Immunomodulatory effect of mesenchymal stromal cell overexpressing HLA-G1 in cell-based therapy for myocardial infarction.

Abstract

BACKGROUND: Our previous study revealed that intravenous administration of mesenchymal stromal cells (MSCs) increases local cell engraftment and improves heart function. This study aims to investigate whether MSCs overexpressing HLA-G1 have further increased local transplanted cells engraftment and improved heart function. METHODS: The mice were intravenously administered saline or human umbilical cord blood-derived MSCs (hUCB-MSCs) 7 days before myocardial infarction (MI) induction. Then, the MI mouse model was established by ligating the left anterior descending coronary artery. The mice were then subjected to intramyocardial transplantation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) 30&#xa0;min after MI induction. Echocardiographic analysis was carried out to assess heart function. Furthermore, in vivo fluorescent imaging analysis was performed to analyze cell engraftment. Moreover, flow cytometry of splenic regulatory T cells (Tregs) and natural killer (NK) cells was conducted to evaluate the immunomodulatory effect of hUCB-MSCs. RESULTS: The results showed that systemic intravenous administration of hUCB-MSCs substantially enhanced Tregs, decreased NK cells, and increased intramyocardially transplanted hiPSC-CMs' engraftment, thus improving heart function. Compared with hUCB-MSCs, HLA-G1 overexpressing hUCB-MSCs reduced systemic NK cells (7.13&#x2009;&#xb1;&#x2009;0.19% vs. 9.12&#x2009;&#xb1;&#x2009;0.06%, p&#x2009;<&#x2009;0.05), increased Tregs (5.03&#x2009;&#xb1;&#x2009;0.17% vs. 3.36&#x2009;&#xb1;&#x2009;0.05%, p&#x2009;<&#x2009;0.05), improved cell engraftment (Radiant efficiency: 3.01&#x2009;&#xb1;&#x2009;0.36&#x2009;&#xd7;&#x2009;10vs. 2.19&#x2009;&#xb1;&#x2009;0.27&#x2009;&#xd7;&#x2009;10, p&#x2009;<&#x2009;0.05) and heart function (LVEF: 73.00&#x2009;&#xb1;&#x2009;0.44 vs. 62.36&#x2009;&#xb1;&#x2009;1.01, p&#x2009;<&#x2009;0.05). The in vitro assays revealed that HLA-G1 overexpressing hUCB-MSCs modulated the immune response by decreasing pro-inflammatory cytokines. CONCLUSIONS: This study showed that systemic intravenous administration of HLA-G1 overexpressing hUCB-MSCs modulated immune response and increased transplanted hiPSC-CMs' engraftment to improve heart function following AMI.