(F1147) LATROPHILIN-2, A SINGLE GENE, REPROGRAMS ADULT FIBROBLASTS INTO FUNCTIONAL CARDIOMYOCYTES VIA A DISTINCT PATHWAY FROM GATA4/MEF2C/TBX5 COMBINATION
Abstract: The heart lacks the ability to self-renew after ischemic injury, primarily due to the limited regenerative potential of mature cardiomyocytes. Latrophilin-2 (Lphn2), a G-protein-coupled receptor, has been identified as a critical player in cardiac development. This study aimed to compare the effectiveness of Lphn2 with that of Gata4, Mef2c, and Tbx5 (GMT)—well-known factors in direct cardiac reprogramming—in repairing the heart after ischemic disease by transdifferentiating cardiac fibroblasts into functional cardiomyocytes. Lphn2-OE and GMT-OE lentiviruses were injected into various transgenic mice, including Lphn2-hetero-KO and FSP1-Cre/Rosa-mTmG mice, following permanent ligation of the left anterior descending (LAD) artery. Cardiac function and heart regeneration efficiency were compared using echocardiography and immunofluorescence. Additionally, distinct induction pathways of Lphn2 and GMT were investigated in vitro using single-cell RNA sequencing. In vitro, the Lphn2-OE lentivirus successfully converted adult mouse fibroblasts into functional cardiomyocytes to a degree comparable to the GMT-OE lentivirus. The Lphn2-OE lentivirus induced direct conversion at an earlier time point and generated a more mature population of cardiomyocytes than the GMT-OE lentivirus. In a myocardial infarction model, Lphn2-het-KO mice exhibited severe fibrosis and reduced cardiac function, which were rescued by Lphn2 overexpression. Furthermore, the Lphn2-OE lentivirus alone significantly improved cardiac function and repaired damaged hearts after myocardial infarction, outperforming the GMT-OE lentivirus. Overexpression of Lphn2 directly converted adult mouse fibroblasts into mature and functional cardiomyocytes, resulting in reduced fibrosis and improved cardiac function following myocardial infarction. From these results, we can conclude that Lphn2 overexpression can be utilized as a gene therapy approach to reduce fibrosis and promote myocardial regeneration.
Funding Source: Bio & Medical Technology Development Program of the NRF, funded by Korean government (MSIT) (No.RS-2022-NR067329), “Korea Research-Driven Hospital” (HI14C1277) through the KHIDI, funded by the MOHW.
