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1.
Nat Cardiovasc Res ; 2(4): 383-398, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37974970

RESUMO

Cardiomyocyte proliferation and dedifferentiation have fueled the field of regenerative cardiology in recent years, whereas the reverse process of redifferentiation remains largely unexplored. Redifferentiation is characterized by the restoration of function lost during dedifferentiation. Previously, we showed that ERBB2-mediated heart regeneration has these two distinct phases: transient dedifferentiation and redifferentiation. Here we survey the temporal transcriptomic and proteomic landscape of dedifferentiation-redifferentiation in adult mouse hearts and reveal that well-characterized dedifferentiation features largely return to normal, although elements of residual dedifferentiation remain, even after the contractile function is restored. These hearts appear rejuvenated and show robust resistance to ischemic injury, even 5 months after redifferentiation initiation. Cardiomyocyte redifferentiation is driven by negative feedback signaling and requires LATS1/2 Hippo pathway activity. Our data reveal the importance of cardiomyocyte redifferentiation in functional restoration during regeneration but also protection against future insult, in what could lead to a potential prophylactic treatment against ischemic heart disease for at-risk patients.

2.
Development ; 145(7)2018 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-29592949

RESUMO

Stem cells are undifferentiated cells that play crucial roles during development, growth and regeneration. Traditionally, these cells have been primarily characterised by histology, cell sorting, cell culture and ex vivo methods. However, as stem cells interact in a complex environment within specific tissue niches, there has been increasing interest in examining their in vivo behaviours, particularly in response to injury. Advances in imaging technologies and genetic tools have converged to enable unprecedented access to the endogenous stem cell niche. In this Spotlight article, we highlight how in vivo imaging can probe a range of biological processes that relate to stem cell activity, behaviour and control.


Assuntos
Microscopia Intravital/métodos , Nicho de Células-Tronco/fisiologia , Células-Tronco/citologia , Animais , Regeneração/fisiologia , Células-Tronco/fisiologia
3.
Cell Stem Cell ; 21(1): 107-119.e6, 2017 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-28686860

RESUMO

Organ growth requires a careful balance between stem cell self-renewal and lineage commitment to ensure proper tissue expansion. The cellular and molecular mechanisms that mediate this balance are unresolved in most organs, including skeletal muscle. Here we identify a long-lived stem cell pool that mediates growth of the zebrafish myotome. This population exhibits extensive clonal drift, shifting from random deployment of stem cells during development to reliance on a small number of dominant clones to fuel the vast majority of muscle growth. This clonal drift requires Meox1, a homeobox protein that directly inhibits the cell-cycle checkpoint gene ccnb1. Meox1 initiates G2 cell-cycle arrest within muscle stem cells, and disrupting this G2 arrest causes premature lineage commitment and the resulting defects in muscle growth. These findings reveal that distinct regulatory mechanisms orchestrate stem cell dynamics during organ growth, beyond the G0/G1 cell-cycle inhibition traditionally associated with maintaining tissue-resident stem cells.


Assuntos
Linhagem da Célula/fisiologia , Pontos de Checagem da Fase G2 do Ciclo Celular/fisiologia , Proteínas de Homeodomínio/metabolismo , Mioblastos/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/embriologia , Animais , Linhagem Celular , Ciclina B1/genética , Ciclina B1/metabolismo , Proteínas de Homeodomínio/genética , Camundongos , Mioblastos/citologia , Fatores de Transcrição , Proteínas de Peixe-Zebra/genética
4.
Science ; 353(6295): aad9969, 2016 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-27198673

RESUMO

Skeletal muscle is an example of a tissue that deploys a self-renewing stem cell, the satellite cell, to effect regeneration. Recent in vitro studies have highlighted a role for asymmetric divisions in renewing rare "immortal" stem cells and generating a clonal population of differentiation-competent myoblasts. However, this model currently lacks in vivo validation. We define a zebrafish muscle stem cell population analogous to the mammalian satellite cell and image the entire process of muscle regeneration from injury to fiber replacement in vivo. This analysis reveals complex interactions between satellite cells and both injured and uninjured fibers and provides in vivo evidence for the asymmetric division of satellite cells driving both self-renewal and regeneration via a clonally restricted progenitor pool.


Assuntos
Divisão Celular/fisiologia , Rastreamento de Células/métodos , Músculo Esquelético/fisiologia , Regeneração/fisiologia , Células Satélites de Músculo Esquelético/fisiologia , Animais , Animais Geneticamente Modificados , Divisão Celular/genética , Células Clonais , Desenvolvimento Muscular/genética , Desenvolvimento Muscular/fisiologia , Músculo Esquelético/embriologia , Músculo Esquelético/lesões , Mutação , Fator Regulador Miogênico 5/genética , Miogenina/genética , Regeneração/genética , Células Satélites de Músculo Esquelético/citologia , Transgenes , Peixe-Zebra
5.
Nature ; 512(7514): 314-8, 2014 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-25119043

RESUMO

Haematopoietic stem cells (HSCs) are self-renewing stem cells capable of replenishing all blood lineages. In all vertebrate embryos that have been studied, definitive HSCs are generated initially within the dorsal aorta (DA) of the embryonic vasculature by a series of poorly understood inductive events. Previous studies have identified that signalling relayed from adjacent somites coordinates HSC induction, but the nature of this signal has remained elusive. Here we reveal that somite specification of HSCs occurs via the deployment of a specific endothelial precursor population, which arises within a sub-compartment of the zebrafish somite that we have defined as the endotome. Endothelial cells of the endotome are specified within the nascent somite by the activity of the homeobox gene meox1. Specified endotomal cells consequently migrate and colonize the DA, where they induce HSC formation through the deployment of chemokine signalling activated in these cells during endotome formation. Loss of meox1 activity expands the endotome at the expense of a second somitic cell type, the muscle precursors of the dermomyotomal equivalent in zebrafish, the external cell layer. The resulting increase in endotome-derived cells that migrate to colonize the DA generates a dramatic increase in chemokine-dependent HSC induction. This study reveals the molecular basis for a novel somite lineage restriction mechanism and defines a new paradigm in induction of definitive HSCs.


Assuntos
Células Endoteliais/citologia , Células-Tronco Hematopoéticas/citologia , Proteínas de Homeodomínio/metabolismo , Somitos/citologia , Fatores de Transcrição/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Animais , Aorta/citologia , Aorta/embriologia , Biomarcadores/análise , Movimento Celular , Quimiocina CXCL12/análise , Quimiocina CXCL12/metabolismo , Embrião de Galinha , Células Endoteliais/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Proteínas de Homeodomínio/análise , Proteínas de Homeodomínio/genética , Humanos , Camundongos , Músculos/citologia , Músculos/metabolismo , Mutação/genética , Somitos/metabolismo , Fatores de Transcrição/análise , Fatores de Transcrição/genética , Proteínas Wnt/análise , Proteínas Wnt/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/análise , Proteínas de Peixe-Zebra/genética
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