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

Chan, X.Y., Black, R., Dickerman, K., Federico, J., Levesque, M., Mumm, J., Gerecht, S.
Arteriosclerosis, Thrombosis, and Vascular Biology   35(12): 2677-85 (Journal)
Registered Authors
Mumm, Jeff
diabetes mellitus, endothelial cells, hyaluronic acid, induced pluripotent stem cells, tumor necrosis factor-alpha
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Antigens, CD/metabolism
  • Cadherins/metabolism
  • Case-Control Studies
  • Cell Differentiation*
  • Cell Hypoxia
  • Cell Line
  • Cell Separation
  • Cell Shape
  • Diabetes Mellitus, Type 1/blood
  • Diabetes Mellitus, Type 1/pathology*
  • Endothelial Progenitor Cells/drug effects
  • Endothelial Progenitor Cells/metabolism
  • Endothelial Progenitor Cells/pathology*
  • Endothelial Progenitor Cells/transplantation
  • Green Fluorescent Proteins/biosynthesis
  • Green Fluorescent Proteins/genetics
  • Heterografts
  • Humans
  • Hyaluronic Acid/chemistry
  • Hydrogels
  • Induced Pluripotent Stem Cells/drug effects
  • Induced Pluripotent Stem Cells/metabolism
  • Induced Pluripotent Stem Cells/pathology*
  • Induced Pluripotent Stem Cells/transplantation
  • Lipoproteins, LDL/metabolism
  • Neovascularization, Pathologic*
  • Nitric Oxide Synthase Type III/metabolism
  • Phenotype
  • Tumor Necrosis Factor-alpha/pharmacology
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • von Willebrand Factor/metabolism
26449749 Full text @ Arterio., Thromb., and Vas. Bio.
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.
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.
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.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes