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Cell Rep. 2018 Dec 4;25(10):2821-2835.e7. doi: 10.1016/j.celrep.2018.11.032.

Cooperative Transcription Factor Induction Mediates Hemogenic Reprogramming.

Author information

1
Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1496, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1496, New York, NY 10029, USA; Doctoral Programme in Experimental Biology and Biomedicine, University of Coimbra, Largo Marquês do Pombal 3004-517, Coimbra, Portugal; Centre for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês do Pombal 3004-517, Coimbra, Portugal.
2
Skolkovo Institute of Science and Technology, Nobel Street, Building 3, Moscow 143026, Russia.
3
Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1496, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1496, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1496, New York, NY 10029, USA.
4
Division of Infectious Disease, Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1496, New York, NY 10029, USA.
5
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1496, New York, NY 10029, USA.
6
Centre for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês do Pombal 3004-517, Coimbra, Portugal.
7
Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1496, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1496, New York, NY 10029, USA; Skolkovo Institute of Science and Technology, Nobel Street, Building 3, Moscow 143026, Russia.
8
Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1496, New York, NY 10029, USA; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1496, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1496, New York, NY 10029, USA.
9
Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1496, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1496, New York, NY 10029, USA. Electronic address: kateri.moore@mssm.edu.
10
Centre for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês do Pombal 3004-517, Coimbra, Portugal; Molecular Medicine and Gene Therapy, Lund Stem Cell Centre, Lund University, BMC A12, 221 84, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden. Electronic address: filipe.pereira@med.lu.se.

Abstract

During development, hematopoietic stem and progenitor cells (HSPCs) arise from specialized endothelial cells by a process termed endothelial-to-hematopoietic transition (EHT). The genetic program driving human HSPC emergence remains largely unknown. We previously reported that the generation of hemogenic precursor cells from mouse fibroblasts recapitulates developmental hematopoiesis. Here, we demonstrate that human fibroblasts can be reprogrammed into hemogenic cells by the same transcription factors. Induced cells display dynamic EHT transcriptional programs, generate hematopoietic progeny, possess HSPC cell surface phenotype, and repopulate immunodeficient mice for 3 months. Mechanistically, GATA2 and GFI1B interact and co-occupy a cohort of targets. This cooperative binding is reflected by engagement of open enhancers and promoters, initiating silencing of fibroblast genes and activating the hemogenic program. However, GATA2 displays dominant and independent targeting activity during the early phases of reprogramming. These findings shed light on the processes controlling human HSC specification and support generation of reprogrammed HSCs for clinical applications.

KEYWORDS:

FOS; GATA2; GFI1B; cooperative binding; direct cell reprogramming; hematopoietic stem cell; hematopoietic transcription factor; hemogenic endothelium; hemogenic reprogramming; human endothelial-to-hematopoietic transition

PMID:
30517869
DOI:
10.1016/j.celrep.2018.11.032
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