TARGETED DELIVERY OF CYTOKINES, GROWTH FACTORS AND PRE-DIFFERENTIATED CELLS FOR MI TREATMENT

Abstract

Following myocardial infarction (MI), cardiac tissue undergoes irreversible cellular alterations, with cardiomyocytes being replaced by fibrotic tissue. To combat this our lab synthesized a novel chitosan-based cryogel containing heparin and poly-vinyl alcohol, showcasing distinct porosity and interconnected pore design. A novel cryogel system was previously established as efficacious for tissue regeneration and sustained drug delivery and has been optimized for the repair of cardiac tissue post-MI in a murine model. The treatment regime involved the systematic loading and sequential injection of the cryogel with specific cytokines, growth factors, and pre-differentiated cells. Initially, the cryogel loaded with interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) was injected intramyocardially immediately post-MI, targeting the acute inflammatory response. On day 4 post- MI, a second injection was administered, this time utilizing cryogel loaded with vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2), aiming at promoting tissue regeneration and neo-angiogenesis. Subsequently, on day 6 post-MI, the group received cells previously differentiated from mouse mesenchymal stem cells: cardiomyocyte-like cells, smooth muscle cells, and endothelial cells. These cells, in synergy with cytokines and growth factors, aim to repopulate the lost cellular populations, thereby enhancing myocardial repair. Our results highlighted significant myocardial repair in cohorts treated with the combination of cryogel loaded with IL-10,TGF-β and VEGF,FGF-2 and pre-differentiated cells (Cryo/GFs/Cells). Echocardiographic assessments revealed amplified ejection fraction, fractional shortening, and reduced fibrotic regions, as confirmed by Masson Trichrome staining. Further analyses confirmed the immunomodulatory and regenerative capacity of the treatment. Our novel chitosan-based cryogel, enriched with anti-inflammatory and proangiogenic factors, serves as a promising platform for the controlled release of therapeutics, significantly helping tissue repair and regeneration post-MI. In addition, the separate administration of pre-differentiated cells acts in synergy with the Cryo/GFs, further enhancing the regenerative process. The combination of cellular therapy with the Cryo/GFs treatment provides a comprehensive approach for myocardial recovery, using the unique benefits of both techniques to maximize the efficacy of the therapy.