Reproductive Endocrinology Lab

You are here

Reprogramming human endothelial cells to haematopoietic cells requires vascular induction.

TitleReprogramming human endothelial cells to haematopoietic cells requires vascular induction.
Publication TypeJournal Article
Year of Publication2014
AuthorsSandler VM, Lis R, Liu Y, Kedem A, James D, Elemento O, Butler JM, Scandura JM, Rafii S
JournalNature
Volume511
Issue7509
Pagination312-8
Date Published2014 Jul 17
ISSN1476-4687
KeywordsAdult Stem Cells, Animals, Aorta, Cell Lineage, Cellular Microenvironment, Cellular Reprogramming, Endothelial Cells, Female, Gene Expression Regulation, Gonads, Hematopoiesis, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Humans, Lymphocytes, Mesonephros, Mice, Multipotent Stem Cells, Myeloid Cells, Pluripotent Stem Cells, Time Factors, Transcription Factors, Transgenes
Abstract

Generating engraftable human haematopoietic cells from autologous tissues is a potential route to new therapies for blood diseases. However, directed differentiation of pluripotent stem cells yields haematopoietic cells that engraft poorly. Here, we have devised a method to phenocopy the vascular-niche microenvironment of haemogenic cells, thereby enabling reprogramming of human endothelial cells into engraftable haematopoietic cells without transition through a pluripotent intermediate. Highly purified non-haemogenic human umbilical vein endothelial cells or adult dermal microvascular endothelial cells were transduced with the transcription factors FOSB, GFI1, RUNX1 and SPI1 (hereafter referred to as FGRS), and then propagated on serum-free instructive vascular niche monolayers to induce outgrowth of haematopoietic colonies containing cells with functional and immunophenotypic features of multipotent progenitor cells (MPPs). These endothelial cells that have been reprogrammed into human MPPs (rEC-hMPPs) acquire colony-forming-cell potential and durably engraft into immune-deficient mice after primary and secondary transplantation, producing long-term rEC-hMPP-derived myeloid (granulocytic/monocytic, erythroid, megakaryocytic) and lymphoid (natural killer and B cell) progenies. Conditional expression of FGRS transgenes, combined with vascular induction, activates endogenous FGRS genes, endowing rEC-hMPPs with a transcriptional and functional profile similar to that of self-renewing MPPs. Our approach underscores the role of inductive cues from the vascular niche in coordinating and sustaining haematopoietic specification and may prove useful for engineering autologous haematopoietic grafts to treat inherited and acquired blood disorders.

DOI10.1038/nature13547
Alternate JournalNature
PubMed ID25030167
PubMed Central IDPMC4159670
Grant ListCA159175 / CA / NCI NIH HHS / United States
CA163167 / CA / NCI NIH HHS / United States
HL055748 / HL / NHLBI NIH HHS / United States
HL119872 / HL / NHLBI NIH HHS / United States
R01 DK095039 / DK / NIDDK NIH HHS / United States
R01 HL097797 / HL / NHLBI NIH HHS / United States
R01 HL115128 / HL / NHLBI NIH HHS / United States
R01 HL119872 / HL / NHLBI NIH HHS / United States
R01DK095039 / DK / NIDDK NIH HHS / United States
R01HL097797 / HL / NHLBI NIH HHS / United States
R01HL119872 / HL / NHLBI NIH HHS / United States
U01 HL099997 / HL / NHLBI NIH HHS / United States
U01 HL099997 / HL / NHLBI NIH HHS / United States
U01-HL099997 / HL / NHLBI NIH HHS / United States
U54 CA163167 / CA / NCI NIH HHS / United States
U54CA163167 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States