Dual Stem Cell Therapy Improves the Myocardial Recovery Post-Infarction through Reciprocal Modulation of Cell Functions

Abstract

Mesenchymal stromal cells (MSC) are promising candidates for regenerative therapy of the infarcted heart. However, poor cell retention within the transplantation site limits their potential. We hypothesized that MSC benefits could be enhanced through a dual-cell approach using jointly endothelial colony forming cells (ECFC) and MSC. To assess this, we comparatively evaluated the effects of the therapy with MSC and ECFC versus MSC-only in a mouse model of myocardial infarction. Heart function was assessed by echocardiography, and the molecular crosstalk between MSC and ECFC was evaluated in vitro through direct or indirect co-culture systems. We found that dual-cell therapy improved cardiac function in terms of ejection fraction and stroke volume. In vitro experiments showed that ECFC augmented MSC effector properties by increasing Connexin 43 and Integrin alpha-5 and the secretion of healing-associated molecules. Moreover, MSC prompted the organization of ECFC into vascular networks. This indicated a reciprocal modulation in the functionality of MSC and ECFC. In conclusion, the crosstalk between MSC and ECFC augments the therapeutic properties of MSC and enhances the angiogenic properties of ECFC. Our data consolidate the dual-cell therapy as a step forward for the development of effective treatments for patients affected by myocardial infarction.

Regulation of Endothelial Progenitor Cell Functions in Ischemic Heart Disease: New Therapeutic Targets for Cardiac Remodeling and Repair

“…Crosstalk between MSCs and EPCs enhances cardiac repair and cardiac function after MI through paracrine signaling and direct cell contact ( 130 , 131 ). On the one hand, coculturing MSCs and EPCs enhanced the therapeutic properties of the MSCs, and up-regulation of connexin 43 and integrin-5 expression promoted local intercellular communication and increased MSC engraftment integration capacity ( 132 ). Paracrine factors in EPCs stimulated MSCs while maintaining the adhesion and proliferation properties of ECs, thereby supporting efficient angiogenesis ( 133 ).…”

“…On the other hand, coculturing enhanced the angiogenic properties of the EPCs. Both MSCs and EPCs secrete angiogenic factors; however, MSCs secrete additional proangiogenic factors (VEGF and IGFBP-3) that promote the migration, invasion and angiogenesis of EPCs ( 132 ).…”

“…They found that cell sheet engineering of bioengineered tissues in the repaired heart led to more efficient cell delivery than intracoronary or myocardial injection ( 141 ). The implantation of double-layered cell sheets constructed by coculturing EPCs with SMCs or MSCs improved the ability of tissues to form capillary-like networks and a functional vascular bed, while coculturing stimulated mutual paracrine effects to enhance cell survival and differentiation ( 113 , 114 , 132 ). New regenerative medicine approaches were used to treat CVDs through cell-free therapy by exploiting the paracrine signaling mechanisms of stem and progenitor cells, EXs derived from EPCs that carry proangiogenic and cardioprotective cargo, and transplantation of EPC EXs to promote myocardial angiogenesis and recovery of cardiac function after infarction ( 142 ).…”

A photopolymerizable hydrogel enhances intramyocardial vascular cell delivery and promotes post-myocardial infarction healing by polarizing pro-regenerative neutrophils

“…A significant number of patients go on to develop late sequelae, including heart failure and arrhythmia 2 . For years, considerable effort has been focused on delivering therapeutic genes, growth factors, and cells to promote post-myocardial infarction healing [7][8][9][10][11] . However, these strategies are insufficient partly because of the complexity of the hyper-inflammatory microenvironment in the infarcted myocardium [12][13][14][15][16] .…”

Molecular Research in Cardiovascular Disease

“…A short consideration of the presented papers could start with Popescu et al [1], who show in their article that mesenchymal stromal cells (MSC) in conjunction with endothelial colony forming cells (ECFC) augment the therapeutic effect of MSC and enhance the angiogenic properties of ECFC. The use of these types of cells together in a mouse model of MI resulted in a better recovery postinfarction as assessed by left ventricular ejection fraction (LVEF) and stroke volume.…”