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Efficient direct reprogramming of mature amniotic cells into endothelial cells by ETS factors and TGFβ suppression.

TitleEfficient direct reprogramming of mature amniotic cells into endothelial cells by ETS factors and TGFβ suppression.
Publication TypeJournal Article
Year of Publication2012
AuthorsGinsberg M, James D, Ding B-S, Nolan D, Geng F, Butler JM, Schachterle W, Pulijaal VR, Mathew S, Chasen ST, Xiang J, Rosenwaks Z, Shido K, Elemento O, Rabbany SY, Rafii S
JournalCell
Volume151
Issue3
Pagination559-75
Date Published2012 Oct 26
ISSN1097-4172
KeywordsAmniotic Fluid, Cell Differentiation, Embryonic Stem Cells, Endothelial Cells, Humans, Proto-Oncogene Proteins c-ets, Retroviridae Proteins, Oncogenic, Transforming Growth Factor beta
Abstract

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 TGFβ-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 TGFβ 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.

DOI10.1016/j.cell.2012.09.032
Alternate JournalCell
PubMed ID23084400
PubMed Central IDPMC3507451
Grant ListDK095039 / DK / NIDDK NIH HHS / United States
HL097797 / HL / NHLBI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
/ / Howard Hughes Medical Institute / United States