Conversion of adult endothelium to immunocompetent haematopoietic stem cells.

TitleConversion of adult endothelium to immunocompetent haematopoietic stem cells.
Publication TypeJournal Article
Year of Publication2017
AuthorsLis R, Karrasch CC, Poulos MG, Kunar B, Redmond D, Duran JGBarcia, Badwe CR, Schachterle W, Ginsberg M, Xiang J, Tabrizi ARafii, Shido K, Rosenwaks Z, Elemento O, Speck NA, Butler JM, Scandura JM, Rafii S
JournalNature
Volume545
Issue7655
Pagination439-445
Date Published2017 05 25
ISSN1476-4687
KeywordsAdaptive Immunity, Aging, Animals, Cell Differentiation, Cell Line, Cell Lineage, Cell Self Renewal, Cellular Reprogramming, Clone Cells, Core Binding Factor Alpha 2 Subunit, DNA-Binding Proteins, Endothelial Cells, Endothelium, Hematopoiesis, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Humans, Male, Mice, Mice, Inbred C57BL, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-fos, T-Lymphocytes, Trans-Activators, Transcription Factors, Transcriptome
Abstract

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 TGFβ 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.

DOI10.1038/nature22326
Alternate JournalNature
PubMed ID28514438
PubMed Central IDPMC5794215
Grant ListR01 HL133021 / HL / NHLBI NIH HHS / United States
R01 CA204308 / CA / NCI NIH HHS / United States
HL128158 / NH / NIH HHS / United States
U01 HL099997 / HL / NHLBI NIH HHS / United States
R01 HL115128 / HL / NHLBI NIH HHS / United States
R01 HL091724 / HL / NHLBI NIH HHS / United States
HL099997 / NH / NIH HHS / United States
HL133021 / NH / NIH HHS / United States
U54 CA163167 / CA / NCI NIH HHS / United States
R01 HL128158 / HL / NHLBI NIH HHS / United States
R01 DK095039 / DK / NIDDK NIH HHS / United States
HL119872 / NH / NIH HHS / United States
R01 HL097797 / HL / NHLBI NIH HHS / United States
NIH-R01 HL091724 / NH / NIH HHS / United States
T32 HD060600 / HD / NICHD NIH HHS / United States
R01 HL119872 / HL / NHLBI NIH HHS / United States
HL115128 / NH / NIH HHS / United States