Functional and transcriptional characterization of human embryonic stem cell-derived endothelial cells for treatment of myocardial infarction.
BACKGROUND
Differentiation of human embryonic stem cells into endothelial cells (hESC-ECs) has the potential to provide an unlimited source of cells for novel transplantation therapies of ischemic diseases by supporting angiogenesis and vasculogenesis. However, the endothelial differentiation efficiency of the conventional embryoid body (EB) method is low while the 2-dimensional method of co-culturing with mouse embryonic fibroblasts (MEFs) require animal product, both of which can limit the future clinical application of hESC-ECs. Moreover, to fully understand the beneficial effects of stem cell therapy, investigators must be able to track the functional biology and physiology of transplanted cells in living subjects over time.


METHODS
In this study, we developed an extracellular matrix (ECM) culture system for increasing endothelial differentiation and free from contaminating animal cells. We investigated the transcriptional changes that occur during endothelial differentiation of hESCs using whole genome microarray, and compared to human umbilical vein endothelial cells (HUVECs). We also showed functional vascular formation by hESC-ECs in a mouse dorsal window model. Moreover, our study is the first so far to transplant hESC-ECs in a myocardial infarction model and monitor cell fate using molecular imaging methods.


CONCLUSIONS
Taken together, we report a more efficient method for derivation of hESC-ECs that express appropriate patterns of endothelial genes, form functional vessels in vivo, and improve cardiac function. These studies suggest that hESC-ECs may provide a novel therapy for ischemic heart disease in the future.
Li
Zongjin
Z
Department of Radiology and Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, Stanford, California, USA.
Wilson
Kitchener D
KD
Smith
Bryan
B
Kraft
Daniel L
DL
Jia
Fangjun
F
Huang
Mei
M
Xie
Xiaoyan
X
Robbins
Robert C
RC
Gambhir
Sanjiv S
SS
Weissman
Irving L
IL
Wu
Joseph C
JC
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism* / Q000637:transplantation; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D020127:Recovery of Function / Q000187:drug effects; D015203:Reproducibility of Results; D033581:Stem Cell Transplantation; D014022:Tissue Survival / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
D003094:Collagen