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

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 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 and confirmed the transient and sequential expression of SOX17 and LPAR4 during in vivo cardiac development. In an adult bone marrow transplantation model using LPAR4 promoter-driven GFP cells, we observed two LPAR4⁺ cell types in the heart following myocardial infarction (MI). Cardiac differentiation potential was shown in heart-resident LPAR4⁺ cells, which are SOX17⁺, but not bone marrow-derived infiltrated LPAR4⁺ cells. Furthermore, we tested various strategies to enhance cardiac repair through the regulation of downstream signals of LPAR4. During the early stages following MI, the downstream inhibition of LPAR4 by a p38 mitogen-activated protein kinase (p38 MAPK) blocker improved cardiac function and reduced fibrotic scarring compared to that observed following LPAR4 stimulation. These findings improve our understanding of heart development and suggest novel therapeutic strategies that enhance repair and regeneration after injury by modulating LPAR4 signaling.

Heart attack: controlling the signals that repair the heart

Molecular signals that control early heart development could be targeted to repair the heart after a heart attack. Hyun-Jai Cho at Seoul National University Hospital, South Korea, and co-workers previously revealed that lysophosphatidic acid receptor 4 (LPAR4) is expressed widely when embryonic stem cells differentiate into cardiac cells and in adult hearts after a heart attack. Now they have shown that a regulatory protein called SOX17 acts as a crucial mediator of LPAR4. The team identified two types of LPAR4-positive cells in mouse embryos: one type in the heart co-expresses SOX17, while the other in the bone marrow does not. They propose a simple blocker drug that promotes the differentiation of LPAR4 cells in the heart into cardiac cells but prevents inflammation by inhibiting the activity of LPAR4 cells from the bone marrow after a heart attack.