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
  • 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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