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hapln1a+ cells guide coronary growth during heart morphogenesis and regeneration
Jisheng Sun1, Elizabeth A Peterson1, Xin Chen1
1Cardiology Division, School of Medicine, Emory University, Atlanta, GA, 30322, USA.
Insights
Hapln1a+ cells and serpine1 guide coronary vessel growth in zebrafish by forming linear structures. Their depletion blocks coronary vascularization and regeneration, revealing key mechanisms for heart vessel development.
Area of Science:
- Cardiovascular Biology
- Developmental Biology
- Zebrafish Models
Background:
- Coronary formation involves multiple tissues and chemokines, but guidance cues for coronary growth remain incompletely understood.
- Understanding the cellular and molecular mechanisms driving coronary vascularization is crucial for addressing heart disease.
Purpose of the Study:
- To identify guidance cues and cellular players involved in coronary vascularization and regeneration in juvenile zebrafish.
- To elucidate the role of hapln1a+ cells and serpine1 in directing coronary growth.
Main Methods:
- Single-cell RNA sequencing of the juvenile zebrafish epicardium during coronary vascularization.
- Live-imaging microscopy to observe coronary sprout behavior and hapln1a+ cell dynamics.
- Genetic manipulation (depletion) and pharmacological inhibition (serpine1) to assess functional roles.
Main Results:
- Hapln1a+ cells were identified as key orchestrators, forming linear structures that guide coronary sprouts during initial vascularization and regeneration.
- Depletion of hapln1a+ cells or inhibition of serpine1 (expressed by hapln1a+ cells) significantly blocked coronary growth and revascularization.
- Hyaluronan, a substrate of hapln1a, was observed in linear structures preceding vessels, with its organization disrupted upon hapln1a+ cell depletion or serpine1 inhibition.
Conclusions:
- Hapln1a+ cells and serpine1 are essential for guided coronary growth by creating a specific microenvironment.
- These findings reveal a novel mechanism involving hapln1a+ cells and hyaluronan in orchestrating coronary vascular development and repair.
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.
