Abstract 339: A Novel Strategy to Harness Stem Cell-Intrinsic Mechanobiological Properties for Advanced Tissue Repair: Implication in Cardiac Tissue Injury

Rationale: Stem cells are constantly exposed to biomechanical and biochemical signals when transplanted in a continuously beating cardiac environment for treatment. Here, we postulated that an in vitro miniaturized beating cardiac microenvironment can induce unique biomechanical stimuli to co-cultured MSCs that can influence therapeutic potential of the later. This project aimed (i) to pre-condition mesenchymal stem cells (MSCs) with continuous mechanobiological stimuli using a 3D cardiac tissue environment (ii) to intramyocardially inject pre-conditioned MSCs into mice heart with myocardial infarction (MI) for tissue repair. Methods: We fabricated an in vitro cardiac platform as shown in Fig 1, using an electro-conductive hydrogel and human iPSC-derived cardiac cells. Adipose MSCs were then injected to the beating hydrogel platform. After 7 days, activated (MB+) and non-activated MSCs (MB-) were isolated for in vitro and in vivo analysis. Results: The force generated by the constant beating of cardiomyocytes induced profound effects in on MSC behavior in the MB+ group. Several mechano-transduction factors (YAP1, TAZ), actin polymerization genes involved in cardiac muscle contractions (ACTA2, CDC42, TNNT2) and angiogenic genes were upregulated in MB+. RNA-seq analysis further confirmed these findings. 3 week study in mice with MI demonstrated significant increase in capillary density and reduction in infarct sizes in MB+ (n=6) compared to MB- group. Furthermore, the MB+ group showed significantly higher cardiac performance in echocardiography. We can conclude MB-activated MSCs can have significant impact in future treatment strategies for patients with MI.