Heterogeneous pdgfrb+ cells regulate coronary vessel development and revascularization during heart regeneration

Author:

Kapuria Subir1ORCID,Bai Haipeng12ORCID,Fierros Juancarlos13ORCID,Huang Ying1,Ma Feiyang4,Yoshida Tyler15ORCID,Aguayo Antonio1,Kok Fatma6ORCID,Wiens Katie M.17,Yip Joycelyn K.8,McCain Megan L.89ORCID,Pellegrini Matteo4ORCID,Nagashima Mikiko10,Hitchcock Peter F.10ORCID,Mochizuki Naoki11ORCID,Lawson Nathan D.6ORCID,Harrison Michael M. R.1ORCID,Lien Ching-Ling112ORCID

Affiliation:

1. Department of Surgery, The Saban Research Institute and Heart Institute of Children's Hospital Los Angeles, Los Angeles, CA 90027, USA

2. Laboratory of Chemical Genomics, School of Chemical Biology & Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, People's Republic of China

3. Department of Biology, California State University, San Bernardino, San Bernardino, CA 92407, USA

4. Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California Los Angeles, Los Angeles, CA 90095, USA

5. Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90007, USA

6. Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA

7. Science Department, Bay Path University, Longmeadow, MA 01106, USA

8. Laboratory for Living Systems Engineering, Department of Biomedical Engineering, USC Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA

9. Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA

10. Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA

11. Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Osaka, 564-8565, Japan

12. Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA

Abstract

ABSTRACT Endothelial cells emerge from the atrioventricular canal to form coronary blood vessels in juvenile zebrafish hearts. We find that pdgfrb is first expressed in the epicardium around the atrioventricular canal and later becomes localized mainly in the mural cells. pdgfrb mutant fish show severe defects in mural cell recruitment and coronary vessel development. Single-cell RNA sequencing analyses identified pdgfrb+ cells as epicardium-derived cells (EPDCs) and mural cells. Mural cells associated with coronary arteries also express cxcl12b and smooth muscle cell markers. Interestingly, these mural cells remain associated with coronary arteries even in the absence of Pdgfrβ, although smooth muscle gene expression is downregulated. We find that pdgfrb expression dynamically changes in EPDCs of regenerating hearts. Differential gene expression analyses of pdgfrb+ EPDCs and mural cells suggest that they express genes that are important for regeneration after heart injuries. mdka was identified as a highly upregulated gene in pdgfrb+ cells during heart regeneration. However, pdgfrb but not mdka mutants show defects in heart regeneration after amputation. Our results demonstrate that heterogeneous pdgfrb+ cells are essential for coronary development and heart regeneration.

Funder

Saban Research Institute of Children's Hospital Los Angeles

National Institutes of Health

Research to Prevent Blindness

Publisher

The Company of Biologists

Subject

Developmental Biology,Molecular Biology

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