Journal
CELL
Volume 151, Issue 3, Pages 559-575Publisher
CELL PRESS
DOI: 10.1016/j.cell.2012.09.032
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Funding
- Howard Hughes Medical Institute
- Ansary Stem Cell Institute
- Empire State Stem Cell Board
- NHLBI [R01s HL097797, DK095039]
- Qatar National Priorities Research Foundation [NPRP08-663-3-140]
- Qatar foundation BioMedical Research Program (BMRP)
- New York State Department of Health (NYSTEM) [C024180, C026438, C026878]
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ETS transcription factors ETV2, FLI1, and ERG1 specify pluripotent stem cells into induced vascular endothelial cells (iVECs). However, iVECs are unstable and drift toward nonvascular cells. We show that human midgestation c-Kit(-) lineage-committed amniotic cells (ACs) can be reprogrammed into vascular endothelial cells (rAC-VECs) without transitioning through a pluripotent state. Transient ETV2 expression in ACs generates immature rAC-VECs, whereas coexpression with FLI1/ERG1 endows rAC-VECs with a vascular repertoire and morphology matching mature endothelial cells (ECs). Brief TGF beta-inhibition functionalizes VEGFR2 signaling, augmenting specification of ACs into rAC-VECs. Genome-wide transcriptional analyses showed that rAC-VECs are similar to adult ECs in which vascular-specific genes are expressed and nonvascular genes are silenced. Functionally, rAC-VECs form stable vasculature in Matrigel plugs and regenerating livers. Therefore, short-term ETV2 expression and TGF beta inhibition with constitutive ERG1/FLI1 coexpression reprogram mature ACs into durable rAC-VECs with clinical-scale expansion potential. Banking of HLA-typed rAC-VECs establishes a vascular inventory for treatment of diverse disorders.
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