Abstract
Introduction: Clinical use of induced pluripotent derived cardiomyocytes (iPSC-CMs) has been slow because their mechanism is not well defined. Our lab developed a cardiac patch composed of iPSC-CMs and human neonatal dermal fibroblast (NDF) seeded on a bioresorbable matrix. Implantation on the epicardium of the infarcted heart in immune competent animal models of ischemic CHF (mice, rats, swine) repaired the damaged heart, improved cardiac function/structure with increased viable myocardium, increased myocardial blood flow, improved left ventricular (LV) contractility, and reversal of maladaptive LV remodeling. Preliminary analysis indicates that the patch created a novel host derived immune response not observed in untreated animals. Hypothesis: The iPSC-CMs and NDFs coordinate an immunomodulatory response that results in reduction of inflammatory cytokine producing M1 macrophages with concomitant polarization to the M2 state. Methods: Spatial transcriptomics and histological analysis was utilized for investigation of patch driven immunomodulatory responses in WT BL6 mice. All animals underwent two procedures; 1) Infarct via left coronary ligation 2) Left lateral sternotomy with patch placement (N=5) (no patch for controls, N=3) 3 weeks post MI. Patch secretions underwent quantitative mass spectroscopy to identify drivers of immunomodulation. Results: Histology demonstrated reduction of left chamber dimension and presence of viable cardiomyocytes in the LV wall. IF demonstrated a novel immune response in the treated group absent in the controls. This response is isolated to the epicardial infarct-patch interface. Cellular deconvolution of the infarct region revealed macrophages and dendritic cells compose this response. Macrophage phenotype was assessed via expression of classical M1(CD68, NOS2, AXL) as well as M2 markers (RETNLA, MRC1, ADGRE1) which were found to be significantly elevated in treated groups. Proteomic analysis of the patch secretome indicates the patch has a role in coordinating this response by upregulation of Il-4/Il-13 signaling and wound healing that stimulates enrichment of pathways associated with reorganization of the ECM.
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