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Effects of cellular origin on differentiation of human induced pluripotent stem cell–derived endothelial cells
Shijun Hu, … , Michael P. Snyder, Joseph C. Wu
Shijun Hu, … , Michael P. Snyder, Joseph C. Wu
Published June 2, 2016
Citation Information: JCI Insight. 2016;1(8):e85558. https://doi.org/10.1172/jci.insight.85558.
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Research Article Stem cells Transplantation

Effects of cellular origin on differentiation of human induced pluripotent stem cell–derived endothelial cells

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Abstract

Human induced pluripotent stem cells (iPSCs) can be derived from various types of somatic cells by transient overexpression of 4 Yamanaka factors (OCT4, SOX2, C-MYC, and KLF4). Patient-specific iPSC derivatives (e.g., neuronal, cardiac, hepatic, muscular, and endothelial cells [ECs]) hold great promise in drug discovery and regenerative medicine. In this study, we aimed to evaluate whether the cellular origin can affect the differentiation, in vivo behavior, and single-cell gene expression signatures of human iPSC–derived ECs. We derived human iPSCs from 3 types of somatic cells of the same individuals: fibroblasts (FB-iPSCs), ECs (EC-iPSCs), and cardiac progenitor cells (CPC-iPSCs). We then differentiated them into ECs by sequential administration of Activin, BMP4, bFGF, and VEGF. EC-iPSCs at early passage (10 < P < 20) showed higher EC differentiation propensity and gene expression of EC-specific markers (PECAM1 and NOS3) than FB-iPSCs and CPC-iPSCs. In vivo transplanted EC-iPSC–ECs were recovered with a higher percentage of CD31+ population and expressed higher EC-specific gene expression markers (PECAM1, KDR, and ICAM) as revealed by microfluidic single-cell quantitative PCR (qPCR). In vitro EC-iPSC–ECs maintained a higher CD31+ population than FB-iPSC–ECs and CPC-iPSC–ECs with long-term culturing and passaging. These results indicate that cellular origin may influence lineage differentiation propensity of human iPSCs; hence, the somatic memory carried by early passage iPSCs should be carefully considered before clinical translation.

Authors

Shijun Hu, Ming-Tao Zhao, Fereshteh Jahanbani, Ning-Yi Shao, Won Hee Lee, Haodong Chen, Michael P. Snyder, Joseph C. Wu

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Figure 1

Isolation of fibroblasts (FBs), endothelial cells (ECs), and cardiac progenitor cells (CPCs) from the same human fetuses.

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Isolation of fibroblasts (FBs), endothelial cells (ECs), and cardiac pro...
(A) Schematic overview of the experimental design. Three types of somatic cells (FBs, ECs, and CPCs) were reprogrammed to iPSCs (FB-iPSCs, EC-iPSCs, and CPC-iPSCs). These iPSCs were then differentiated into endothelial cells (FB-iPSC–ECs, EC-iPSC–ECs, and CPC-iPSC–ECs). Both in vitro and in vivo assays were performed to assess the effects of donor cell source on endothelial differentiation and gene expression of human iPSCs. (B and C) Endothelial cells exhibited typical cobblestone morphology and expressed CD31 and CD144. (D) FACS analysis confirmed the high percentage of CD31+CD144+ cells in fetal ECs. (E and F) Fibroblasts were positive for mesenchymal marker vimentin. (G) Sca-1+ cardiac progenitor cells expressed CD105. (H) EC differentiation protocol by sequential administration of cytokines and growth factors. A, Activin A (10 ng/ml); B, BMP4 (20 ng/ml); F, bFGF (8 ng/ml); V, VEGF (25 ng/ml); and S, SB431542 (10 μM) . Scale bars: 50 μm.

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