2. Academic Validation
  3. 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

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

  • Stem Cell Res Ther. 2018 Nov 15;9(1):313. doi: 10.1186/s13287-018-1061-4.
Liping Su 1,  Xiaocen Kong 2,  Szeyun Lim 1,  Szejie Loo 1,  Shihua Tan 1,  Kiankeong Poh 3,  James Dutton 4,  Colin Stewart 5,  Stuart Cook 1 6 7,  Xiaofei Su 2,  Jianhua Ma 8,  Jianyi Zhang 9,  Lei Ye 10
Affiliations

Affiliations

  • 1 National Heart Research Institute of Singapore, National Heart Centre Singapore, Singapore, 117609, Singapore.
  • 2 Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China.
  • 3 Department of Cardiology, National University Health System Singapore and Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 4 Stem cell Institute, University of Minnesota, Minneapolis, MN, USA.
  • 5 Institute of Medical Biology, A*STAR, Singapore, Singapore.
  • 6 Programme in Cardiovascular & Metabolic Disorders, Duke-National University of Singapore, Singapore, Singapore.
  • 7 NHLI, Imperial College, London, UK.
  • 8 Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China. [email protected].
  • 9 Department of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, AL, 35294-2182, USA. [email protected].
  • 10 National Heart Research Institute of Singapore, National Heart Centre Singapore, Singapore, 117609, Singapore. [email protected].
PMID: 30442193 DOI: 10.1186/s13287-018-1061-4
Abstract

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.

Keywords

Endothelial differentiation; Human-induced pluripotent stem cells; Signaling pathways.

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