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Multicellular Transcriptional Analysis of Mammalian Heart Regeneration

BACKGROUND: The inability of the adult mammalian heart to regenerate following injury represents a major barrier in cardiovascular medicine. In contrast, the neonatal mammalian heart retains a transient capacity for regeneration, which is lost shortly after birth. Defining the molecular mechanisms t...

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Autores principales: Quaife-Ryan, Gregory A., Sim, Choon Boon, Ziemann, Mark, Kaspi, Antony, Rafehi, Haloom, Ramialison, Mirana, El-Osta, Assam, Hudson, James E., Porrello, Enzo R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5598916/
https://www.ncbi.nlm.nih.gov/pubmed/28733351
http://dx.doi.org/10.1161/CIRCULATIONAHA.117.028252
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author Quaife-Ryan, Gregory A.
Sim, Choon Boon
Ziemann, Mark
Kaspi, Antony
Rafehi, Haloom
Ramialison, Mirana
El-Osta, Assam
Hudson, James E.
Porrello, Enzo R.
author_facet Quaife-Ryan, Gregory A.
Sim, Choon Boon
Ziemann, Mark
Kaspi, Antony
Rafehi, Haloom
Ramialison, Mirana
El-Osta, Assam
Hudson, James E.
Porrello, Enzo R.
author_sort Quaife-Ryan, Gregory A.
collection PubMed
description BACKGROUND: The inability of the adult mammalian heart to regenerate following injury represents a major barrier in cardiovascular medicine. In contrast, the neonatal mammalian heart retains a transient capacity for regeneration, which is lost shortly after birth. Defining the molecular mechanisms that govern regenerative capacity in the neonatal period remains a central goal in cardiac biology. Here, we assemble a transcriptomic framework of multiple cardiac cell populations during postnatal development and following injury, which enables comparative analyses of the regenerative (neonatal) versus nonregenerative (adult) state for the first time. METHODS: Cardiomyocytes, fibroblasts, leukocytes, and endothelial cells from infarcted and noninfarcted neonatal (P1) and adult (P56) mouse hearts were isolated by enzymatic dissociation and fluorescence-activated cell sorting at day 3 following surgery. RNA sequencing was performed on these cell populations to generate the transcriptome of the major cardiac cell populations during cardiac development, repair, and regeneration. To complement our transcriptomic data, we also surveyed the epigenetic landscape of cardiomyocytes during postnatal maturation by performing deep sequencing of accessible chromatin regions by using the Assay for Transposase-Accessible Chromatin from purified mouse cardiomyocyte nuclei (P1, P14, and P56). RESULTS: Profiling of cardiomyocyte and nonmyocyte transcriptional programs uncovered several injury-responsive genes across regenerative and nonregenerative time points. However, the majority of transcriptional changes in all cardiac cell types resulted from developmental maturation from neonatal stages to adulthood rather than activation of a distinct regeneration-specific gene program. Furthermore, adult leukocytes and fibroblasts were characterized by the expression of a proliferative gene expression network following infarction, which mirrored the neonatal state. In contrast, cardiomyocytes failed to reactivate the neonatal proliferative network following infarction, which was associated with loss of chromatin accessibility around cell cycle genes during postnatal maturation. CONCLUSIONS: This work provides a comprehensive framework and transcriptional resource of multiple cardiac cell populations during cardiac development, repair, and regeneration. Our findings define a regulatory program underpinning the neonatal regenerative state and identify alterations in the chromatin landscape that could limit reinduction of the regenerative program in adult cardiomyocytes.
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spelling pubmed-55989162017-10-11 Multicellular Transcriptional Analysis of Mammalian Heart Regeneration Quaife-Ryan, Gregory A. Sim, Choon Boon Ziemann, Mark Kaspi, Antony Rafehi, Haloom Ramialison, Mirana El-Osta, Assam Hudson, James E. Porrello, Enzo R. Circulation Original Research Articles BACKGROUND: The inability of the adult mammalian heart to regenerate following injury represents a major barrier in cardiovascular medicine. In contrast, the neonatal mammalian heart retains a transient capacity for regeneration, which is lost shortly after birth. Defining the molecular mechanisms that govern regenerative capacity in the neonatal period remains a central goal in cardiac biology. Here, we assemble a transcriptomic framework of multiple cardiac cell populations during postnatal development and following injury, which enables comparative analyses of the regenerative (neonatal) versus nonregenerative (adult) state for the first time. METHODS: Cardiomyocytes, fibroblasts, leukocytes, and endothelial cells from infarcted and noninfarcted neonatal (P1) and adult (P56) mouse hearts were isolated by enzymatic dissociation and fluorescence-activated cell sorting at day 3 following surgery. RNA sequencing was performed on these cell populations to generate the transcriptome of the major cardiac cell populations during cardiac development, repair, and regeneration. To complement our transcriptomic data, we also surveyed the epigenetic landscape of cardiomyocytes during postnatal maturation by performing deep sequencing of accessible chromatin regions by using the Assay for Transposase-Accessible Chromatin from purified mouse cardiomyocyte nuclei (P1, P14, and P56). RESULTS: Profiling of cardiomyocyte and nonmyocyte transcriptional programs uncovered several injury-responsive genes across regenerative and nonregenerative time points. However, the majority of transcriptional changes in all cardiac cell types resulted from developmental maturation from neonatal stages to adulthood rather than activation of a distinct regeneration-specific gene program. Furthermore, adult leukocytes and fibroblasts were characterized by the expression of a proliferative gene expression network following infarction, which mirrored the neonatal state. In contrast, cardiomyocytes failed to reactivate the neonatal proliferative network following infarction, which was associated with loss of chromatin accessibility around cell cycle genes during postnatal maturation. CONCLUSIONS: This work provides a comprehensive framework and transcriptional resource of multiple cardiac cell populations during cardiac development, repair, and regeneration. Our findings define a regulatory program underpinning the neonatal regenerative state and identify alterations in the chromatin landscape that could limit reinduction of the regenerative program in adult cardiomyocytes. Lippincott Williams & Wilkins 2017-09-19 2017-09-19 /pmc/articles/PMC5598916/ /pubmed/28733351 http://dx.doi.org/10.1161/CIRCULATIONAHA.117.028252 Text en © 2017 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.
spellingShingle Original Research Articles
Quaife-Ryan, Gregory A.
Sim, Choon Boon
Ziemann, Mark
Kaspi, Antony
Rafehi, Haloom
Ramialison, Mirana
El-Osta, Assam
Hudson, James E.
Porrello, Enzo R.
Multicellular Transcriptional Analysis of Mammalian Heart Regeneration
title Multicellular Transcriptional Analysis of Mammalian Heart Regeneration
title_full Multicellular Transcriptional Analysis of Mammalian Heart Regeneration
title_fullStr Multicellular Transcriptional Analysis of Mammalian Heart Regeneration
title_full_unstemmed Multicellular Transcriptional Analysis of Mammalian Heart Regeneration
title_short Multicellular Transcriptional Analysis of Mammalian Heart Regeneration
title_sort multicellular transcriptional analysis of mammalian heart regeneration
topic Original Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5598916/
https://www.ncbi.nlm.nih.gov/pubmed/28733351
http://dx.doi.org/10.1161/CIRCULATIONAHA.117.028252
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