Immunomodulation by systemic administration of human-induced pluripotent stem cell-derived mesenchymal stromal cells to enhance the therapeutic efficacy of cell-based therapy for treatment of myocardial infarction.
Rationale: Poor survival and engraftment are major hurdles of stem cell therapy in the treatment of myocardial infarction (MI). We sought to determine whether pre-transplantation systemic intravenous administration of human induced pluripotent stem cell (hiPSC)-derived mesenchymal stromal cells (hiPSC-MSCs) could improve the survival of hiPSC-MSCs or hiPSC-derived cardiomyocytes (hiPSC-CMs) following direct intramyocardial transplantation in a mouse model of MI. Methods: Mice were randomized to undergo intravenous administration of saline or 5×105 hiPSC-MSCs one week prior to MI, induced by ligation of the left anterior descending coronary artery. Mice were further assigned to undergo direct intramyocardial transplantation of hiPSC-MSCs (1×106) or hiPSC-CMs (1×106) 10 minutes following MI. Echocardiographic and invasive hemodynamic assessment were performed to determine cardiac function. In-vivo fluorescent imaging analysis, immunofluorescence staining and polymerase chain reaction were performed to detect cell engraftment. Flow cytometry of splenic regulatory T cells (Tregs) and natural killer (NK) cells was performed to assess the immunomodulatory effects. Results: Pre-transplantation systemic administration of hiPSC-MSCs increased systemic Tregs activation, decreased the number of splenic NK cells and inflammation, and enhanced survival of transplanted hiPSC-MSCs and hiPSC-CMs. These improvements were associated with increased neovascularization and decreased myocardial inflammation and apoptosis at the peri-infract zone with consequent improved left ventricular function four weeks later. Co-culture of splenic CD4 cells with hiPSC-MSCs also modulated their cytokine expression profile with a decreased level of interferon-γ, tumor necrosis factor-α, and interleukin (IL)-17A, but not IL-2, IL-6 and IL-10. Conclusion: Pre-transplantation systemic intravenous administration of hiPSC-MSCs induced immunomodulation and facilitated the survival of intramyocardially transplanted cells to improve cardiac function in MI.
['Sun|Si-Jia|SJ|', 'Lai|Wing-Hon|WH|', 'Jiang|Yu|Y|', 'Zhen|Zhe|Z|', 'Wei|Rui|R|', 'Lian|Qizhou|Q|', 'Liao|Song-Yan|SY|', 'Tse|Hung-Fat|HF|']
D000818:Animals D064987:Cell- and Tissue-Based Therapy D002478:Cells, Cultured D018920:Coculture Techniques D004195:Disease Models, Animal D006801:Humans D056747:Immunomodulation D057026:Induced Pluripotent Stem Cells D045164:Mesenchymal Stem Cell Transplantation D059630:Mesenchymal Stem Cells D051379:Mice D009203:Myocardial Infarction
immunomodulation mesenchymal stromal cell myocardial infarction human induced pluripotent stem cell cardiomyocyte