Reprogramming mouse fibroblasts into engraftable myeloerythroid and lymphoid progenitors

Hui Cheng, Heather Yin-Kuan Ang, Chadi A. EL Farran, Pin Li, Hai Tong Fang, Tong Ming Liu, Say Li Kong, Michael Lingzi Chin, Wei Yin Ling, Edwin Kok Hao Lim, Hu Li, Tara Huber, Kyle M. Loh, Yuin-Han Loh () and Bing Lim ()
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Hui Cheng: Stem Cell and Regenerative Biology Group, Genome Institute of Singapore
Heather Yin-Kuan Ang: Stem Cell and Regenerative Biology Group, Genome Institute of Singapore
Chadi A. EL Farran: Epigenetics and Cell Fates Laboratory, Institute of Molecular and Cell Biology
Pin Li: Stem Cell and Regenerative Biology Group, Genome Institute of Singapore
Hai Tong Fang: Epigenetics and Cell Fates Laboratory, Institute of Molecular and Cell Biology
Tong Ming Liu: Stem Cell and Regenerative Biology Group, Genome Institute of Singapore
Say Li Kong: Stem Cell and Regenerative Biology Group, Genome Institute of Singapore
Michael Lingzi Chin: Stem Cell and Regenerative Biology Group, Genome Institute of Singapore
Wei Yin Ling: Stem Cell and Regenerative Biology Group, Genome Institute of Singapore
Edwin Kok Hao Lim: Stem Cell and Regenerative Biology Group, Genome Institute of Singapore
Hu Li: Center for Individualized Medicine, Mayo Clinic
Tara Huber: Stem Cell and Regenerative Biology Group, Genome Institute of Singapore
Kyle M. Loh: Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
Yuin-Han Loh: Epigenetics and Cell Fates Laboratory, Institute of Molecular and Cell Biology
Bing Lim: Stem Cell and Regenerative Biology Group, Genome Institute of Singapore

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: Abstract Recent efforts have attempted to convert non-blood cells into hematopoietic stem cells (HSCs) with the goal of generating blood lineages de novo. Here we show that hematopoietic transcription factors Scl, Lmo2, Runx1 and Bmi1 can convert a developmentally distant lineage (fibroblasts) into ‘induced hematopoietic progenitors’ (iHPs). Functionally, iHPs generate acetylcholinesterase+ megakaryocytes and phagocytic myeloid cells in vitro and can also engraft immunodeficient mice, generating myeloerythoid and B-lymphoid cells for up to 4 months in vivo. Molecularly, iHPs transcriptionally resemble native Kit+ hematopoietic progenitors. Mechanistically, reprogramming factor Lmo2 implements a hematopoietic programme in fibroblasts by rapidly binding to and upregulating the Hhex and Gfi1 genes within days. Moreover the reprogramming transcription factors also require extracellular BMP and MEK signalling to cooperatively effectuate reprogramming. Thus, the transcription factors that orchestrate embryonic hematopoiesis can artificially reconstitute this programme in developmentally distant fibroblasts, converting them into engraftable blood progenitors.

Date: 2016
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DOI: 10.1038/ncomms13396

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