Abstract 11548: Nanofibrous Collagen Scaffolds Seeded With Human Pluripotent Stem Cell-derived Cardiomyocytes Induce Cardiac Remodeling in Dilated Cardiomyopathy

Abstract

Introduction: Limited data are available on the effect of stem cells in non-ischemic dilated cardiomyopathy (DCM). Hypothesis: Since the diffuse nature of DCM calls for a broad distribution of cells, we tested the scaffold-based delivery of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) in a mouse model of DCM. Methods: (1) In vitro protocol: A clinical grade atelocollagen was electrospun and crosslinked under different conditions to optimize production of nanofibrous scaffolds. (2) In vivo protocol: The biocompatibility of acellular collagen scaffolds was first tested in C57BL6 (n=24) and αMHCMerCreMerSf/Sf (n=18) mice, a strain in which DCM is induced by a cardiac (αMHC)-specific and tamoxifen(T)-inducible invalidation of serum response factor (SRF). Scaffolds seeded with hiPSC-CM (obtained by a sequential activation/inhibition of the Wnt pathway) or kept acellular (controls) were then implanted in 8 and 6 αMHCMerCreMerSf/Sf mice, respectively. Results: As assessed by SEM and shear wave elastography, a 10% citric acid concentration and 150 min of baking at 150°C producing a scaffold with an average fiber thickness of 1400 nm, an average pore size of 2500 nm and an elasticity modulus of 10.1 kPa were associated with optimal hiPSC-CM differentiation and colonization of the scaffold. Seven and 14 days after implantation, the biocompatibility of cell-free scaffolds was confirmed by echocardiography and histology. Scaffolds seeded or not with hiPSC-CM were then grafted in DCM mice. After 14 days, heart function drastically decreased in hearts receiving cell-free scaffolds while it remained stable in the treated mice (p<0.001 for LVEDV, LVESV and EF). This pattern was associated with (1) a significantly (p<0.01) increased genomic and proteomic expression of SRF possibly reflecting an activation of resident stem cells (unaffected by T) and/or an increase in endothelial cells (also T-unaffected), in line with the greater vascularity of the scaffold, and (2) a reduced fibrosis consistent with the upregulation of several genes involved in extracellular matrix remodeling. Conclusion: These data suggest that a hiPSC-CM loaded electrospun collagen patch stabilizes function in DCM, most likely through paracrine signaling.