Unknown,Transcriptomics,Genomics,Proteomics

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Transcriptional Reversion of Cardiac Myocyte Fate During Mammalian Cardiac Regeneration.

ABSTRACT: Rationale: Neonatal mice have the capacity to regenerate their hearts in response to injury, but this potential is lost after the first week of life. The transcriptional changes that underpin mammalian cardiac regeneration have not been fully characterized at the molecular level. Objective: The objectives of our study were to determine if myocytes revert the transcriptional phenotype to a less differentiated state during regeneration and to systematically interrogate the transcriptional data to identify and validate potential regulators of this process. Methods and Results: We derived a core transcriptional signature of injury-induced cardiac myocyte regeneration in mouse by comparing global transcriptional programs in a dynamic model of in vitro and in vivo cardiac myocyte differentiation, in vitro cardiac myocyte explant model, as well as a neonatal heart resection model. The regenerating mouse heart revealed a transcriptional reversion of cardiac myocyte differentiation processes including reactivation of latent developmental programs similar to those observed during de-stabilization of a mature cardiac myocyte phenotype in the explant model. We identified potential upstream regulators of the core network, including interleukin 13 (IL13), which induced cardiac myocyte cell cycle entry and STAT6/STAT3 signaling in vitro. We demonstrate that STAT3/periostin and STAT6 signaling are critical mediators of IL13 signaling in cardiac myocytes. These downstream signaling molecules are also modulated in the regenerating mouse heart. Conclusions: Our work reveals new insights into the transcriptional regulation of mammalian cardiac regeneration and provides the founding circuitry for identifying potential regulators for stimulating heart regeneration. Comparison of transcriptional programs of primary myocardial tissues sampled from neonatal mice and murine hearts undergoing post-injury regeneration, along with in vitro ESC-differentiated cardiomyocytes

ORGANISM(S): Mus musculus

SUBMITTER: Laurie Boyer

PROVIDER: E-GEOD-64403 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Transcriptional reversion of cardiac myocyte fate during mammalian cardiac regeneration.

O'Meara Caitlin C CC Wamstad Joseph A JA Gladstone Rachel A RA Fomovsky Gregory M GM Butty Vincent L VL Shrikumar Avanti A Gannon Joseph B JB Boyer Laurie A LA Lee Richard T RT

Circulation research 20141204 5

<h4>Rationale</h4>Neonatal mice have the capacity to regenerate their hearts in response to injury, but this potential is lost after the first week of life. The transcriptional changes that underpin mammalian cardiac regeneration have not been fully characterized at the molecular level.<h4>Objective</h4>The objectives of our study were to determine whether myocytes revert the transcriptional phenotype to a less differentiated state during regeneration and to systematically interrogate the transc ...[more]

PMID: 25477501

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Project 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 construct a transcriptional atlas of multiple cardiac cell populations, which enables comparative analyses of the regenerative (neonatal) versus non-regenerative (adult) state for the first time. Methods - Cardiomyocytes, fibroblasts, leukocytes and endothelial cells from infarcted and non-infarcted neonatal (P1) and adult (P56) hearts were isolated by enzymatic dissociation and FACS. RNA sequencing (RNA-seq) was performed on these cell populations to generate a transcriptomic atlas of the major cardiac cell populations during cardiac development, repair and regeneration. In addition, we surveyed the epigenetic landscape of cardiomyocytes during post-natal maturation by performing deep sequencing of accessible chromatin regions using the Assay for Transposase-Accessible Chromatin (ATAC-seq) from purified cardiomyocyte nuclei (P1, P14 and P56). Results - Profiling of cardiomyocyte and non-myocyte transcriptional programs uncovered several injury responsive genes across regenerative and non-regenerative 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 reverted to a neonatal state and re-activated a neonatal proliferative network following infarction. In contrast, cardiomyocytes failed to re-activate the neonatal proliferative network following infarction, which was associated with loss of chromatin accessibility around cell cycle genes during post-natal maturation. Conclusions – This work provides a comprehensive transcriptional resource of multiple cardiac cell populations during cardiac development, repair and regeneration. Our findings define a transcriptional program underpinning the neonatal regenerative state and identifies an epigenetic barrier to re-induction of the regenerative program in adult cardiomyocytes.

Dataset Information

Transcriptional Reversion of Cardiac Myocyte Fate During Mammalian Cardiac Regeneration.

Publications

Transcriptional reversion of cardiac myocyte fate during mammalian cardiac regeneration.

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