npj Regenerative Medicine最新文献_第10页

DNA methyltransferase 1 deficiency improves macrophage motility and wound healing by ameliorating cholesterol accumulation. DNA甲基转移酶1缺乏通过改善胆固醇积累改善巨噬细胞运动和伤口愈合。

IF 7.2 1区医学

npj Regenerative Medicine Pub Date : 2023-06-08 DOI: 10.1038/s41536-023-00306-2

Chuanrong Zhao, Qianru Yang, Runze Tang, Wang Li, Jin Wang, Fangfang Yang, Jianan Zhao, Juanjuan Zhu, Wei Pang, Ning Li, Xu Zhang, Xiao Yu Tian, Weijuan Yao, Jing Zhou

{"title":"DNA methyltransferase 1 deficiency improves macrophage motility and wound healing by ameliorating cholesterol accumulation.","authors":"Chuanrong Zhao, Qianru Yang, Runze Tang, Wang Li, Jin Wang, Fangfang Yang, Jianan Zhao, Juanjuan Zhu, Wei Pang, Ning Li, Xu Zhang, Xiao Yu Tian, Weijuan Yao, Jing Zhou","doi":"10.1038/s41536-023-00306-2","DOIUrl":"https://doi.org/10.1038/s41536-023-00306-2","url":null,"abstract":"Healing of the cutaneous wound requires macrophage recruitment at the sites of injury, where chemotactic migration of macrophages toward the wound is regulated by local inflammation. Recent studies suggest a positive contribution of DNA methyltransferase 1 (Dnmt1) to macrophage pro-informatory responses; however, its role in regulating macrophage motility remains unknown. In this study, myeloid-specific depletion of Dnmt1 in mice promoted cutaneous wound healing and de-suppressed the lipopolysaccharides (LPS)-inhibited macrophage motility. Dnmt1 inhibition in macrophages eliminated the LPS-stimulated changes in cellular mechanical properties in terms of elasticity and viscoelasticity. LPS increased the cellular accumulation of cholesterol in a Dnmt1-depedent manner; cholesterol content determined cellular stiffness and motility. Lipidomic analysis indicated that Dnmt1 inhibition altered the cellular lipid homeostasis, probably through down-regulating the expression of cluster of differentiation 36 CD36 (facilitating lipid influx) and up-regulating the expression of ATP-binding cassette transporter ABCA1 (mediating lipid efflux) and sterol O-acyltransferase 1 SOAT1 (also named ACAT1, catalyzing the esterification of cholesterol). Our study revealed a Dnmt1-dependent epigenetic mechanism in the control of macrophage mechanical properties and the related chemotactic motility, indicating Dnmt1 as both a marker of diseases and a potential target of therapeutic intervention for wound healing.","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"29"},"PeriodicalIF":7.2,"publicationDate":"2023-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10250321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9612427","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: 1

Janus porous polylactic acid membranes with versatile metal-phenolic interface for biomimetic periodontal bone regeneration. 具有多功能金属-酚醛界面的聚乳酸多孔膜用于仿生牙周骨再生。

IF 7.2 1区医学

npj Regenerative Medicine Pub Date : 2023-06-03 DOI: 10.1038/s41536-023-00305-3

Yaping Zhang, Yi Chen, Tian Ding, Yandi Zhang, Daiwei Yang, Yajun Zhao, Jin Liu, Baojin Ma, Alberto Bianco, Shaohua Ge, Jianhua Li

{"title":"Janus porous polylactic acid membranes with versatile metal-phenolic interface for biomimetic periodontal bone regeneration.","authors":"Yaping Zhang, Yi Chen, Tian Ding, Yandi Zhang, Daiwei Yang, Yajun Zhao, Jin Liu, Baojin Ma, Alberto Bianco, Shaohua Ge, Jianhua Li","doi":"10.1038/s41536-023-00305-3","DOIUrl":"https://doi.org/10.1038/s41536-023-00305-3","url":null,"abstract":"Conventional treatment to periodontal and many other bone defects requires the use of barrier membranes to guided tissue regeneration (GTR) and guided bone regeneration (GBR). However, current barrier membranes normally lack of the ability to actively regulate the bone repairing process. Herein, we proposed a biomimetic bone tissue engineering strategy enabled by a new type of Janus porous polylactic acid membrane (PLAM), which was fabricated by combining unidirectional evaporation-induced pore formation with subsequent self-assembly of a bioactive metal-phenolic network (MPN) nanointerface. The prepared PLAM-MPN simultaneously possesses barrier function on the dense side and bone-forming function on the porous side. In vitro, the presence of MPN nanointerface potently alleviated the proinflammatory polarization of mice bone marrow-derived macrophages (BMDMs), induced angiogenesis of human umbilical vein endothelial cells (HUVECs), and enhanced the attachment, migration and osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs). The implantation of PLAM-MPN into rat periodontal bone defects remarkably enhanced bone regeneration. This bioactive MPN nanointerface within a Janus porous membrane possesses versatile capacities to regulate cell physiology favoring bone regeneration, demonstrating great potential as GTR and GBR membranes for clinical applications.","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"28"},"PeriodicalIF":7.2,"publicationDate":"2023-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10239453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9569728","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: 3

Cerebral organoids transplantation repairs infarcted cortex and restores impaired function after stroke. 脑类器官移植修复脑卒中后梗死皮质和恢复受损功能。

IF 7.2 1区医学

npj Regenerative Medicine Pub Date : 2023-05-30 DOI: 10.1038/s41536-023-00301-7

Shi-Ying Cao, Di Yang, Zhen-Quan Huang, Yu-Hui Lin, Hai-Yin Wu, Lei Chang, Chun-Xia Luo, Yun Xu, Yan Liu, Dong-Ya Zhu

{"title":"Cerebral organoids transplantation repairs infarcted cortex and restores impaired function after stroke.","authors":"Shi-Ying Cao, Di Yang, Zhen-Quan Huang, Yu-Hui Lin, Hai-Yin Wu, Lei Chang, Chun-Xia Luo, Yun Xu, Yan Liu, Dong-Ya Zhu","doi":"10.1038/s41536-023-00301-7","DOIUrl":"https://doi.org/10.1038/s41536-023-00301-7","url":null,"abstract":"Stroke usually causes prolonged or lifelong disability, owing to the permanent loss of infarcted tissue. Although a variety of stem cell transplantation has been explored to improve neuronal defect behavior by enhancing neuroplasticity, it remains unknown whether the infarcted tissue can be reconstructed. We here cultured human cerebral organoids derived from human pluripotent stem cells (hPSCs) and transplanted them into the junction of the infarct core and the peri-infarct zone of NOD-SCID mice subjected to stroke. Months later, we found that the grafted organoids survived well in the infarcted core, differentiated into target neurons, repaired infarcted tissue, sent axons to distant brain targets, and integrated into the host neural circuit and thereby eliminated sensorimotor defect behaviors of stroke mice, whereas transplantation of dissociated single cells from organoids failed to repair the infarcted tissue. Our study offers a new strategy for reconstructing infarcted tissue via organoids transplantation thereby reversing stroke-induced disability.","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"27"},"PeriodicalIF":7.2,"publicationDate":"2023-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10229586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9564946","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: 1

Pluripotent stem cell-derived committed cardiac progenitors remuscularize damaged ischemic hearts and improve their function in pigs. 多能干细胞来源的心脏祖细胞对猪受损的缺血心脏进行再灌注并改善其功能。

IF 7.2 1区医学

npj Regenerative Medicine Pub Date : 2023-05-26 DOI: 10.1038/s41536-023-00302-6

Lynn Yap, Li Yen Chong, Clarissa Tan, Swarnaseetha Adusumalli, Millie Seow, Jing Guo, Zuhua Cai, Sze Jie Loo, Eric Lim, Ru San Tan, Elina Grishina, Poh Loong Soong, Narayan Lath, Lei Ye, Enrico Petretto, Karl Tryggvason

{"title":"Pluripotent stem cell-derived committed cardiac progenitors remuscularize damaged ischemic hearts and improve their function in pigs.","authors":"Lynn Yap, Li Yen Chong, Clarissa Tan, Swarnaseetha Adusumalli, Millie Seow, Jing Guo, Zuhua Cai, Sze Jie Loo, Eric Lim, Ru San Tan, Elina Grishina, Poh Loong Soong, Narayan Lath, Lei Ye, Enrico Petretto, Karl Tryggvason","doi":"10.1038/s41536-023-00302-6","DOIUrl":"https://doi.org/10.1038/s41536-023-00302-6","url":null,"abstract":"Ischemic heart disease, which is often associated with irreversibly damaged heart muscle, is a major global health burden. Here, we report the potential of stem cell-derived committed cardiac progenitors (CCPs) have in regenerative cardiology. Human pluripotent embryonic stem cells were differentiated to CCPs on a laminin 521 + 221 matrix, characterized with bulk and single-cell RNA sequencing, and transplanted into infarcted pig hearts. CCPs differentiated for eleven days expressed a set of genes showing higher expression than cells differentiated for seven days. Functional heart studies revealed significant improvement in left ventricular ejection fraction at four and twelve weeks following transplantation. We also observed significant improvements in ventricular wall thickness and a reduction in infarction size after CCP transplantation (p-value < 0.05). Immunohistology analyses revealed in vivo maturation of the CCPs into cardiomyocytes (CM). We observed temporary episodes of ventricular tachyarrhythmia (VT) in four pigs and persistent VT in one pig, but the remaining five pigs exhibited normal sinus rhythm. Importantly, all pigs survived without the formation of any tumors or VT-related abnormalities. We conclude that pluripotent stem cell-derived CCPs constitute a promising possibility for myocardial infarction treatment and that they may positively impact regenerative cardiology.","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"26"},"PeriodicalIF":7.2,"publicationDate":"2023-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10219927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9532138","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: 1

A superior extracellular matrix binding motif to enhance the regenerative activity and safety of therapeutic proteins. 一个优越的细胞外基质结合基序，以提高再生活性和治疗蛋白的安全性。

IF 7.2 1区医学

npj Regenerative Medicine Pub Date : 2023-05-22 DOI: 10.1038/s41536-023-00297-0

Yasmin K Alshoubaki, Yen-Zhen Lu, Julien M D Legrand, Rezvan Karami, Mathilde Fossat, Ekaterina Salimova, Ziad Julier, Mikaël M Martino

{"title":"A superior extracellular matrix binding motif to enhance the regenerative activity and safety of therapeutic proteins.","authors":"Yasmin K Alshoubaki, Yen-Zhen Lu, Julien M D Legrand, Rezvan Karami, Mathilde Fossat, Ekaterina Salimova, Ziad Julier, Mikaël M Martino","doi":"10.1038/s41536-023-00297-0","DOIUrl":"https://doi.org/10.1038/s41536-023-00297-0","url":null,"abstract":"Among therapeutic proteins, cytokines and growth factors have great potential for regenerative medicine applications. However, these molecules have encountered limited clinical success due to low effectiveness and major safety concerns, highlighting the need to develop better approaches that increase efficacy and safety. Promising approaches leverage how the extracellular matrix (ECM) controls the activity of these molecules during tissue healing. Using a protein motif screening strategy, we discovered that amphiregulin possesses an exceptionally strong binding motif for ECM components. We used this motif to confer the pro-regenerative therapeutics platelet-derived growth factor-BB (PDGF-BB) and interleukin-1 receptor antagonist (IL-1Ra) a very high affinity to the ECM. In mouse models, the approach considerably extended tissue retention of the engineered therapeutics and reduced leakage in the circulation. Prolonged retention and minimal systemic diffusion of engineered PDGF-BB abolished the tumour growth-promoting adverse effect that was observed with wild-type PDGF-BB. Moreover, engineered PDGF-BB was substantially more effective at promoting diabetic wound healing and regeneration after volumetric muscle loss, compared to wild-type PDGF-BB. Finally, while local or systemic delivery of wild-type IL-1Ra showed minor effects, intramyocardial delivery of engineered IL-1Ra enhanced cardiac repair after myocardial infarction by limiting cardiomyocyte death and fibrosis. This engineering strategy highlights the key importance of exploiting interactions between ECM and therapeutic proteins for developing effective and safer regenerative therapies.","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"25"},"PeriodicalIF":7.2,"publicationDate":"2023-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10202959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9568908","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: 1

Author Correction: Chondrogenic differentiation induced by extracellular vesicles bound to a nanofibrous substrate. 作者更正:软骨分化是由结合在纳米纤维基质上的细胞外囊泡诱导的。

IF 7.2 1区医学

npj Regenerative Medicine Pub Date : 2023-05-22 DOI: 10.1038/s41536-023-00300-8

Marta R Casanova, Hugo Osório, Rui L Reis, Albino Martins, Nuno M Neves

引用次数: 0

Macrophages maintain mammary stem cell activity and mammary homeostasis via TNF-α-PI3K-Cdk1/Cyclin B1 axis. 巨噬细胞通过TNF-α-PI3K-Cdk1/Cyclin B1轴维持乳腺干细胞活性和乳腺稳态。

IF 7.2 1区医学

npj Regenerative Medicine Pub Date : 2023-05-02 DOI: 10.1038/s41536-023-00296-1

Yu Zhou, Zi Ye, Wei Wei, Mengna Zhang, Fujing Huang, Jinpeng Li, Cheguo Cai

{"title":"Macrophages maintain mammary stem cell activity and mammary homeostasis via TNF-α-PI3K-Cdk1/Cyclin B1 axis.","authors":"Yu Zhou, Zi Ye, Wei Wei, Mengna Zhang, Fujing Huang, Jinpeng Li, Cheguo Cai","doi":"10.1038/s41536-023-00296-1","DOIUrl":"https://doi.org/10.1038/s41536-023-00296-1","url":null,"abstract":"Adult stem cell niche is a special environment composed of a variety stromal cells and signals, which cooperatively regulate tissue development and homeostasis. It is of great interest to study the role of immune cells in niche. Here, we show that mammary resident macrophages regulate mammary epithelium cell division and mammary development through TNF-α-Cdk1/Cyclin B1 axis. In vivo, depletion of macrophages reduces the number of mammary basal cells and mammary stem cells (MaSCs), while increases mammary luminal cells. In vitro, we establish a three-dimensional culture system in which mammary basal cells are co-cultured with macrophages, and interestingly, macrophage co-culture promotes the formation of branched functional mammary organoids. Moreover, TNF-α produced by macrophages activates the intracellular PI3K/Cdk1/Cyclin B1 signaling in mammary cells, thereby maintaining the activity of MaSCs and the formation of mammary organoids. Together, these findings reveal the functional significance of macrophageal niche and intracellular PI3K/Cdk1/Cyclin B1 axis for maintaining MaSC activity and mammary homeostasis.","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"23"},"PeriodicalIF":7.2,"publicationDate":"2023-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10154328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9411371","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

Rational engineering of lung alveolar epithelium. 肺泡上皮的合理工程。

IF 7.2 1区医学

npj Regenerative Medicine Pub Date : 2023-04-28 DOI: 10.1038/s41536-023-00295-2

Katherine L Leiby, Yifan Yuan, Ronald Ng, Micha Sam Brickman Raredon, Taylor S Adams, Pavlina Baevova, Allison M Greaney, Karen K Hirschi, Stuart G Campbell, Naftali Kaminski, Erica L Herzog, Laura E Niklason

{"title":"Rational engineering of lung alveolar epithelium.","authors":"Katherine L Leiby, Yifan Yuan, Ronald Ng, Micha Sam Brickman Raredon, Taylor S Adams, Pavlina Baevova, Allison M Greaney, Karen K Hirschi, Stuart G Campbell, Naftali Kaminski, Erica L Herzog, Laura E Niklason","doi":"10.1038/s41536-023-00295-2","DOIUrl":"10.1038/s41536-023-00295-2","url":null,"abstract":"Engineered whole lungs may one day expand therapeutic options for patients with end-stage lung disease. However, the feasibility of ex vivo lung regeneration remains limited by the inability to recapitulate mature, functional alveolar epithelium. Here, we modulate multimodal components of the alveolar epithelial type 2 cell (AEC2) niche in decellularized lung scaffolds in order to guide AEC2 behavior for epithelial regeneration. First, endothelial cells coordinate with fibroblasts, in the presence of soluble growth and maturation factors, to promote alveolar scaffold population with surfactant-secreting AEC2s. Subsequent withdrawal of Wnt and FGF agonism synergizes with tidal-magnitude mechanical strain to induce the differentiation of AEC2s to squamous type 1 AECs (AEC1s) in cultured alveoli, in situ. These results outline a rational strategy to engineer an epithelium of AEC2s and AEC1s contained within epithelial-mesenchymal-endothelial alveolar-like units, and highlight the critical interplay amongst cellular, biochemical, and mechanical niche cues within the reconstituting alveolus.","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"22"},"PeriodicalIF":7.2,"publicationDate":"2023-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10147714/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10138870","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

Endothelial Brg1 fine-tunes Notch signaling during zebrafish heart regeneration. 内皮细胞Brg1微调斑马鱼心脏再生过程中的Notch信号。

IF 7.2 1区医学

npj Regenerative Medicine Pub Date : 2023-04-07 DOI: 10.1038/s41536-023-00293-4

Chenglu Xiao, Junjie Hou, Fang Wang, Yabing Song, Jiyuan Zheng, Lingfei Luo, Jianbin Wang, Wanqiu Ding, Xiaojun Zhu, Jing-Wei Xiong

{"title":"Endothelial Brg1 fine-tunes Notch signaling during zebrafish heart regeneration.","authors":"Chenglu Xiao, Junjie Hou, Fang Wang, Yabing Song, Jiyuan Zheng, Lingfei Luo, Jianbin Wang, Wanqiu Ding, Xiaojun Zhu, Jing-Wei Xiong","doi":"10.1038/s41536-023-00293-4","DOIUrl":"https://doi.org/10.1038/s41536-023-00293-4","url":null,"abstract":"Myocardial Brg1 is essential for heart regeneration in zebrafish, but it remains unknown whether and how endothelial Brg1 plays a role in heart regeneration. Here, we found that both brg1 mRNA and protein were induced in cardiac endothelial cells after ventricular resection and endothelium-specific overexpression of dominant-negative Xenopus Brg1 (dn-xbrg1) inhibited myocardial proliferation and heart regeneration and increased cardiac fibrosis. RNA-seq and ChIP-seq analysis revealed that endothelium-specific overexpression of dn-xbrg1 changed the levels of H3K4me3 modifications in the promoter regions of the zebrafish genome and induced abnormal activation of Notch family genes upon injury. Mechanistically, Brg1 interacted with lysine demethylase 7aa (Kdm7aa) to fine-tune the level of H3K4me3 within the promoter regions of Notch family genes and thus regulated notch gene transcription. Together, this work demonstrates that the Brg1-Kdm7aa-Notch axis in cardiac endothelial cells, including the endocardium, regulates myocardial proliferation and regeneration via modulating the H3K4me3 of the notch promoters in zebrafish.","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":"8 1","pages":"21"},"PeriodicalIF":7.2,"publicationDate":"2023-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10082087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9288092","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: 1

The MRN complex maintains the biliary-derived hepatocytes in liver regeneration through ATR-Chk1 pathway. MRN复合物通过ATR-Chk1途径维持肝再生中的胆道源性肝细胞。

IF 7.2 1区医学

npj Regenerative Medicine Pub Date : 2023-04-06 DOI: 10.1038/s41536-023-00294-3

Jingmei Song, Jianlong Ma, Xing Liu, Zhuofu Huang, Lianghui Li, Linke Li, Lingfei Luo, Rui Ni, Jianbo He

{"title":"The MRN complex maintains the biliary-derived hepatocytes in liver regeneration through ATR-Chk1 pathway.","authors":"Jingmei Song, Jianlong Ma, Xing Liu, Zhuofu Huang, Lianghui Li, Linke Li, Lingfei Luo, Rui Ni, Jianbo He","doi":"10.1038/s41536-023-00294-3","DOIUrl":"https://doi.org/10.1038/s41536-023-00294-3","url":null,"abstract":"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.","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}

引用次数: 2