Transdifferentiation of human fibroblasts to endothelial cells role of innate immunity

Nazish Sayed, Wing Tak Wong, Frank Ospino, Shu Meng, Jieun Lee, Arshi Jha, Phillip Dexheimer, Bruce J. Aronow, John P. Cooke

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

Background-Cell fate is fluid and may be altered experimentally by the forced expression of master regulators mediating cell lineage. Such reprogramming has been achieved with the use of viral vectors encoding transcription factors. We recently discovered that the viral vectors are more than passive vehicles for transcription factors because they participate actively in the process of nuclear reprogramming to pluripotency by increasing epigenetic plasticity. On the basis of this recognition, we hypothesized that small-molecule activators of toll-like receptor 3, together with external microenvironmental cues that drive endothelial cell (EC) specification, might be sufficient to induce transdifferentiation of fibroblasts into ECs (induced ECs). Methods and Results-We show that toll-like receptor 3 agonist Poly I:C, combined with exogenous EC growth factors, transdifferentiated human fibroblasts into ECs. These induced ECs were comparable to human dermal microvascular ECs in immunohistochemical, genetic, and functional assays, including the ability to form capillary-like structures and to incorporate acetylated low-density lipoprotein. Furthermore, induced ECs significantly improved limb perfusion and neovascularization in the murine ischemic hindlimb. Finally, using genetic knockdown studies, we found that the effective transdifferentiation of human fibroblasts to ECs requires innate immune activation. Conclusions-This study suggests that manipulation of innate immune signaling may be generally used to modify cell fate. Because similar signaling pathways are activated by damage-associated molecular patterns, epigenetic plasticity induced by innate immunity may play a fundamental role in transdifferentiation during wound healing and regeneration. Finally, this study is a first step toward development of a small-molecule strategy for therapeutic transdifferentiation for vascular disease.

Original languageEnglish (US)
Pages (from-to)300-309
Number of pages10
JournalCirculation
Volume131
Issue number3
DOIs
StatePublished - 2015

Keywords

  • Endothelial cell
  • Endothelial function
  • Immune system
  • Stem cell
  • Transdifferentiation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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