Abstract MP206: Cortical Bone Derived Stem Cells Modulate The Adaptive Immune Response Post-MI

Abstract

Background: The inflammatory response mounted following myocardial infarction (MI) is closely coupled to myocardial wound healing processes such as angiogenesis, fibroblast maturation, and cardiomyocyte survival. A consortium of pro-reparative Tregs occupy the myocardium during ischemic injury and are essential in modulating cardiac homeostasis. However, Treg exposure to chronic, ischemic microenvironments compromises Tregs’ pro-reparative signatures and induces pathogenic remodeling of Tregs, compromising cardiac wound healing. Cortical Bone Derived Stem Cells (CBSCs) have superior engraftment capabilities compared to other stem cell types and can modulate the post-MI inflammatory response by establishing anti-inflammatory paracrine signaling dominance and the expansion of CD45+ leukocytes and CD4+ T cells residence in the MI heart. Therefore, we hypothesized CBSC cell therapy can modulate the recruitment and phenotype of Treg residence in the MI heart to permit their enhanced cardiogenic properties. Methods and Results: Animals that received intramyocardial injection of CBSCs along the infarct border zone of the permanently ligated LAD possessed smaller infarct sizes and improved cardiac function, that paralleled pro-reparative, TNFRII+ Treg expansion and repressed pathogenic TNFRI+, Treg residence 1- and 8- weeks post-MI compared to Mesenchymal Stem Cells (MSCs) or vehicle (PBS) treated animals. Similar TNFRI/II Treg dynamics were also observed in the spleen. Diphtheria toxin (DTR) mediated Treg ablation and S1P1 agonist administration, in the presence of CBSC therapy, reverted pro-reparative Treg expansion and solicited infarct size expansion and compromised cardiac function. The exposure of CBSC paracrine secretome to naïve CD4+ T cell cultures induces pro-reparative TNFRII+ Treg expansion. Paracrine profiling of CBSC secretome identifies Osteoprotegerin (OPG) enrichment and OPG depletion, via siRNA and lentivirus, compromises T cell survival signaling and pro-reparative, TNFRII+ Treg establishment both in vitro and in the MI heart. Conclusions: CBSCs can modulate the induction and preservation of pro-reparative TNFRII+ Tregs in the MI heart to solicit cardiac repair during acute and chronic ischemic injury.