Neonatal Mesenchymal Cells Promote Recovery Of Infracted Myocardium Through Immune Modulation Of CD44 Mediated Foxp3 Tregulatory Cells After Vascular Infusion

Intravenous infusion has been used as the method of cell delivery in many preclinical studies as well as in some early clinical trials. Among its advantages are broad distribution, ability to handle a large-volume infusion, and ease of access. Progenitor cells used in cell-based therapy act through their secretomes, rather than their ability to differentiate into lineage-specific cell type. Since not all progenitor cells have similar secretome potency, the innate abilities of the secretome of cells used in clinical trials will obviously dictate their efficacy. We previously showed intramyocardial injection of cardiac neonatal mesenchymal stromal cells (nMSCs) are more effective in repairing the infarcted myocardium compared to adult mesenchymal stromal cells (aMSCs) due to their robust secretome. In this study, we explored the efficacy of intravenous (IV) delivery of nMSCs for myocardial recovery. Six-week-old male Brown Norway rats underwent acute MI by ligation of the left anterior descending artery, followed by IV infusion of cell dose 5 х 10 6 nMSCs/rat body weight (kg) or saline on days 0 and 5. We found cardiac parameters in the rodent ischemia model improved 1 month after nMSCs infusion, and the result is comparable with the intramyocardial injection of nMSCs. Tracking the infused cells in target organs revealed that their movement after IV delivery was mediated by the cell surface receptor CD44. Systemic injection of nMSCs stimulated immunomodulatory responses specifically by increasing FoxP3 + T-regulatory cell influenced anti-inflammatory macrophages (M2) in heart. These data demonstrate that nMSCs promote immunogenic tolerance via CD44-driven T-reg/M2 stimulation for functional recovery of injured heart. Our data also provide a rationale for a clinical trial of IV infusion of nMSCs to promote functional myocardial improvement in patients with myocardial infarction.