SOX17-mediated LPAR4 expression plays a pivotal role in cardiac development and regeneration after myocardial infarction

Abstract

Abstract Lysophosphatidic acid receptor 4 (LPAR4) exhibits transient expression at the cardiac progenitor stage during pluripotent stem cell (PSC)-derived cardiac differentiation. Using RNA-sequencing, promoter analyses, and a loss-of-function study in human PSCs, we discovered that the SRY-box transcription factor 17 (SOX17) is an essential upstream factor of LPAR4 during cardiac differentiation. We conducted mouse embryo analyses to further verify our human PSC in vitro findings. We confirmed the transient and sequential expression of SOX17 and LPAR4 during in vivo cardiac development. In the adult bone marrow transplantation model using LPAR4 promoter-driven GFP cells, we observed two LPAR4+ cell types in the heart following myocardial infarction (MI). Heart-resident LPAR4+ cells, which are SOX17+, but not bone marrow-derived infiltrated LPAR4+ cells, showed cardiac differentiation potential. Furthermore, we tested various strategies to enhance cardiac repair through the regulation of downstream signals of LPAR4. During the early stage after MI, the downstream inhibition of LPAR4 by a p38 mitogen-activated protein kinase (p38MAPK) blocker improved cardiac function and reduced fibrotic scar, compared with that observed following LPAR4 stimulation. These findings improve our understanding of heart development and suggest novel therapeutic strategies meant to enhance repair and regeneration after injury by modulating the LPAR4 signaling.