Suicide gene-mediated sequencing ablation revealed the potential therapeutic mechanism of induced pluripotent stem cell-derived cardiovascular cell patch post-myocardial infarction.
OBJECTIVE
This study is designed to assess the protective cardiac effects after myocardial infarction (MI) of (i) cardiovascular progenitor cells (PC) differentiated directly into cardiomyocytes (CM) and endothelial cells (ECs) at the injury site, as separable from the effects of (ii) paracrine factors released from PC.


RESULTS
In vivo: bi-cell patch containing induced pluripotent stem cell (iPSC)-derived CM and EC (BIC) was transplanted onto the infarcted heart. BIC were transduced with herpes simplex virus thymidine kinase "suicide" gene driven by cardiac NCX1 or endothelial vascular endothelium-cadherin promoter. IGF-1α and VEGF levels released from ischemic tissues were significantly enhanced in the BIC patch treatment group. Heart function, infarction size, and vessel density were significantly improved after BIC patch treatment. These effects were completely abolished in the group given ganciclovir (GCV) at week 1 as a suicide gene activator, and partially abolished in the group given GCV at week 3 as compared with the untreated cell patch group.


METHODS
This study was designed to distinguish between cell-based and noncell-based therapeutic effects of PC lineages after MI. PCs derived from iPSC were genetically modified to express "suicide" gene. iPSC-derived CM and EC were then ablated in situ at week 1 and 3 by intraperitoneal administration of GCV. This enabled direct assessment of the effects of iPSC transplantation on myocardial function and tissue regeneration potential.


CONCLUSIONS
Data support a mechanism in which iPSC-derived cardiovascular lineages contribute directly to improved cardiac performance and attenuated remodeling. Paracrine factors provide additional support to the restoration of heart function.
1 Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center , Cincinnati, Ohio.
Yuhua
Y
Wang
Wei
W
Huang
Jialiang
J
Liang
Zhili
Z
Wen
Dehua
D
Chang
Kai
K
Kang
Jiapeng
J
Wang
Meifeng
M
Xu
Ronald W
RW
Millard
Yigang
Y
Wang
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000637:transplantation*; D015774:Ganciclovir / Q000494:pharmacology; D041722:Genes, Transgenic, Suicide; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000637:transplantation*; D018919:Neovascularization, Physiologic; D039904:Pluripotent Stem Cells / Q000166:cytology*; D011401:Promoter Regions, Genetic; D051381:Rats; D018139:Simplexvirus / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D020257:Ventricular Remodeling; D014764:Viral Proteins / Q000235:genetics
D000998:Antiviral Agents; D042461:Vascular Endothelial Growth Factor A; D014764:Viral Proteins; C548904:insulin-like growth factor-1, rat; C467498:vascular endothelial growth factor A, rat; D007334:Insulin-Like Growth Factor I; D013937:Thymidine Kinase; D015774:Ganciclovir