7) replicated full-length OGN's regenerative effects, significantly ameliorating elastase-induced lung injury in lung slices and improving lung function in vivo. These findings highlight OGN as a pivotal secreted protein for alveolar epithelial repair, positioning its active fragment as a promising therapeutic for COPD.","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"10 1","pages":"16"},"PeriodicalIF":6.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11937367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712129","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}

引用次数: 0

Quantum dots as biocompatible small RNA nanocarriers modulating macrophage polarization to treat Asherman's syndrome.

IF 6.4 1区医学

npj Regenerative Medicine Pub Date : 2025-03-25 DOI: 10.1038/s41536-025-00403-4

Ji Eun Won, Mira Park, Seok-Ho Hong, Yeon Sun Kim, Haengseok Song

{"title":"Quantum dots as biocompatible small RNA nanocarriers modulating macrophage polarization to treat Asherman's syndrome.","authors":"Ji Eun Won, Mira Park, Seok-Ho Hong, Yeon Sun Kim, Haengseok Song","doi":"10.1038/s41536-025-00403-4","DOIUrl":"10.1038/s41536-025-00403-4","url":null,"abstract":"Macrophages play a key role in host defense and inflammation, with polarization ranging from pro-inflammatory M1 to anti-inflammatory M2 states. However, effective modulation of macrophage polarity via nucleotide delivery is challenging. This study developed polyethyleneimine-modified carboxyl quantum dots (QDP) as a biocompatible carrier for small RNA delivery to modulate macrophage polarization. QDP-mediated delivery of miR-10a (QDP/miR-10a) rebalanced macrophage polarity and alleviated uterine inflammation and fibrosis in a mouse model of Asherman's syndrome (AS). In vitro, QDP effectively delivered small RNA into RAW 264.7 cells without cytotoxicity, converting LPS-induced M1 to M2 macrophages by inhibiting NF-κB, MAPK, and AKT signaling. In vivo, QDP/miR-10a reduced M1 macrophages, restored polarization, and enhanced uterine restoration in AS mice without affecting systemic immunity. Thus, QDP represents a safe and effective nanocarrier for small RNA delivery to modulate macrophage polarization for inflammatory disease treatment, including AS.","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"10 1","pages":"15"},"PeriodicalIF":6.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11937404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712130","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}

引用次数: 0

A novel therapy to ameliorate nitrogen mustard-induced limbal stem cell deficiency using lipoprotein-like nanoparticles.

IF 6.4 1区医学

npj Regenerative Medicine Pub Date : 2025-03-20 DOI: 10.1038/s41536-025-00402-5

Elif Kayaalp Nalbant, Timothy J Feliciano, Aliakbar Mohammadlou, Vincent L Xiong, Jacquelyn E Trujillo, Andrea E Calvert, Nihal Kaplan, Parisa Foroozandeh, Jayden Kim, Emma M Bai, Xiaolin Qi, Fernando Tobias, Eric W Roth, Vinayak P Dravid, Kurt Q Lu, SonBinh T Nguyen, C Shad Thaxton, Han Peng, Robert M Lavker

{"title":"A novel therapy to ameliorate nitrogen mustard-induced limbal stem cell deficiency using lipoprotein-like nanoparticles.","authors":"Elif Kayaalp Nalbant, Timothy J Feliciano, Aliakbar Mohammadlou, Vincent L Xiong, Jacquelyn E Trujillo, Andrea E Calvert, Nihal Kaplan, Parisa Foroozandeh, Jayden Kim, Emma M Bai, Xiaolin Qi, Fernando Tobias, Eric W Roth, Vinayak P Dravid, Kurt Q Lu, SonBinh T Nguyen, C Shad Thaxton, Han Peng, Robert M Lavker","doi":"10.1038/s41536-025-00402-5","DOIUrl":"10.1038/s41536-025-00402-5","url":null,"abstract":"Chronic corneal inflammation, a component of sulfur mustard (SM) and nitrogen mustard (NM) injuries frequently leads to limbal stem cell deficiency (LSCD), which can compromise vision. Corneal conjunctivalization, neovascularization, and persistent inflammation are hallmarks of LSCD. Ocular exposure to SM and NM results in an acute and delayed phase of corneal disruption, culminating in LSCD. Available therapies for mustard keratopathy (e.g., topical corticosteroids) often have adverse side effects, and generally are ineffective in preventing the development of LSCD. We developed a novel, optically transparent HDL nanoparticle (NP) with an organic core (oc) molecular scaffold. This unique oc-HDL NP: (i) markedly improved corneal haze during the acute and delayed phases in vivo; (ii) significantly reduced the inflammatory response; and (iii) blunted conjunctivalization and corneal neovascularization during the delayed phase. These findings strongly suggest that our HDL NP is an ideal treatment for mustard keratopathy and other chronic corneal inflammatory diseases.","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"10 1","pages":"14"},"PeriodicalIF":6.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11926173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671852","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}

引用次数: 0

Immune-mediated regeneration of cell-free vascular grafts in an ovine model.

IF 6.4 1区医学

npj Regenerative Medicine Pub Date : 2025-03-19 DOI: 10.1038/s41536-025-00400-7

Bita Nasiri, Arundhati Das, Karthik Ramachandran, Sai Harsha Bhamidipati, Yulun Wu, Shriramprasad Venkatesan, Rudiyanto Gunawan, Daniel D Swartz, Stelios T Andreadis

{"title":"Immune-mediated regeneration of cell-free vascular grafts in an ovine model.","authors":"Bita Nasiri, Arundhati Das, Karthik Ramachandran, Sai Harsha Bhamidipati, Yulun Wu, Shriramprasad Venkatesan, Rudiyanto Gunawan, Daniel D Swartz, Stelios T Andreadis","doi":"10.1038/s41536-025-00400-7","DOIUrl":"10.1038/s41536-025-00400-7","url":null,"abstract":"We developed acellular tissue engineered vessels (ATEV) using small intestine submucosa (SIS) incorporating heparin and a novel protein named H2R5. ATEVs were implanted into the arterial circulation of an ovine animal model, demonstrating high primary patency rates over a period of three months. Implanted grafts were infiltrated by host cells, the majority of which were monocytes/macrophages (MC/MΦ), as demonstrated by scRNA sequencing and immunostaining. They also developed functional endothelial and medial layers that deposited new extracellular matrix leading to matrix remodeling and acquisition of mechanical properties that were similar to those of native arteries. Notably, during this short implantation time, ATEVs turned into functional neo-arteries, as evidenced by the development of the vascular contractile function. Our findings underscore the potential of H2R5-functionalized ATEVs as promising candidates for tissue replacement grafts in a large pre-clinical animal model and highlight the contribution of macrophages in vascular regeneration.","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"10 1","pages":"13"},"PeriodicalIF":6.4,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11923281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665318","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}

引用次数: 0

Cell-scale porosity minimizes foreign body reaction and promotes innervated myofiber formation after volumetric muscle loss.

IF 6.4 1区医学

npj Regenerative Medicine Pub Date : 2025-03-01 DOI: 10.1038/s41536-025-00395-1

Areli Rodriguez Ayala, George Christ, Donald Griffin

引用次数: 0

Digit regeneration is expedited in LG/J healer mice compared to SM/J non-healer mice.

IF 6.4 1区医学

npj Regenerative Medicine Pub Date : 2025-02-15 DOI: 10.1038/s41536-025-00399-x

Feini Qu, Kristin L Lenz, Gwendalyn L Krekeler, Xin Duan, Muhammad Farooq Rai, Farshid Guilak

{"title":"Digit regeneration is expedited in LG/J healer mice compared to SM/J non-healer mice.","authors":"Feini Qu, Kristin L Lenz, Gwendalyn L Krekeler, Xin Duan, Muhammad Farooq Rai, Farshid Guilak","doi":"10.1038/s41536-025-00399-x","DOIUrl":"10.1038/s41536-025-00399-x","url":null,"abstract":"Limb loss resulting from disease or trauma affects an estimated 185,000 Americans annually, significantly reducing their quality of life. Consequently, successful attempts to regrow missing appendages could substantially improve the prognosis for amputees. In mice, the digit tip spontaneously regenerates resected tissues following distal amputation, whereas this capacity diminishes at more proximal levels after amputation. Moreover, regenerative potential is influenced by genetic variations among inbred mouse strains: LG/J (healer) mice exhibit superior reparative potential compared to SM/J (non-healer) mice. This study investigated the response to various levels of digit amputation in these mice to determine whether this strain-dependent healing response translates to the regeneration of complex tissues. Evaluation of skeletal regrowth, cell proliferation, and differential gene and protein expression reveals that digit regeneration is more robust in LG/J mice compared to SM/J mice at multiple amputation levels, suggesting that the regenerative capacity of composite tissues is genetically heritable in mice.","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"10 1","pages":"11"},"PeriodicalIF":6.4,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11828864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426610","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}

引用次数: 0

Advancements in bioengineering for descemet membrane endothelial keratoplasty (DMEK).

IF 6.4 1区医学

npj Regenerative Medicine Pub Date : 2025-02-14 DOI: 10.1038/s41536-025-00396-0

Sarah Barbara Zwingelberg, Gizem Karabiyik, Paul Gehle, Melanie von Brandenstein, Sabina Eibichova, Christian Lotz, Florian Groeber-Becker, Daniel Kampik, Ula Jurkunas, Gerd Geerling, Gregor Lang

引用次数: 0

Effects of injury size on local and systemic immune cell dynamics in volumetric muscle loss.

IF 6.4 1区医学

npj Regenerative Medicine Pub Date : 2025-02-13 DOI: 10.1038/s41536-025-00397-z

Ricardo Whitaker, Samuel Sung, Tina Tylek, Gregory E Risser, Erin M O'Brien, Phoebe Ellin Chua, Thomas Li, Ryan J Petrie, Lin Han, Benjamin I Binder-Markey, Kara L Spiller

{"title":"Effects of injury size on local and systemic immune cell dynamics in volumetric muscle loss.","authors":"Ricardo Whitaker, Samuel Sung, Tina Tylek, Gregory E Risser, Erin M O'Brien, Phoebe Ellin Chua, Thomas Li, Ryan J Petrie, Lin Han, Benjamin I Binder-Markey, Kara L Spiller","doi":"10.1038/s41536-025-00397-z","DOIUrl":"10.1038/s41536-025-00397-z","url":null,"abstract":"We took a systems approach to the analysis of macrophage phenotype in regenerative and fibrotic volumetric muscle loss outcomes in mice together with analysis of systemic inflammation and of other leukocytes in the muscle, spleen, and bone marrow. Differences in expression of macrophage phenotype markers occurred as early as day 1, persisted to at least day 28, and were associated with increased numbers of leukocytes in the muscle and bone marrow, increased pro-inflammatory marker expression in splenic macrophages, and changes in the levels of pro-inflammatory cytokines in the blood. The most prominent differences were in muscle neutrophils, which were much more abundant in fibrotic outcomes compared to regenerative outcomes at day 1 after injury. However, neutrophil depletion had little to no effect on macrophage phenotype or on muscle repair outcomes. Together, these results suggest that the entire system of immune cell interactions must be considered to improve muscle repair outcomes.","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"10 1","pages":"9"},"PeriodicalIF":6.4,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11822203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411501","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}

引用次数: 0

Proteomic profiling of iPSC and tissue-derived MSC secretomes reveal a global signature of inflammatory licensing.

IF 6.4 1区医学

npj Regenerative Medicine Pub Date : 2025-02-04 DOI: 10.1038/s41536-024-00382-y

Margeaux Hodgson-Garms, Matthew J Moore, Mikaël M Martino, Kilian Kelly, Jessica E Frith

{"title":"Proteomic profiling of iPSC and tissue-derived MSC secretomes reveal a global signature of inflammatory licensing.","authors":"Margeaux Hodgson-Garms, Matthew J Moore, Mikaël M Martino, Kilian Kelly, Jessica E Frith","doi":"10.1038/s41536-024-00382-y","DOIUrl":"10.1038/s41536-024-00382-y","url":null,"abstract":"Much of the therapeutic potential of mesenchymal stromal cells (MSCs) is underpinned by their secretome which varies significantly with source, donor and microenvironmental cues. Understanding these differences is essential to define the mechanisms of MSC-based tissue repair and optimise cell therapies. This study analysed the secretomes of bone-marrow (BM.MSCs), umbilical-cord (UC.MSCs), adipose-tissue (AT.MSCs) and clinical/commercial-grade induced pluripotent stem cell-derived MSCs (iMSCs), under resting and inflammatory licenced conditions. iMSCs recapitulated the inflammatory licensing process, validating their comparability to tissue-derived MSCs. Overall, resting secretomes were defined by extracellular matrix (ECM) and pro-regenerative proteins, while licensed secretomes were enriched in chemotactic and immunomodulatory proteins. iMSC and UC.MSC secretomes contained proteins indicating proliferative potential and telomere maintenance, whereas adult tissue-derived secretomes contained fibrotic and ECM-related proteins. The data and findings from this study will inform the optimum MSC source for particular applications and underpin further development of MSC therapies.","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"10 1","pages":"7"},"PeriodicalIF":6.4,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11794695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191182","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}

引用次数: 0