Conversion of human fibroblasts to functional endothelial cells by defined factors

Jun Li, Ngan F. Huang, Jun Zou, Timothy J. Laurent, Jerry C. Lee, Janet Okogbaa, John P. Cooke, Sheng Ding

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

Abstract

Objective-Transdifferentiation of fibroblasts to endothelial cells (ECs) may provide a novel therapeutic avenue for diseases, including ischemia and fibrosis. Here, we demonstrate that human fibroblasts can be transdifferentiated into functional ECs by using only 2 factors, Oct4 and Klf4, under inductive signaling conditions. Approach and Results-To determine whether human fibroblasts could be converted into ECs by transient expression of pluripotency factors, human neonatal fibroblasts were transduced with lentiviruses encoding Oct4 and Klf4 in the presence of soluble factors that promote the induction of an endothelial program. After 28 days, clusters of induced endothelial (iEnd) cells seemed and were isolated for further propagation and subsequent characterization. The iEnd cells resembled primary human ECs in their transcriptional signature by expressing endothelial phenotypic markers, such as CD31, vascular endothelial-cadherin, and von Willebrand Factor. Furthermore, the iEnd cells could incorporate acetylated low-density lipoprotein and form vascular structures in vitro and in vivo. When injected into the ischemic limb of mice, the iEnd cells engrafted, increased capillary density, and enhanced tissue perfusion. During the transdifferentiation process, the endogenous pluripotency network was not activated, suggesting that this process bypassed a pluripotent intermediate step. Conclusions-Pluripotent factor-induced transdifferentiation can be successfully applied for generating functional autologous ECs for therapeutic applications.

Original languageEnglish (US)
Pages (from-to)1366-1375
Number of pages10
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume33
Issue number6
DOIs
StatePublished - Jun 2013

Keywords

  • Angiogenesis
  • Direct reprogramming
  • Endothelium
  • Peripheral vascular disease
  • Stem cells
  • Transdifferentiation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Fingerprint

Dive into the research topics of 'Conversion of human fibroblasts to functional endothelial cells by defined factors'. Together they form a unique fingerprint.

Cite this