Reprogramming human endothelial cells to haematopoietic cells requires vascular induction

Vladislav M. Sandler, Raphael Lis, Ying Liu, Alon Kedem, Daylon James, Olivier Elemento, Jason M. Butler, Joseph M. Scandura and Shahin Rafii ()
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Vladislav M. Sandler: Ansary Stem Cell Institute, and Howard Hughes Medical Institute, Weill Cornell Medical College
Raphael Lis: Ansary Stem Cell Institute, and Howard Hughes Medical Institute, Weill Cornell Medical College
Ying Liu: Ansary Stem Cell Institute, and Howard Hughes Medical Institute, Weill Cornell Medical College
Alon Kedem: Ansary Stem Cell Institute, and Howard Hughes Medical Institute, Weill Cornell Medical College
Daylon James: Ansary Stem Cell Institute, and Howard Hughes Medical Institute, Weill Cornell Medical College
Olivier Elemento: HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College
Jason M. Butler: Ansary Stem Cell Institute, and Howard Hughes Medical Institute, Weill Cornell Medical College
Joseph M. Scandura: Hematology-Oncology, Weill Cornell Medical College and the New York Presbyterian Hospital
Shahin Rafii: Ansary Stem Cell Institute, and Howard Hughes Medical Institute, Weill Cornell Medical College

Nature, 2014, vol. 511, issue 7509, 312-318

Abstract: 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.

Date: 2014
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DOI: 10.1038/nature13547

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