Pub Date : 2024-11-26DOI: 10.1038/s41556-024-01556-y
Yingjie Zhang, Connor M. Hill, Kelsey A. Leach, Luca Grillini, Sandra Deliard, Sarah R. Offley, Martina Gatto, Francis Picone, Avery Zucco, Alessandro Gardini
Lineage-specific transcription factors operate as master orchestrators of developmental processes by activating select cis-regulatory enhancers and proximal promoters. Direct DNA binding of transcription factors ultimately drives context-specific recruitment of the basal transcriptional machinery that comprises RNA polymerase II (RNAPII) and a host of polymerase-associated multiprotein complexes, including the metazoan-specific Integrator complex. Integrator is primarily known to modulate RNAPII processivity and to surveil RNA integrity across coding genes. Here we describe an enhancer module of Integrator that directs cell fate specification by promoting epigenetic changes and transcription factor binding at neural enhancers. Depletion of Integrator’s INTS10 subunit upends neural traits and derails cells towards mesenchymal identity. Commissioning of neural enhancers relies on Integrator’s enhancer module, which stabilizes SOX2 binding at chromatin upon exit from pluripotency. We propose that Integrator is a functional bridge between enhancers and promoters and a main driver of early development, providing new insight into a growing family of neurodevelopmental syndromes. Zhang et al. report that INST10, part of the Integrator enhancer module, promotes epigenetic changes and transcription factor binding at enhancers that drive neural cell fate commitment by stabilizing SOX2 binding at chromatin upon pluripotency exit.
{"title":"The enhancer module of Integrator controls cell identity and early neural fate commitment","authors":"Yingjie Zhang, Connor M. Hill, Kelsey A. Leach, Luca Grillini, Sandra Deliard, Sarah R. Offley, Martina Gatto, Francis Picone, Avery Zucco, Alessandro Gardini","doi":"10.1038/s41556-024-01556-y","DOIUrl":"10.1038/s41556-024-01556-y","url":null,"abstract":"Lineage-specific transcription factors operate as master orchestrators of developmental processes by activating select cis-regulatory enhancers and proximal promoters. Direct DNA binding of transcription factors ultimately drives context-specific recruitment of the basal transcriptional machinery that comprises RNA polymerase II (RNAPII) and a host of polymerase-associated multiprotein complexes, including the metazoan-specific Integrator complex. Integrator is primarily known to modulate RNAPII processivity and to surveil RNA integrity across coding genes. Here we describe an enhancer module of Integrator that directs cell fate specification by promoting epigenetic changes and transcription factor binding at neural enhancers. Depletion of Integrator’s INTS10 subunit upends neural traits and derails cells towards mesenchymal identity. Commissioning of neural enhancers relies on Integrator’s enhancer module, which stabilizes SOX2 binding at chromatin upon exit from pluripotency. We propose that Integrator is a functional bridge between enhancers and promoters and a main driver of early development, providing new insight into a growing family of neurodevelopmental syndromes. Zhang et al. report that INST10, part of the Integrator enhancer module, promotes epigenetic changes and transcription factor binding at enhancers that drive neural cell fate commitment by stabilizing SOX2 binding at chromatin upon pluripotency exit.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 1","pages":"103-117"},"PeriodicalIF":17.3,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142713099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-15DOI: 10.1038/s41556-024-01567-9
Carissa L. Sirois, Soraya O. Sandoval, Xinyu Zhao
Mitochondrial fission and fusion are crucial for neurons. The RNA-binding protein FMRP regulates mitochondrial dynamics, including fusion and trafficking in neurons. A study now identifies a mechanism by which FMRP regulates mitochondrial fission.
{"title":"FMRP gains mitochondrial fission control","authors":"Carissa L. Sirois, Soraya O. Sandoval, Xinyu Zhao","doi":"10.1038/s41556-024-01567-9","DOIUrl":"10.1038/s41556-024-01567-9","url":null,"abstract":"Mitochondrial fission and fusion are crucial for neurons. The RNA-binding protein FMRP regulates mitochondrial dynamics, including fusion and trafficking in neurons. A study now identifies a mechanism by which FMRP regulates mitochondrial fission.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 12","pages":"2014-2015"},"PeriodicalIF":17.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-15DOI: 10.1038/s41556-024-01544-2
Adam R. Fenton, Ruchao Peng, Charles Bond, Siewert Hugelier, Melike Lakadamyali, Yi-Wei Chang, Erika L. F. Holzbaur, Thomas A. Jongens
Fragile X messenger ribonucleoprotein (FMRP) is a critical regulator of translation, whose dysfunction causes fragile X syndrome. FMRP dysfunction disrupts mitochondrial health in neurons, but it is unclear how FMRP supports mitochondrial homoeostasis. Here we demonstrate that FMRP granules are recruited to the mitochondrial midzone, where they mark mitochondrial fission sites in axons and dendrites. Endolysosomal vesicles contribute to FMRP granule positioning around mitochondria and facilitate FMRP-associated fission via Rab7 GTP hydrolysis. Cryo-electron tomography and real-time translation imaging reveal that mitochondria-associated FMRP granules are ribosome-rich structures that serve as sites of local protein synthesis. Specifically, FMRP promotes local translation of mitochondrial fission factor (MFF), selectively enabling replicative fission at the mitochondrial midzone. Disrupting FMRP function dysregulates mitochondria-associated MFF translation and perturbs fission dynamics, resulting in increased peripheral fission and an irregular distribution of mitochondrial nucleoids. Thus, FMRP regulates local translation of MFF in neurons, enabling precise control of mitochondrial fission. Fenton et al. show that FMRP granules dock at the mitochondrial midzone in a Rab7-dependent manner in axons and dendrites, where they promote local MFF synthesis and fission at the mitochondrial midzone.
脆性 X 信使核糖核蛋白（FMRP）是翻译的关键调节因子，其功能障碍会导致脆性 X 综合征。FMRP功能障碍会破坏神经元线粒体的健康，但目前还不清楚FMRP如何支持线粒体的平衡。在这里，我们证明了 FMRP 颗粒被招募到线粒体中区，并在那里标记轴突和树突中的线粒体裂变位点。溶酶体内囊泡有助于FMRP颗粒在线粒体周围的定位，并通过Rab7 GTP水解促进FMRP相关裂变。低温电子断层扫描和实时翻译成像显示，线粒体相关的FMRP颗粒是富含核糖体的结构，是局部蛋白质合成的场所。具体来说，FMRP 促进线粒体裂变因子（MFF）的局部翻译，有选择性地促成线粒体中区的复制裂变。干扰 FMRP 的功能会使线粒体相关 MFF 翻译失调并扰乱裂变动力学，导致外围裂变增加和线粒体核仁分布不规则。因此，FMRP 可调节神经元中 MFF 的局部翻译，从而实现对线粒体裂变的精确控制。
{"title":"FMRP regulates MFF translation to locally direct mitochondrial fission in neurons","authors":"Adam R. Fenton, Ruchao Peng, Charles Bond, Siewert Hugelier, Melike Lakadamyali, Yi-Wei Chang, Erika L. F. Holzbaur, Thomas A. Jongens","doi":"10.1038/s41556-024-01544-2","DOIUrl":"10.1038/s41556-024-01544-2","url":null,"abstract":"Fragile X messenger ribonucleoprotein (FMRP) is a critical regulator of translation, whose dysfunction causes fragile X syndrome. FMRP dysfunction disrupts mitochondrial health in neurons, but it is unclear how FMRP supports mitochondrial homoeostasis. Here we demonstrate that FMRP granules are recruited to the mitochondrial midzone, where they mark mitochondrial fission sites in axons and dendrites. Endolysosomal vesicles contribute to FMRP granule positioning around mitochondria and facilitate FMRP-associated fission via Rab7 GTP hydrolysis. Cryo-electron tomography and real-time translation imaging reveal that mitochondria-associated FMRP granules are ribosome-rich structures that serve as sites of local protein synthesis. Specifically, FMRP promotes local translation of mitochondrial fission factor (MFF), selectively enabling replicative fission at the mitochondrial midzone. Disrupting FMRP function dysregulates mitochondria-associated MFF translation and perturbs fission dynamics, resulting in increased peripheral fission and an irregular distribution of mitochondrial nucleoids. Thus, FMRP regulates local translation of MFF in neurons, enabling precise control of mitochondrial fission. Fenton et al. show that FMRP granules dock at the mitochondrial midzone in a Rab7-dependent manner in axons and dendrites, where they promote local MFF synthesis and fission at the mitochondrial midzone.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 12","pages":"2061-2074"},"PeriodicalIF":17.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01544-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-15DOI: 10.1038/s41556-024-01550-4
Mardi Fink, Kizito Njah, Shyam J. Patel, David P. Cook, Vanessa Man, Francesco Ruso, Arsheen Rajan, Masahiro Narimatsu, Andreea Obersterescu, Melanie J. Pye, Daniel Trcka, Kin Chan, Arshad Ayyaz, Jeffrey L. Wrana
Cell state dynamics underlying successful tissue regeneration are undercharacterized. In the intestine, damage prompts epithelial reprogramming into revival stem cells (revSCs) that reconstitute Lgr5+ intestinal stem cells (ISCs). Here single-nuclear multi-omics of mouse crypts regenerating from irradiation shows revSC chromatin accessibility overlaps with ISCs and differentiated lineages. While revSC genes themselves are accessible throughout homeostatic epithelia, damage-induced remodelling of chromatin in the crypt converges on Hippo and the transforming growth factor-beta (TGFβ) signalling pathway, which we show is transiently activated and directly induces functional revSCs. Combinatorial gene expression analysis further suggests multiple sources of revSCs, and we demonstrate TGFβ can reprogramme enterocytes, goblet and paneth cells into revSCs and show individual revSCs form organoids. Despite this, loss of TGFβ signalling yields mild regenerative defects, whereas interference in both Hippo and TGFβ leads to profound defects and death. Intestinal regeneration is thus poised for activation by a compensatory system of crypt-localized, transient morphogen cues that support epithelial reprogramming and robust intestinal repair. Using deep single-nucleus multi-omics profiling, Fink et al. report transition states between crypt epithelial cells and a revival stem cell lineage. They find that the TGFβ and Hippo signalling pathways cooperatively drive intestinal regeneration.
{"title":"Chromatin remodelling in damaged intestinal crypts orchestrates redundant TGFβ and Hippo signalling to drive regeneration","authors":"Mardi Fink, Kizito Njah, Shyam J. Patel, David P. Cook, Vanessa Man, Francesco Ruso, Arsheen Rajan, Masahiro Narimatsu, Andreea Obersterescu, Melanie J. Pye, Daniel Trcka, Kin Chan, Arshad Ayyaz, Jeffrey L. Wrana","doi":"10.1038/s41556-024-01550-4","DOIUrl":"10.1038/s41556-024-01550-4","url":null,"abstract":"Cell state dynamics underlying successful tissue regeneration are undercharacterized. In the intestine, damage prompts epithelial reprogramming into revival stem cells (revSCs) that reconstitute Lgr5+ intestinal stem cells (ISCs). Here single-nuclear multi-omics of mouse crypts regenerating from irradiation shows revSC chromatin accessibility overlaps with ISCs and differentiated lineages. While revSC genes themselves are accessible throughout homeostatic epithelia, damage-induced remodelling of chromatin in the crypt converges on Hippo and the transforming growth factor-beta (TGFβ) signalling pathway, which we show is transiently activated and directly induces functional revSCs. Combinatorial gene expression analysis further suggests multiple sources of revSCs, and we demonstrate TGFβ can reprogramme enterocytes, goblet and paneth cells into revSCs and show individual revSCs form organoids. Despite this, loss of TGFβ signalling yields mild regenerative defects, whereas interference in both Hippo and TGFβ leads to profound defects and death. Intestinal regeneration is thus poised for activation by a compensatory system of crypt-localized, transient morphogen cues that support epithelial reprogramming and robust intestinal repair. Using deep single-nucleus multi-omics profiling, Fink et al. report transition states between crypt epithelial cells and a revival stem cell lineage. They find that the TGFβ and Hippo signalling pathways cooperatively drive intestinal regeneration.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 12","pages":"2084-2098"},"PeriodicalIF":17.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13DOI: 10.1038/s41556-024-01520-w
Kuo Du, David Scott Umbaugh, Rajesh Kumar Dutta, Anna Mae Diehl
A study shows that senescence induced in the liver can spread systemically to precipitate multi-organ dysfunction. The work identifies TGFβ signalling as a key mediator of this transmission, suggesting therapeutic avenues to prevent multi-organ failure in severe liver diseases.
{"title":"A systemic effect for liver senescence","authors":"Kuo Du, David Scott Umbaugh, Rajesh Kumar Dutta, Anna Mae Diehl","doi":"10.1038/s41556-024-01520-w","DOIUrl":"10.1038/s41556-024-01520-w","url":null,"abstract":"A study shows that senescence induced in the liver can spread systemically to precipitate multi-organ dysfunction. The work identifies TGFβ signalling as a key mediator of this transmission, suggesting therapeutic avenues to prevent multi-organ failure in severe liver diseases.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 12","pages":"2016-2017"},"PeriodicalIF":17.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13DOI: 10.1038/s41556-024-01543-3
Christos Kiourtis, Maria Terradas-Terradas, Lucy M. Gee, Stephanie May, Anastasia Georgakopoulou, Amy L. Collins, Eoin D. O’Sullivan, David P. Baird, Mohsin Hassan, Robin Shaw, Ee Hong Tan, Miryam Müller, Cornelius Engelmann, Fausto Andreola, Ya-Ching Hsieh, Lee H. Reed, Lee A. Borthwick, Colin Nixon, William Clark, Peter S. Hanson, David Sumpton, Gillian Mackay, Toshiyasu Suzuki, Arafath K. Najumudeen, Gareth J. Inman, Andrew Campbell, Simon T. Barry, Alberto Quaglia, Christopher M. Morris, Fiona E. N. LeBeau, Owen J. Sansom, Kristina Kirschner, Rajiv Jalan, Fiona Oakley, Thomas G. Bird
Cellular senescence is not only associated with ageing but also impacts physiological and pathological processes, such as embryonic development and wound healing. Factors secreted by senescent cells affect their microenvironment and can induce spreading of senescence locally. Acute severe liver disease is associated with hepatocyte senescence and frequently progresses to multi-organ failure. Why the latter occurs is poorly understood. Here we demonstrate senescence development in extrahepatic organs and associated organ dysfunction in response to liver senescence using liver injury models and genetic models of hepatocyte-specific senescence. In patients with severe acute liver failure, we show that the extent of hepatocellular senescence predicts disease outcome, the need for liver transplantation and the occurrence of extrahepatic organ failure. We identify the TGFβ pathway as a critical mediator of systemic spread of senescence and demonstrate that TGFβ inhibition in vivo blocks senescence transmission to other organs, preventing liver senescence induced renal dysfunction. Our results highlight the systemic consequences of organ-specific senescence, which, independent of ageing, contributes to multi-organ dysfunction. Kiourtis et al. show that liver senescence triggers senescence and dysfunction in other organs through TGFβ secretion from the liver.
{"title":"Hepatocellular senescence induces multi-organ senescence and dysfunction via TGFβ","authors":"Christos Kiourtis, Maria Terradas-Terradas, Lucy M. Gee, Stephanie May, Anastasia Georgakopoulou, Amy L. Collins, Eoin D. O’Sullivan, David P. Baird, Mohsin Hassan, Robin Shaw, Ee Hong Tan, Miryam Müller, Cornelius Engelmann, Fausto Andreola, Ya-Ching Hsieh, Lee H. Reed, Lee A. Borthwick, Colin Nixon, William Clark, Peter S. Hanson, David Sumpton, Gillian Mackay, Toshiyasu Suzuki, Arafath K. Najumudeen, Gareth J. Inman, Andrew Campbell, Simon T. Barry, Alberto Quaglia, Christopher M. Morris, Fiona E. N. LeBeau, Owen J. Sansom, Kristina Kirschner, Rajiv Jalan, Fiona Oakley, Thomas G. Bird","doi":"10.1038/s41556-024-01543-3","DOIUrl":"10.1038/s41556-024-01543-3","url":null,"abstract":"Cellular senescence is not only associated with ageing but also impacts physiological and pathological processes, such as embryonic development and wound healing. Factors secreted by senescent cells affect their microenvironment and can induce spreading of senescence locally. Acute severe liver disease is associated with hepatocyte senescence and frequently progresses to multi-organ failure. Why the latter occurs is poorly understood. Here we demonstrate senescence development in extrahepatic organs and associated organ dysfunction in response to liver senescence using liver injury models and genetic models of hepatocyte-specific senescence. In patients with severe acute liver failure, we show that the extent of hepatocellular senescence predicts disease outcome, the need for liver transplantation and the occurrence of extrahepatic organ failure. We identify the TGFβ pathway as a critical mediator of systemic spread of senescence and demonstrate that TGFβ inhibition in vivo blocks senescence transmission to other organs, preventing liver senescence induced renal dysfunction. Our results highlight the systemic consequences of organ-specific senescence, which, independent of ageing, contributes to multi-organ dysfunction. Kiourtis et al. show that liver senescence triggers senescence and dysfunction in other organs through TGFβ secretion from the liver.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 12","pages":"2075-2083"},"PeriodicalIF":17.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01543-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-11DOI: 10.1038/s41556-024-01560-2
Stylianos Lefkopoulos
{"title":"To eat or not to eat","authors":"Stylianos Lefkopoulos","doi":"10.1038/s41556-024-01560-2","DOIUrl":"10.1038/s41556-024-01560-2","url":null,"abstract":"","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 11","pages":"1825-1825"},"PeriodicalIF":17.3,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-11DOI: 10.1038/s41556-024-01545-1
Vishal Mohanakrishnan, Kishor K. Sivaraj, Hyun-Woo Jeong, Esther Bovay, Backialakshmi Dharmalingam, M. Gabriele Bixel, Van Vuong Dinh, Milena Petkova, Isidora Paredes Ugarte, Yi-Tong Kuo, Malarvizhi Gurusamy, Brian Raftrey, Nelson Tsz Long Chu, Soumyashree Das, Pamela E. Rios Coronado, Martin Stehling, Lars Sävendahl, Andrei S. Chagin, Taija Mäkinen, Kristy Red-Horse, Ralf H. Adams
The vasculature of the skeletal system is crucial for bone formation, homoeostasis and fracture repair, yet the diversity and specialization of bone-associated vessels remain poorly understood. Here we identify a specialized type of post-arterial capillary, termed type R, involved in bone remodelling. Type R capillaries emerge during adolescence around trabecular bone, possess a distinct morphology and molecular profile, and are associated with osteoprogenitors and bone-resorbing osteoclasts. Endothelial cell-specific overexpression of the transcription factor DACH1 in postnatal mice induces a strong increase in arteries and type R capillaries, leading to local metabolic changes and enabling trabecular bone formation in normally highly hypoxic areas of the diaphysis. Indicating potential clinical relevance of type R capillaries, these vessels respond to anti-osteoporosis treatments and emerge during ageing inside porous structures that are known to weaken compact bone. Our work outlines fundamental principles of vessel specialization in the developing, adult and ageing skeletal system. Mohanakrishnan et al. identify a distinct subset of post-arterial capillaries, termed type R. They show that type R capillaries contribute to trabecular bone formation in the diaphysis and respond to anti-osteoporosis treatments.
骨骼系统的血管对骨的形成、平衡和骨折修复至关重要，但人们对骨相关血管的多样性和特化仍知之甚少。在这里，我们发现了一种参与骨重塑的特化后动脉毛细血管类型，称为 R 型。R 型毛细血管在青春期出现在骨小梁周围，具有独特的形态和分子特征，并与成骨细胞和骨吸收破骨细胞相关。在出生后的小鼠体内，内皮细胞特异性过量表达转录因子 DACH1 会诱导动脉和 R 型毛细血管的大量增加，从而导致局部新陈代谢发生变化，并使干骺端通常高度缺氧的区域形成骨小梁。这些血管对抗骨质疏松症治疗有反应，并在已知会削弱骨密度的多孔结构内老化过程中出现，这表明 R 型毛细血管具有潜在的临床意义。我们的工作概述了发育中、成年和老化骨骼系统中血管特化的基本原理。
{"title":"Specialized post-arterial capillaries facilitate adult bone remodelling","authors":"Vishal Mohanakrishnan, Kishor K. Sivaraj, Hyun-Woo Jeong, Esther Bovay, Backialakshmi Dharmalingam, M. Gabriele Bixel, Van Vuong Dinh, Milena Petkova, Isidora Paredes Ugarte, Yi-Tong Kuo, Malarvizhi Gurusamy, Brian Raftrey, Nelson Tsz Long Chu, Soumyashree Das, Pamela E. Rios Coronado, Martin Stehling, Lars Sävendahl, Andrei S. Chagin, Taija Mäkinen, Kristy Red-Horse, Ralf H. Adams","doi":"10.1038/s41556-024-01545-1","DOIUrl":"10.1038/s41556-024-01545-1","url":null,"abstract":"The vasculature of the skeletal system is crucial for bone formation, homoeostasis and fracture repair, yet the diversity and specialization of bone-associated vessels remain poorly understood. Here we identify a specialized type of post-arterial capillary, termed type R, involved in bone remodelling. Type R capillaries emerge during adolescence around trabecular bone, possess a distinct morphology and molecular profile, and are associated with osteoprogenitors and bone-resorbing osteoclasts. Endothelial cell-specific overexpression of the transcription factor DACH1 in postnatal mice induces a strong increase in arteries and type R capillaries, leading to local metabolic changes and enabling trabecular bone formation in normally highly hypoxic areas of the diaphysis. Indicating potential clinical relevance of type R capillaries, these vessels respond to anti-osteoporosis treatments and emerge during ageing inside porous structures that are known to weaken compact bone. Our work outlines fundamental principles of vessel specialization in the developing, adult and ageing skeletal system. Mohanakrishnan et al. identify a distinct subset of post-arterial capillaries, termed type R. They show that type R capillaries contribute to trabecular bone formation in the diaphysis and respond to anti-osteoporosis treatments.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 12","pages":"2020-2034"},"PeriodicalIF":17.3,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01545-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142598342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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