Abstract Thu009: Unlocking Cardiac Regeneration: Dorsomorphin-Induced MSC Differentiation and Metabolic Reprogramming in Myocardial Infarction

Background: Therapeutic options for myocardial infarction (MI) are limited and primarily address symptoms rather than the underlying cause. Stem cell-based regenerative medicine has emerged as a promising approach to regenerate cardiomyocytes, with the potential to restore cardiac function. Research Questions: If BMP pathway modulator dorsomorphin dihydrochloride (Dorso) can be differentiated MSCs into cardiac progenitor cells (CPCs), and they can regenerate MI. Aims: We aim to evaluate if Dorso can induce the differentiation of MSCs into CPCs and to assess their potential for cardiac regeneration. Methods: MSCs were isolated from cord tissue, expanded, and characterized, treated with Dorso to induce differentiation into CPCs. An MI model was established, and CPCs were transplanted into the infarcted myocardium. Cardiac function was assessed via echocardiography, and tissue histology. Metabolic profiling was performed using gas chromatography/mass spectrometry analysis. Results: Dorso-treated MSCs successfully differentiated into CPCs, confirmed by morphological changes, upregulation of cardiac-specific genes (alpha-actinin, Na-channel [P < 0.01], Mef2D, cTnT, cTnC, cTnI, and Nkx2.5 [P < 0.001]), and increased expression of cardiac-specific proteins (Nkx2.5, alpha-actinin, cTnI, Connexin-43, GATA-4, and Desmin [P < 0.001]). BMP pathway analysis revealed downregulation of Smad6 (P < 0.001) and Smad7 (P < 0.05) and upregulation of Smad1/5/8 (P < 0.001). Echocardiography demonstrated significant improvement in heart function (P < 0.001), while histological analysis confirmed cell survival, engraftment, reduced infarct size, and increased angiogenesis. Metabolic profiling of heart tissue identified 978 metabolites. Significant differences were observed among groups: nine metabolites in the control group (MI, normal, and MSCs treated), 55 between the control and Dorso-treated MSCs, and three between the MI and Dorso-treated MSCs. Fatty acid oxidation metabolites, including palmitic and linoleic acids, were upregulated in the MI group, suggesting a link between increased fatty acid oxidation, inflammation, and the severity of cardiac dysfunction. Conclusion: MSCs differentiate into CPCs by inhibiting the BMP pathway, upon transplantation, they restore heart function. Additionally, fatty acid metabolism pathways, particularly linoleic acid metabolism, biosynthesis of fatty acids, are associated with MI and can serve as a therapeutic target.