leptin b and its regeneration enhancer illustrate the regenerative features of zebrafish hearts

Abstract

BackgroundZebrafish possess a remarkable regenerative capacity, which is mediated by the induction of various genes upon injury. Injury‐dependent transcription is governed by the tissue regeneration enhancer elements (TREEs). Here, we utilized leptin b (lepb), an injury‐specific factor, and its TREE to dissect heterogeneity of noncardiomyocytes (CMs) in regenerating hearts.ResultsOur single‐cell RNA sequencing (scRNA‐seq) analysis demonstrated that the endothelium/endocardium(EC) is activated to induce distinct subpopulations upon injury. We demonstrated that lepb can be utilized as a regeneration‐specific marker to subset injury‐activated ECs. lepb+ ECs robustly induce pro‐regenerative factors, implicating lepb+ ECs as a signaling center to interact with other cardiac cells. Our scRNA‐seq analysis identified that lepb is also produced by subpopulation of epicardium (Epi) and epicardium‐derived cells (EPDCs). To determine whether lepb labels injury‐emerging non‐CM cells, we tested the activity of lepb‐linked regeneration enhancer (LEN) with chromatin accessibility profiles and transgenic lines. While nondetectable in uninjured hearts, LEN directs EC and Epi/EPDC expression upon injury. The endogenous LEN activity was assessed using LEN deletion lines, demonstrating that LEN deletion abolished injury‐dependent expression of lepb, but not other nearby genes.ConclusionsOur integrative analyses identify regeneration‐emerging cell‐types and factors, leading to the discovery of regenerative features of hearts.

From pumps to pipes: A special issue on mechanisms of cardiovascular development

“…Finally, a special edition on cardiovascular mechanisms would not be complete without new insights into how the heart regenerates and in this case, how cells including the endocardium interact to regulate regeneration. A study in zebrafish by Shin et al, 9 investigates an enhancer element associated with regeneration at the leptinb locus. Re-analyzed single-cell studies implicate leptinb expressing endocardial cells as producing regenerative factors.…”