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Neonatal and adult cardiac fibroblasts exhibit inherent differences in cardiac regenerative capacity

Directly reprogramming fibroblasts into cardiomyocytes improves cardiac function in the infarcted heart. However, the low efficacy of this approach hinders clinical applications. Unlike the adult mammalian heart, the neonatal heart has an intrinsic regenerative capacity. Consequently, we hypothesize...

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Autores principales: Sun, Hualing, Pratt, Richard E., Dzau, Victor J., Hodgkinson, Conrad P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10193010/
https://www.ncbi.nlm.nih.gov/pubmed/37044217
http://dx.doi.org/10.1016/j.jbc.2023.104694
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author Sun, Hualing
Pratt, Richard E.
Dzau, Victor J.
Hodgkinson, Conrad P.
author_facet Sun, Hualing
Pratt, Richard E.
Dzau, Victor J.
Hodgkinson, Conrad P.
author_sort Sun, Hualing
collection PubMed
description Directly reprogramming fibroblasts into cardiomyocytes improves cardiac function in the infarcted heart. However, the low efficacy of this approach hinders clinical applications. Unlike the adult mammalian heart, the neonatal heart has an intrinsic regenerative capacity. Consequently, we hypothesized that birth imposes fundamental changes in cardiac fibroblasts which limit their regenerative capabilities. In support, we found that reprogramming efficacy in vitro was markedly lower with fibroblasts derived from adult mice versus those derived from neonatal mice. Notably, fibroblasts derived from adult mice expressed significantly higher levels of pro-angiogenic genes. Moreover, under conditions that promote angiogenesis, only fibroblasts derived from adult mice differentiated into tube-like structures. Targeted knockdown screening studies suggested a possible role for the transcription factor Epas1. Epas1 expression was higher in fibroblasts derived from adult mice, and Epas1 knockdown improved reprogramming efficacy in cultured adult cardiac fibroblasts. Promoter activity assays indicated that Epas1 functions as both a transcription repressor and an activator, inhibiting cardiomyocyte genes while activating angiogenic genes. Finally, the addition of an Epas1 targeting siRNA to the reprogramming cocktail markedly improved reprogramming efficacy in vivo with both the number of reprogramming events and cardiac function being markedly improved. Collectively, our results highlight differences between neonatal and adult cardiac fibroblasts and the dual transcriptional activities of Epas1 related to reprogramming efficacy.
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spelling pubmed-101930102023-05-19 Neonatal and adult cardiac fibroblasts exhibit inherent differences in cardiac regenerative capacity Sun, Hualing Pratt, Richard E. Dzau, Victor J. Hodgkinson, Conrad P. J Biol Chem Research Article Directly reprogramming fibroblasts into cardiomyocytes improves cardiac function in the infarcted heart. However, the low efficacy of this approach hinders clinical applications. Unlike the adult mammalian heart, the neonatal heart has an intrinsic regenerative capacity. Consequently, we hypothesized that birth imposes fundamental changes in cardiac fibroblasts which limit their regenerative capabilities. In support, we found that reprogramming efficacy in vitro was markedly lower with fibroblasts derived from adult mice versus those derived from neonatal mice. Notably, fibroblasts derived from adult mice expressed significantly higher levels of pro-angiogenic genes. Moreover, under conditions that promote angiogenesis, only fibroblasts derived from adult mice differentiated into tube-like structures. Targeted knockdown screening studies suggested a possible role for the transcription factor Epas1. Epas1 expression was higher in fibroblasts derived from adult mice, and Epas1 knockdown improved reprogramming efficacy in cultured adult cardiac fibroblasts. Promoter activity assays indicated that Epas1 functions as both a transcription repressor and an activator, inhibiting cardiomyocyte genes while activating angiogenic genes. Finally, the addition of an Epas1 targeting siRNA to the reprogramming cocktail markedly improved reprogramming efficacy in vivo with both the number of reprogramming events and cardiac function being markedly improved. Collectively, our results highlight differences between neonatal and adult cardiac fibroblasts and the dual transcriptional activities of Epas1 related to reprogramming efficacy. American Society for Biochemistry and Molecular Biology 2023-04-10 /pmc/articles/PMC10193010/ /pubmed/37044217 http://dx.doi.org/10.1016/j.jbc.2023.104694 Text en © 2023 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Sun, Hualing
Pratt, Richard E.
Dzau, Victor J.
Hodgkinson, Conrad P.
Neonatal and adult cardiac fibroblasts exhibit inherent differences in cardiac regenerative capacity
title Neonatal and adult cardiac fibroblasts exhibit inherent differences in cardiac regenerative capacity
title_full Neonatal and adult cardiac fibroblasts exhibit inherent differences in cardiac regenerative capacity
title_fullStr Neonatal and adult cardiac fibroblasts exhibit inherent differences in cardiac regenerative capacity
title_full_unstemmed Neonatal and adult cardiac fibroblasts exhibit inherent differences in cardiac regenerative capacity
title_short Neonatal and adult cardiac fibroblasts exhibit inherent differences in cardiac regenerative capacity
title_sort neonatal and adult cardiac fibroblasts exhibit inherent differences in cardiac regenerative capacity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10193010/
https://www.ncbi.nlm.nih.gov/pubmed/37044217
http://dx.doi.org/10.1016/j.jbc.2023.104694
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