The prostaglandin H2 analog U-46619 improves the differentiation efficiency of human induced pluripotent stem cells into endothelial cells by activating both p38MAPK and ERK1/2 signaling pathways 06 Biological Sciences 0601 Biochemistry and Cell Biology

Liping Su, Xiaocen Kong, Szeyun Lim, Szejie Loo, Shihua Tan, Kiankeong Poh, James Dutton, Colin Stewart, Stuart Cook, Xiaofei Su, Jianhua Ma, Jianyi Zhang, Lei Ye

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Background: We have shown that the differentiation of human-induced pluripotent stem cells (hiPSCs) into endothelial cells (ECs) is more efficient when performed with a 3-dimensional (3D) scaffold of biomaterial than in monolayers. The current study aims to further increase hiPSC-EC differentiation efficiency by deciphering the signaling pathways in 3D scaffolds. Methods and results: We modified our 3D protocol by using U-46619 to upregulate both p38 mitogen-activated protein kinase (p38MAPK) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling, which increased the differentiation efficiency (as measured by CD31 expression) to as high as 89% in two established hiPSC lines. The differentiated cells expressed arteriovenous, but not lymphatic, markers; formed tubular structures and EC lumen in vitro; had significantly shorter population-doubling times than monolayer-differentiated hiPSC-ECs; and restored perfusion and vascularity in a murine hind limb ischemia model. The differentiation efficiency was also > 85% in three hiPSC lines that had been derived from patients with diseases or disease symptoms that have been linked to endothelial dysfunction. Conclusions: These observations demonstrate that activating both p38MAPK and ERK1/2 signaling pathways with U-46619 improves the efficiency of arteriovenous hiPSC-EC differentiation and produces cells with greater proliferative capacity.

Original languageEnglish (US)
Article number313
JournalStem Cell Research and Therapy
Issue number1
StatePublished - Nov 15 2018



  • Endothelial differentiation
  • Human-induced pluripotent stem cells
  • Signaling pathways

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