hapln1a⁺ cells guide coronary growth during heart morphogenesis and regeneration.

Abstract

Although several tissues and chemokines orchestrate coronary formation, the guidance cues for coronary growth remain unclear. Here, we profile the juvenile zebrafish epicardium during coronary vascularization and identify hapln1a⁺ cells enriched with vascular-regulating genes. hapln1a⁺ cells not only envelop vessels but also form linear structures ahead of coronary sprouts. Live-imaging demonstrates that coronary growth occurs along these pre-formed structures, with depletion of hapln1a⁺ cells blocking this growth. hapln1a⁺ cells also pre-lead coronary sprouts during regeneration and hapln1a⁺ cell loss inhibits revascularization. Further, we identify serpine1 expression in hapln1a⁺ cells adjacent to coronary sprouts, and serpine1 inhibition blocks vascularization and revascularization. Moreover, we observe the hapln1a substrate, hyaluronan, forming linear structures along and preceding coronary vessels. Depletion of hapln1a⁺ cells or serpine1 activity inhibition disrupts hyaluronan structure. Our studies reveal that hapln1a⁺ cells and serpine1 are required for coronary production by establishing a microenvironment to facilitate guided coronary growth.