Human induced pluripotent stem cell-derived endothelial cells exhibit functional heterogeneity

Abdul Jalil Rufaihah, Ngan F. Huang, Jeanna Kim, Joerg Herold, Katharina S. Volz, Tea Soon Park, Jerry C. Lee, Elias Zambidis, Renee Reijo-Pera, John P. Cooke

Research output: Contribution to journalArticle


Human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs) are promising for treatment of vascular diseases. However, hiPSC-ECs purifed based on CD31 expression are comprised of arterial, venous, and lymphatic subtypes. It is unclear whether hiPSC-ECs are heterogeneous in nature, and whether there may be functional benefits of enriching for specific subtypes. Therefore, we sought to characterize the hiPSC-ECs and enrich for each subtype, and demonstrate whether such enrichment would have functional significance. The hiPSC-ECs were generated from differentiation of hiPSCs using vascular endothelial growth factor (VEGF)-A and bone morphogenetic protein-4. The hiPSC-ECs were purified based on positive expression of CD31. Subsequently, we sought to enrich for each subtype. Arterial hiPSC-ECs were induced using higher concentrations of VEGF-A and 8-bromoadenosine-3':5'-cyclic monophosphate in the media, whereas lower concentrations of VEGF-A favored venous subtype. VEGF- C and angiopoietin-1 promoted the expression of lymphatic phenotype. Upon FACS purification based on CD31+ expression, the hiPSC-EC population was observed to display typical endothelial surface markers and functions. However, the hiPSC-EC population was heterogeneous in that they displayed arterial, venous, and to a lesser degree, lymphatic lineage markers. Upon comparing vascular formation in matrigel plugs in vivo, we observed that arterial enriched hiPSC-ECs formed a more extensive capillary network in this model, by comparison to a heterogeneous population of hiPSC-ECs. This study demonstrates that FACS purification of CD31+ hiPSC-ECs produces a diverse population of ECs. Refining the differentiation methods can enrich for subtype-specific hiPSC-ECs with functional benefts of enhancing neovascularization.

Original languageEnglish (US)
Pages (from-to)21-35
Number of pages15
JournalAmerican Journal of Translational Research
Issue number1
StatePublished - 2013



  • Angiogenesis
  • Differentiation
  • Endothelial cells
  • Heterogeneity
  • Induced pluripotent stem cells

ASJC Scopus subject areas

  • Molecular Medicine
  • Medicine(all)
  • Cancer Research
  • Clinical Biochemistry

Cite this

Rufaihah, A. J., Huang, N. F., Kim, J., Herold, J., Volz, K. S., Park, T. S., Lee, J. C., Zambidis, E., Reijo-Pera, R., & Cooke, J. P. (2013). Human induced pluripotent stem cell-derived endothelial cells exhibit functional heterogeneity. American Journal of Translational Research, 5(1), 21-35.