YAP Induces a Neonatal-Like Pro-Renewal Niche in the Adult Heart

Authors

Rich Gang Li
Xiao Li
Yuka Morikawa
Francisco J Grisanti-Canozo
Fansen Meng
Chang-Ru Tsai
Yi Zhao
Lin Liu
Jong Kim
Bing Xie
Elzbieta Klysik
Shijie Liu
Md Abul Hassan Samee
James F Martin

Publication Date

3-1-2024

Journal

Nature Cardiovascular Research

DOI

10.1038/s44161-024-00428-w

PMID

38510108

PMCID

PMC10954255

PubMedCentral® Posted Date

3-20-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Abstract

After myocardial infarction (MI), mammalian hearts do not regenerate, and the microenvironment is disrupted. Hippo signaling loss of function with activation of transcriptional co-factor YAP induces heart renewal and rebuilds the post-MI microenvironment. In this study, we investigated adult renewal-competent mouse hearts expressing an active version of YAP, called YAP5SA, in cardiomyocytes (CMs). Spatial transcriptomics and single-cell RNA sequencing revealed a conserved, renewal-competent CM cell state called adult (a)CM2 with high YAP activity. aCM2 co-localized with cardiac fibroblasts (CFs) expressing complement pathway component C3 and macrophages (MPs) expressing C3ar1 receptor to form a cellular triad in YAP5SA hearts and renewal-competent neonatal hearts. Although aCM2 was detected in adult mouse and human hearts, the cellular triad failed to co-localize in these non-renewing hearts. C3 and C3ar1 loss-of-function experiments indicated that C3a signaling between MPs and CFs was required to assemble the pro-renewal aCM2, C3+ CF and C3ar1+ MP cellular triad.

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