npj Regenerative Medicine最新文献

{"title":"The MRN complex maintains the biliary-derived hepatocytes in liver regeneration through ATR-Chk1 pathway.","authors":"Jingmei Song,&nbsp;Jianlong Ma,&nbsp;Xing Liu,&nbsp;Zhuofu Huang,&nbsp;Lianghui Li,&nbsp;Linke Li,&nbsp;Lingfei Luo,&nbsp;Rui Ni,&nbsp;Jianbo He","doi":"10.1038/s41536-023-00294-3","DOIUrl":"https://doi.org/10.1038/s41536-023-00294-3","url":null,"abstract":"<p><p>When the proliferation of residual hepatocytes is prohibited, biliary epithelial cells (BECs) transdifferentiate into nascent hepatocytes to accomplish liver regeneration. Despite significant interest in transdifferentiation, little is known about the maintenance of nascent hepatocytes in post-injured environments. Here, we perform an N-ethyl-N-nitrosourea (ENU) forward genetic screen and identify a mutant containing a nonsense mutation in the gene nibrin (nbn), which encodes a component of the Mre11-Rad50-Nbn (MRN) complex that activates DNA damage response (DDR). The regenerated hepatocytes cannot be maintained and exhibit apoptosis in the mutant. Mechanistically, the nbn mutation results in the abrogation of ATR-Chk1 signaling and accumulations of DNA damage in nascent hepatocytes, which eventually induces p53-mediated apoptosis. Furthermore, loss of rad50 or mre11a shows similar phenotypes. This study reveals that the activation of DDR by the MRN complex is essential for the survival of BEC-derived hepatocytes, addressing how to maintain nascent hepatocytes in the post-injured environments.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"20"},"PeriodicalIF":7.2,"publicationDate":"2023-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10079969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9261082","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":"Odd skipped-related 1 controls the pro-regenerative response of fibro-adipogenic progenitors.","authors":"Georgios Kotsaris,&nbsp;Taimoor H Qazi,&nbsp;Christian H Bucher,&nbsp;Hafsa Zahid,&nbsp;Sophie Pöhle-Kronawitter,&nbsp;Vladimir Ugorets,&nbsp;William Jarassier,&nbsp;Stefan Börno,&nbsp;Bernd Timmermann,&nbsp;Claudia Giesecke-Thiel,&nbsp;Aris N Economides,&nbsp;Fabien Le Grand,&nbsp;Pedro Vallecillo-García,&nbsp;Petra Knaus,&nbsp;Sven Geissler,&nbsp;Sigmar Stricker","doi":"10.1038/s41536-023-00291-6","DOIUrl":"https://doi.org/10.1038/s41536-023-00291-6","url":null,"abstract":"<p><p>Skeletal muscle regeneration requires the coordinated interplay of diverse tissue-resident- and infiltrating cells. Fibro-adipogenic progenitors (FAPs) are an interstitial cell population that provides a beneficial microenvironment for muscle stem cells (MuSCs) during muscle regeneration. Here we show that the transcription factor Osr1 is essential for FAPs to communicate with MuSCs and infiltrating macrophages, thus coordinating muscle regeneration. Conditional inactivation of Osr1 impaired muscle regeneration with reduced myofiber growth and formation of excessive fibrotic tissue with reduced stiffness. Osr1-deficient FAPs acquired a fibrogenic identity with altered matrix secretion and cytokine expression resulting in impaired MuSC viability, expansion and differentiation. Immune cell profiling suggested a novel role for Osr1-FAPs in macrophage polarization. In vitro analysis suggested that increased TGFβ signaling and altered matrix deposition by Osr1-deficient FAPs actively suppressed regenerative myogenesis. In conclusion, we show that Osr1 is central to FAP function orchestrating key regenerative events such as inflammation, matrix secretion and myogenesis.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"19"},"PeriodicalIF":7.2,"publicationDate":"2023-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10076435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9270194","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":"3D bioprinting using a new photo-crosslinking method for muscle tissue restoration.","authors":"JaeYoon Lee,&nbsp;Hyeongjin Lee,&nbsp;Eun-Ju Jin,&nbsp;Dongryeol Ryu,&nbsp;Geun Hyung Kim","doi":"10.1038/s41536-023-00292-5","DOIUrl":"https://doi.org/10.1038/s41536-023-00292-5","url":null,"abstract":"<p><p>Three-dimensional (3D) bioprinting is a highly effective technique for fabricating cell-loaded constructs in tissue engineering. However, the versatility of fabricating precise and complex cell-loaded hydrogels is limited owing to the poor crosslinking ability of cell-containing hydrogels. Herein, we propose an optic-fiber-assisted bioprinting (OAB) process to efficiently crosslink methacrylated hydrogels. By selecting appropriate processing conditions for the photo-crosslinking technique, we fabricated biofunctional cell-laden structures including methacrylated gelatin (Gelma), collagen, and decellularized extracellular matrix. To apply the method to skeletal muscle regeneration, cell-laden Gelma constructs were processed with a functional nozzle having a topographical cue and an OAB process that could induce a uniaxial alignment of C2C12 and human adipose stem cells (hASCs). Significantly higher degrees of cell alignment and myogenic activities in the cell-laden Gelma structure were observed compared with those in the cell construct that was printed using a conventional crosslinking method. Moreover, an in vivo regenerative potential was observed in volumetric muscle defects in a mouse model. The hASC-laden construct significantly induced greater muscle regeneration than the cell construct without topographical cues. Based on the results, the newly designed bioprinting process can prove to be highly effective in fabricating biofunctional cell-laden constructs for various tissue engineering applications.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"18"},"PeriodicalIF":7.2,"publicationDate":"2023-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10066283/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9288251","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":"Neurotrophin signaling is a central mechanism of salivary dysfunction after irradiation that disrupts myoepithelial cells.","authors":"Alejandro M Chibly, Vaishali N Patel, Marit H Aure, Mary C Pasquale, Gemma E Martin, Mousa Ghannam, Julianne Andrade, Noah G Denegre, Colleen Simpson, David P Goldstein, Fei-Fei Liu, Isabelle M A Lombaert, Matthew P Hoffman","doi":"10.1038/s41536-023-00290-7","DOIUrl":"10.1038/s41536-023-00290-7","url":null,"abstract":"<p><p>The mechanisms that prevent regeneration of irradiated (IR) salivary glands remain elusive. Bulk RNAseq of IR versus non-IR human salivary glands showed that neurotrophin signaling is highly disrupted post-radiation. Neurotrophin receptors (NTRs) were significantly upregulated in myoepithelial cells (MECs) post-IR, and single cell RNAseq revealed that MECs pericytes, and duct cells are the main sources of neurotrophin ligands. Using two ex vivo models, we show that nerve growth factor (NGF) induces expression of MEC genes during development, and upregulation of NTRs in adult MECs is associated with stress-induced plasticity and morphological abnormalities in IR human glands. As MECs are epithelial progenitors after gland damage and are required for proper acinar cell contraction and secretion, we propose that MEC-specific upregulation of NTRs post-IR disrupts MEC differentiation and potentially impedes the ability of the gland to regenerate.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"17"},"PeriodicalIF":7.2,"publicationDate":"2023-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10039923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9188385","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":"Myoscaffolds reveal laminin scarring is detrimental for stem cell function while sarcospan induces compensatory fibrosis.","authors":"Kristen M Stearns-Reider, Michael R Hicks, Katherine G Hammond, Joseph C Reynolds, Alok Maity, Yerbol Z Kurmangaliyev, Jesse Chin, Adam Z Stieg, Nicholas A Geisse, Sophia Hohlbauch, Stefan Kaemmer, Lauren R Schmitt, Thanh T Pham, Ken Yamauchi, Bennett G Novitch, Roy Wollman, Kirk C Hansen, April D Pyle, Rachelle H Crosbie","doi":"10.1038/s41536-023-00287-2","DOIUrl":"10.1038/s41536-023-00287-2","url":null,"abstract":"<p><p>We developed an on-slide decellularization approach to generate acellular extracellular matrix (ECM) myoscaffolds that can be repopulated with various cell types to interrogate cell-ECM interactions. Using this platform, we investigated whether fibrotic ECM scarring affected human skeletal muscle progenitor cell (SMPC) functions that are essential for myoregeneration. SMPCs exhibited robust adhesion, motility, and differentiation on healthy muscle-derived myoscaffolds. All SPMC interactions with fibrotic myoscaffolds from dystrophic muscle were severely blunted including reduced motility rate and migration. Furthermore, SMPCs were unable to remodel laminin dense fibrotic scars within diseased myoscaffolds. Proteomics and structural analysis revealed that excessive collagen deposition alone is not pathological, and can be compensatory, as revealed by overexpression of sarcospan and its associated ECM receptors in dystrophic muscle. Our in vivo data also supported that ECM remodeling is important for SMPC engraftment and that fibrotic scars may represent one barrier to efficient cell therapy.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"16"},"PeriodicalIF":6.4,"publicationDate":"2023-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10017766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9628656","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":"VEGF dose controls the coupling of angiogenesis and osteogenesis in engineered bone.","authors":"Andrea Grosso,&nbsp;Alexander Lunger,&nbsp;Maximilian G Burger,&nbsp;Priscilla S Briquez,&nbsp;Francesca Mai,&nbsp;Jeffrey A Hubbell,&nbsp;Dirk J Schaefer,&nbsp;Andrea Banfi,&nbsp;Nunzia Di Maggio","doi":"10.1038/s41536-023-00288-1","DOIUrl":"https://doi.org/10.1038/s41536-023-00288-1","url":null,"abstract":"<p><p>Vascular endothelial growth factor-A (VEGF) physiologically regulates both angiogenesis and osteogenesis, but its application in bone tissue engineering led to contradictory outcomes. A poorly understood aspect is how VEGF dose impacts the coordination between these two processes. Taking advantage of a unique and highly tunable platform, here we dissected the effects of VEGF dose over a 1,000-fold range in the context of tissue-engineered osteogenic grafts. We found that osteo-angiogenic coupling is exquisitely dependent on VEGF dose and that only a tightly defined dose range could stimulate both vascular invasion and osteogenic commitment of progenitors, with significant improvement in bone formation. Further, VEGF dose regulated Notch1 activation and the induction of a specific pro-osteogenic endothelial phenotype, independently of the promotion of vascular invasion. Therefore, in a therapeutic perspective, fine-tuning of VEGF dose in the signaling microenvironment is key to ensure physiological coupling of accelerated vascular invasion and improved bone formation.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"15"},"PeriodicalIF":7.2,"publicationDate":"2023-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10011536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9122670","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":"Parishin A-loaded mesoporous silica nanoparticles modulate macrophage polarization to attenuate tendinopathy.","authors":"Lisha Zhu,&nbsp;Yu Wang,&nbsp;Shanshan Jin,&nbsp;Yuting Niu,&nbsp;Min Yu,&nbsp;Zixin Li,&nbsp;Liyuan Chen,&nbsp;Xiaolan Wu,&nbsp;Chengye Ding,&nbsp;Tianhao Wu,&nbsp;Xinmeng Shi,&nbsp;Yixin Zhang,&nbsp;Dan Luo,&nbsp;Yan Liu","doi":"10.1038/s41536-023-00289-0","DOIUrl":"https://doi.org/10.1038/s41536-023-00289-0","url":null,"abstract":"<p><p>Macrophages are involved mainly in the balance between inflammation and tenogenesis during the healing process of tendinopathy. However, etiological therapeutic strategies to efficiently treat tendinopathy by modulating macrophage state are still lacking. In this study, we find that a small molecule compound Parishin-A (PA) isolated from Gastrodia elata could promote anti-inflammatory M2 macrophage polarization by inhibiting gene transcription and protein phosphorylation of signal transducers and activators of transcription 1. Local injection or sustained delivery of PA by mesoporous silica nanoparticles (MSNs) could almost recover the native tendon's dense parallel-aligned collagen matrix in collagenase-induced tendinopathy by modulating macrophage-mediated immune microenvironment and preventing heterotopic ossification. Especially, MSNs decrease doses of PA, frequency of injection and yield preferable therapeutic effects. Mechanistically, intervention with PA could indirectly inhibit activation of mammalian target of rapamycin to repress chondrogenic and osteogenic differentiation of tendon stem/progenitor cells by influencing macrophage inflammatory cytokine secretion. Together, pharmacological intervention with a natural small-molecule compound to modulate macrophage status appears to be a promising strategy for tendinopathy treatment.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"14"},"PeriodicalIF":7.2,"publicationDate":"2023-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10006208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9098495","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":"Return of the Tbx5; lineage-tracing reveals ventricular cardiomyocyte-like precursors in the injured adult mammalian heart.","authors":"Panagiota Siatra, Giannis Vatsellas, Athanasia Chatzianastasiou, Evangelos Balafas, Theodora Manolakou, Andreas Papapetropoulos, Anna Agapaki, Eleni-Taxiarchia Mouchtouri, Prashant J Ruchaya, Artemis G Korovesi, Manolis Mavroidis, Dimitrios Thanos, Dimitris Beis, Ioannis Kokkinopoulos","doi":"10.1038/s41536-023-00280-9","DOIUrl":"10.1038/s41536-023-00280-9","url":null,"abstract":"<p><p>The single curative measure for heart failure patients is a heart transplantation, which is limited due to a shortage of donors, the need for immunosuppression and economic costs. Therefore, there is an urgent unmet need for identifying cell populations capable of cardiac regeneration that we will be able to trace and monitor. Injury to the adult mammalian cardiac muscle, often leads to a heart attack through the irreversible loss of a large number of cardiomyocytes, due to an idle regenerative capability. Recent reports in zebrafish indicate that Tbx5a is a vital transcription factor for cardiomyocyte regeneration. Preclinical data underscore the cardioprotective role of Tbx5 upon heart failure. Data from our earlier murine developmental studies have identified a prominent unipotent Tbx5-expressing embryonic cardiac precursor cell population able to form cardiomyocytes, in vivo, in vitro and ex vivo. Using a developmental approach to an adult heart injury model and by employing a lineage-tracing mouse model as well as the use of single-cell RNA-seq technology, we identify a Tbx5-expressing ventricular cardiomyocyte-like precursor population, in the injured adult mammalian heart. The transcriptional profile of that precursor cell population is closer to that of neonatal than embryonic cardiomyocyte precursors. Tbx5, a cardinal cardiac development transcription factor, lies in the center of a ventricular adult precursor cell population, which seems to be affected by neurohormonal spatiotemporal cues. The identification of a Tbx5-specific cardiomyocyte precursor-like cell population, which is capable of dedifferentiating and potentially deploying a cardiomyocyte regenerative program, provides a clear target cell population for translationally-relevant heart interventional studies.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"13"},"PeriodicalIF":6.4,"publicationDate":"2023-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9984483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10831724","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":"Delay modulates the immune response to nerve repair.","authors":"Masoud Golshadi, Elaine F Claffey, Jennifer K Grenier, Andrew Miller, Michael Willand, Michael G Edwards, Tim P Moore, Michael Sledziona, Tessa Gordon, Gregory H Borschel, Jonathan Cheetham","doi":"10.1038/s41536-023-00285-4","DOIUrl":"10.1038/s41536-023-00285-4","url":null,"abstract":"<p><p>Effective regeneration after peripheral nerve injury requires macrophage recruitment. We investigated the activation of remodeling pathways within the macrophage population when repair is delayed and identified alteration of key upstream regulators of the inflammatory response. We then targeted one of these regulators, using exogenous IL10 to manipulate the response to injury at the repair site. We demonstrate that this approach alters macrophage polarization, promotes macrophage recruitment, axon extension, neuromuscular junction formation, and increases the number of regenerating motor units reaching their target. We also demonstrate that this approach can rescue the effects of delayed nerve graft.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"12"},"PeriodicalIF":7.2,"publicationDate":"2023-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9970988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9383777","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":"Biomineralization-inspired mineralized hydrogel promotes the repair and regeneration of dentin/bone hard tissue.","authors":"Bo Wen,&nbsp;Yuguo Dai,&nbsp;Xue Han,&nbsp;Fangjun Huo,&nbsp;Li Xie,&nbsp;Mei Yu,&nbsp;Yuru Wang,&nbsp;Ning An,&nbsp;Zhonghan Li,&nbsp;Weihua Guo","doi":"10.1038/s41536-023-00286-3","DOIUrl":"https://doi.org/10.1038/s41536-023-00286-3","url":null,"abstract":"<p><p>Maxillofacial hard tissue defects caused by trauma or infection often affect craniofacial function. Taking the natural hard tissue structure as a template, constructing an engineered tissue repair module is an important scheme to realize the functional regeneration and repair of maxillofacial hard tissue. Here, inspired by the biomineralization process, we constructed a composite mineral matrix hydrogel PAA-CMC-TDM containing amorphous calcium phosphates (ACPs), polyacrylic acid (PAA), carboxymethyl chitosan (CMC) and dentin matrix (TDM). The dynamic network composed of Ca²⁺·COO^- coordination and ACPs made the hydrogel loaded with TDM, and exhibited self-repairing ability and injectability. The mechanical properties of PAA-CMC-TDM can be regulated, but the functional activity of TDM remains unaffected. Cytological studies and animal models of hard tissue defects show that the hydrogel can promote the odontogenesis or osteogenic differentiation of mesenchymal stem cells, adapt to irregular hard tissue defects, and promote in situ regeneration of defective tooth and bone tissues. In summary, this paper shows that the injectable TDM hydrogel based on biomimetic mineralization theory can induce hard tissue formation and promote dentin/bone regeneration.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"11"},"PeriodicalIF":7.2,"publicationDate":"2023-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9968336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9351576","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}