Hui Cheng1,*, Heather Yin-Kuan Ang1,*, Chadi A. EL Farran2,3 , Pin Li1 , Hai Tong Fang2 , Tong Ming Liu1, Say Li Kong1 , Michael Lingzi Chin1 , Wei Yin Ling1, Edwin Kok Hao Lim1, Hu Li4 , Tara Huber1 , Kyle M. Loh5 , Yuin-Han Loh2,3 & Bing Lim1,^
1 Stem Cell and Regenerative Biology Group, Genome Institute of Singapore, Singapore 138672, Singapore.
2 Epigenetics and Cell Fates Laboratory, Institute of Molecular and Cell Biology, Singapore 138673, Singapore.
3 Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore.
4 Department of Molecular Pharmacology & Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
5 Department of Developmental Biology, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
* These authors equally contributed to this work.
^ Present address: Translational Medicine Research Center, Merck Research Laboratories, Singapore 138665, Singapore.
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Published online in Nature Communications on 21 November 2016.
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 þ 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 þ 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.
Figure Legend: Scl, Lmo2, Runx1might act as ‘lineage commitment’ regulators whereas Bmi1 or Hoxb4 mightbe ‘self-renewal’ factors in HSC development. The hematopoieticreprograming activity of these transcription factors also jointly requiresextracellular signals mediated through the BMP and MEK cascades. Finally,Lmo2 activates other hematopoietic transcription factors (for example, Gfi1and Hhex) to drive iHP reprogramming.
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