Fereshteh Sadat Younesi, Andrew E. Miller, Thomas H. Barker, Fabio M. V. Rossi, Boris Hinz
{"title":"Fibroblast and myofibroblast activation in normal tissue repair and fibrosis","authors":"Fereshteh Sadat Younesi, Andrew E. Miller, Thomas H. Barker, Fabio M. V. Rossi, Boris Hinz","doi":"10.1038/s41580-024-00716-0","DOIUrl":"10.1038/s41580-024-00716-0","url":null,"abstract":"The term ‘fibroblast’ often serves as a catch-all for a diverse array of mesenchymal cells, including perivascular cells, stromal progenitor cells and bona fide fibroblasts. Although phenotypically similar, these subpopulations are functionally distinct, maintaining tissue integrity and serving as local progenitor reservoirs. In response to tissue injury, these cells undergo a dynamic fibroblast–myofibroblast transition, marked by extracellular matrix secretion and contraction of actomyosin-based stress fibres. Importantly, whereas transient activation into myofibroblasts aids in tissue repair, persistent activation triggers pathological fibrosis. In this Review, we discuss the roles of mechanical cues, such as tissue stiffness and strain, alongside cell signalling pathways and extracellular matrix ligands in modulating myofibroblast activation and survival. We also highlight the role of epigenetic modifications and myofibroblast memory in physiological and pathological processes. Finally, we discuss potential strategies for therapeutically interfering with these factors and the associated signal transduction pathways to improve the outcome of dysregulated healing. Fibroblasts undergo transient activation into myofibroblasts to restore homeostasis to injured tissues. This Review explores the influence of mechanical cues and epigenetic modifications on (myo)fibroblast activation and memory and discusses potential therapeutic prevention of persistent myofibroblast activation in fibrosis.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"25 8","pages":"617-638"},"PeriodicalIF":81.3,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140538527","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}
{"title":"Seeing transcription in real time","authors":"Tineke L. Lenstra","doi":"10.1038/s41580-024-00731-1","DOIUrl":"10.1038/s41580-024-00731-1","url":null,"abstract":"Imaging of fluorescently labelled nascent RNA in live cells enabled real-time observation of transcription of an endogenous gene.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"25 6","pages":"422-422"},"PeriodicalIF":112.7,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140349579","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}
Dina Listov, Casper A. Goverde, Bruno E. Correia, Sarel Jacob Fleishman
{"title":"Opportunities and challenges in design and optimization of protein function","authors":"Dina Listov, Casper A. Goverde, Bruno E. Correia, Sarel Jacob Fleishman","doi":"10.1038/s41580-024-00718-y","DOIUrl":"10.1038/s41580-024-00718-y","url":null,"abstract":"The field of protein design has made remarkable progress over the past decade. Historically, the low reliability of purely structure-based design methods limited their application, but recent strategies that combine structure-based and sequence-based calculations, as well as machine learning tools, have dramatically improved protein engineering and design. In this Review, we discuss how these methods have enabled the design of increasingly complex structures and therapeutically relevant activities. Additionally, protein optimization methods have improved the stability and activity of complex eukaryotic proteins. Thanks to their increased reliability, computational design methods have been applied to improve therapeutics and enzymes for green chemistry and have generated vaccine antigens, antivirals and drug-delivery nano-vehicles. Moreover, the high success of design methods reflects an increased understanding of basic rules that govern the relationships among protein sequence, structure and function. However, de novo design is still limited mostly to α-helix bundles, restricting its potential to generate sophisticated enzymes and diverse protein and small-molecule binders. Designing complex protein structures is a challenging but necessary next step if we are to realize our objective of generating new-to-nature activities. Recent combinations of structure-based and sequence-based calculations and machine learning tools have dramatically improved protein engineering and design. Although designing complex protein structures remains challenging, these methods have enabled the design of therapeutically relevant activities, including vaccine antigens, antivirals and drug-delivery nano-vehicles.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"25 8","pages":"639-653"},"PeriodicalIF":81.3,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140346359","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}
{"title":"How ancient RNA survives and what we can learn from it","authors":"Marc R. Friedländer, M. Thomas P. Gilbert","doi":"10.1038/s41580-024-00726-y","DOIUrl":"10.1038/s41580-024-00726-y","url":null,"abstract":"Although normally transient, RNA can persist postmortem when preserved by cold, desiccation or chemical treatment. In this Comment, we discuss how ancient RNA enables the study of gene expression of (pre)historic viruses, plants and animals going back at least as far as the last Ice Age. Friedländer and Gilbert introduce the study of ancient RNA of viruses, plants and animals, and how it can inform us of (pre)historic gene expression.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"25 6","pages":"417-418"},"PeriodicalIF":112.7,"publicationDate":"2024-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140318796","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}
{"title":"Single-cell live volume measurements using the fluorescence exclusion method","authors":"Larisa Venkova, Henri Popard","doi":"10.1038/s41580-024-00722-2","DOIUrl":"10.1038/s41580-024-00722-2","url":null,"abstract":"In this Tools of the Trade article, Venkova and Popard (Piel lab) discuss recent updates to the fluorescence exclusion method that now enable simultaneous measurement of cellular and nuclear size as well as investigation of small prokaryotic cells.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"25 6","pages":"419-419"},"PeriodicalIF":112.7,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140209839","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}
{"title":"Cellular and molecular mechanisms of skin wound healing","authors":"Oscar A. Peña, Paul Martin","doi":"10.1038/s41580-024-00715-1","DOIUrl":"10.1038/s41580-024-00715-1","url":null,"abstract":"Wound healing is a complex process that involves the coordinated actions of many different tissues and cell lineages. It requires tight orchestration of cell migration, proliferation, matrix deposition and remodelling, alongside inflammation and angiogenesis. Whereas small skin wounds heal in days, larger injuries resulting from trauma, acute illness or major surgery can take several weeks to heal, generally leaving behind a fibrotic scar that can impact tissue function. Development of therapeutics to prevent scarring and successfully repair chronic wounds requires a fuller knowledge of the cellular and molecular mechanisms driving wound healing. In this Review, we discuss the current understanding of the different phases of wound healing, from clot formation through re-epithelialization, angiogenesis and subsequent scar deposition. We highlight the contribution of different cell types to skin repair, with emphasis on how both innate and adaptive immune cells in the wound inflammatory response influence classically studied wound cell lineages, including keratinocytes, fibroblasts and endothelial cells, but also some of the less-studied cell lineages such as adipocytes, melanocytes and cutaneous nerves. Finally, we discuss newer approaches and research directions that have the potential to further our understanding of the mechanisms underpinning tissue repair. This Review discusses the complex mechanisms of wound healing — cell migration, matrix remodelling, inflammation and angiogenesis — and the contributions of different cell types, including immune cells, to this process. It also highlights new methodologies that could inform future therapies to prevent scarring and repair chronic wounds.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"25 8","pages":"599-616"},"PeriodicalIF":81.3,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140209767","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}
{"title":"Protein N-terminal acetylation is entering the degradation end game","authors":"Thomas Arnesen, Ine Kjosås, Nina McTiernan","doi":"10.1038/s41580-024-00723-1","DOIUrl":"10.1038/s41580-024-00723-1","url":null,"abstract":"Despite being one of the most common protein modifications in eukaryotes, the cellular effect of N-terminal acetylation remains cryptic. Four decades ago, the nature of the N terminus was linked to protein stability. In this Comment, we discuss an emerging major role of N-terminal acetylation in shielding the proteome from degradation. Thomas Arnesen and colleagues discuss an emerging major role of one of the most common protein modifications, N-terminal acetylation, in shielding the proteome from degradation.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"25 5","pages":"335-336"},"PeriodicalIF":112.7,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140192676","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}
{"title":"Localized translation in the embryo","authors":"Ahna Skop, Karen Schindler","doi":"10.1038/s41580-024-00725-z","DOIUrl":"10.1038/s41580-024-00725-z","url":null,"abstract":"Ahna Skop and Karen Schindler describe a paper that found localized translation in mammalian embryos, demonstrating the importance of RNA transport for development.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"25 5","pages":"339-339"},"PeriodicalIF":112.7,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140182936","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}
{"title":"A code within the genetic code","authors":"Susanne Bornelöv","doi":"10.1038/s41580-024-00724-0","DOIUrl":"10.1038/s41580-024-00724-0","url":null,"abstract":"The story of a paper that established the concept of codon optimality and its connection with translation efficiency and mRNA decay.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"25 6","pages":"423-423"},"PeriodicalIF":112.7,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140182872","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}
Morgan Shine, Jackson Gordon, Leonard Schärfen, Dagmar Zigackova, Lydia Herzel, Karla M. Neugebauer
{"title":"Co-transcriptional gene regulation in eukaryotes and prokaryotes","authors":"Morgan Shine, Jackson Gordon, Leonard Schärfen, Dagmar Zigackova, Lydia Herzel, Karla M. Neugebauer","doi":"10.1038/s41580-024-00706-2","DOIUrl":"10.1038/s41580-024-00706-2","url":null,"abstract":"Many steps of RNA processing occur during transcription by RNA polymerases. Co-transcriptional activities are deemed commonplace in prokaryotes, in which the lack of membrane barriers allows mixing of all gene expression steps, from transcription to translation. In the past decade, an extraordinary level of coordination between transcription and RNA processing has emerged in eukaryotes. In this Review, we discuss recent developments in our understanding of co-transcriptional gene regulation in both eukaryotes and prokaryotes, comparing methodologies and mechanisms, and highlight striking parallels in how RNA polymerases interact with the machineries that act on nascent RNA. The development of RNA sequencing and imaging techniques that detect transient transcription and RNA processing intermediates has facilitated discoveries of transcription coordination with splicing, 3′-end cleavage and dynamic RNA folding and revealed physical contacts between processing machineries and RNA polymerases. Such studies indicate that intron retention in a given nascent transcript can prevent 3′-end cleavage and cause transcriptional readthrough, which is a hallmark of eukaryotic cellular stress responses. We also discuss how coordination between nascent RNA biogenesis and transcription drives fundamental aspects of gene expression in both prokaryotes and eukaryotes. Methodological advances have enabled discoveries of RNA polymerase interactions with RNA processing machineries, such as the splicing and 3′-end cleavage machineries. This Review discusses the roles of these interactions in gene regulation and eukaryotic cellular stress responses, and highlights parallels between co-transcriptional RNA processing in eukaryotes and prokaryotes.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"25 7","pages":"534-554"},"PeriodicalIF":81.3,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140175700","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}