Three-Dimensional Vascular Network Assembly from Diabetic Patient-Derived Induced Pluripotent Stem Cells

Xin Yi Chan, Rebecca Black, Kayla Dickerman, Joseph Federico, Mathieu Levesque, Jeff Mumm, Sharon Gerecht

Research output: Contribution to journalArticle

Abstract

In diabetics, hyperglycemia results in deficient endothelial progenitors and cells, leading to cardiovascular complications. We aim to engineer 3-dimensional (3D) vascular networks in synthetic hydrogels from type 1 diabetes mellitus (T1D) patient-derived human-induced pluripotent stem cells (hiPSCs), to serve as a transformative autologous vascular therapy for diabetic patients. Approach and Results-We validated and optimized an adherent, feeder-free differentiation procedure to derive early vascular cells (EVCs) with high portions of vascular endothelial cadherin-positive cells from hiPSCs. We demonstrate similar differentiation efficiency from hiPSCs derived from healthy donor and patients with T1D. T1D-hiPSC-derived vascular endothelial cadherin-positive cells can mature to functional endothelial cells-expressing mature markers: von Willebrand factor and endothelial nitric oxide synthase are capable of lectin binding and acetylated low-density lipoprotein uptake, form cords in Matrigel and respond to tumor necrosis factor-α. When embedded in engineered hyaluronic acid hydrogels, T1D-EVCs undergo morphogenesis and assemble into 3D networks. When encapsulated in a novel hypoxia-inducible hydrogel, T1D-EVCs respond to low oxygen and form 3D networks. As xenografts, T1D-EVCs incorporate into developing zebrafish vasculature. Conclusions-Using our robust protocol, we can direct efficient differentiation of T1D-hiPSC to EVCs. Early endothelial cells derived from T1D-hiPSC are functional when mature. T1D-EVCs self-assembled into 3D networks when embedded in hyaluronic acid and hypoxia-inducible hydrogels. The capability of T1D-EVCs to assemble into 3D networks in engineered matrices and to respond to a hypoxic microenvironment is a significant advancement for autologous vascular therapy in diabetic patients and has broad importance for tissue engineering.

Original languageEnglish (US)
Pages (from-to)2677-2685
Number of pages9
JournalArteriosclerosis, thrombosis, and vascular biology
Volume35
Issue number12
DOIs
StatePublished - Dec 1 2015

Keywords

  • Diabetes mellitus
  • endothelial cells
  • hydrogels
  • induced pluripotent stem cells
  • vascular networks

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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