期刊
NATURE
卷 545, 期 7655, 页码 439-+出版社
NATURE PORTFOLIO
DOI: 10.1038/nature22326
关键词
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资金
- Ansary Stem Cell Institute (ASCI)
- New York State Department of Health grants (NYSDOH) [C026878, C028117, C029156, C030160]
- NIH-R01 [DK095039, HL119872, HL128158, HL115128, HL099997]
- Starr foundation TRI-Institution stem cell core project
- Tri-Institutional Stem Cell Initiative [2013-032, 2014-023, 2016-013]
- Qatar National Priorities Research Program [NPRP 8-1898-3-392, NPRP 6-131-3-268]
- NIH [T32 HD060600, CA204308, HL133021, RO1 HL091724]
- ASCI
- TRI-SCI [2014-023, 2013-022, 2014-004, 2016-024]
- Leukemia & Lymphoma Society (LLS) [0859-15]
- Taub Foundation
- LLS grant [2299-14]
- NYSDOH [C029156, C030160]
- NIH R01 [HL119872, HL128158]
- Cancer Research & Treatment Fund (CRT)
- [U54 CA163167]
Developmental pathways that orchestrate the fleeting transition of endothelial cells into haematopoietic stem cells remain undefined. Here we demonstrate a tractable approach for fully reprogramming adult mouse endothelial cells to haematopoietic stem cells (rEC-HSCs) through transient expression of the transcription-factor-encoding genes Fosb, Gfi1, Runx1, and Spi1 (collectively denoted hereafter as FGRS) and vascular-niche-derived angiocrine factors. The induction phase (days 0-8) of conversion is initiated by expression of FGRS in mature endothelial cells, which results in endogenous Runx1 expression. During the specification phase (days 8-20), RUNX1(+) FGRS-transduced endothelial cells commit to a haematopoietic fate, yielding rEC-HSCs that no longer require FGRS expression. The vascular niche drives a robust self-renewal and expansion phase of rEC-HSCs (days 20-28). rEC-HSCs have a transcriptome and long-term self-renewal capacity similar to those of adult haematopoietic stem cells, and can be used for clonal engraftment and serial primary and secondary multi-lineage reconstitution, including antigen-dependent adaptive immune function. Inhibition of TGF beta and CXCR7 or activation of BMP and CXCR4 signalling enhanced generation of rEC-HSCs. Pluripotency-independent conversion of endothelial cells into autologous authentic engraftable haematopoietic stem cells could aid treatment of haematological disorders.
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