PUBLICATION
Three-Dimensional Vascular Network Assembly From Diabetic Patient-Derived Induced Pluripotent Stem Cells
- Authors
- Chan, X.Y., Black, R., Dickerman, K., Federico, J., Levesque, M., Mumm, J., Gerecht, S.
- ID
- ZDB-PUB-151010-8
- Date
- 2015
- Source
- Arteriosclerosis, Thrombosis, and Vascular Biology 35(12): 2677-85 (Journal)
- Registered Authors
- Mumm, Jeff
- Keywords
- 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
- PubMed
- 26449749 Full text @ Arterio., Thromb., and Vas. Bio.
Citation
Chan, X.Y., Black, R., Dickerman, K., Federico, J., Levesque, M., Mumm, J., Gerecht, S. (2015) Three-Dimensional Vascular Network Assembly From Diabetic Patient-Derived Induced Pluripotent Stem Cells. Arteriosclerosis, Thrombosis, and Vascular Biology. 35(12):2677-85.
Abstract
Objective 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping