title: Reprogramming mouse fibroblasts into engraftable myeloerythroid and lymphoid progenitors.
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.
authors.affiliation: Stem Cell and Regenerative Biology Group, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Hui
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Stem Cell and Regenerative Biology Group, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Heather Yin-Kuan
authors.initials: HY
authors.lastname: Ang
authors.affiliation: Epigenetics and Cell Fates Laboratory, Institute of Molecular and Cell Biology, Singapore 138673, Singapore.|Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore.
authors.forename: Chadi
authors.initials: C
authors.lastname: A El Farran
authors.affiliation: Stem Cell and Regenerative Biology Group, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Pin
authors.initials: P
authors.lastname: Li
authors.affiliation: Epigenetics and Cell Fates Laboratory, Institute of Molecular and Cell Biology, Singapore 138673, Singapore.
authors.forename: Hai Tong
authors.initials: HT
authors.lastname: Fang
authors.affiliation: Stem Cell and Regenerative Biology Group, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Tong Ming
authors.initials: TM
authors.lastname: Liu
authors.affiliation: Stem Cell and Regenerative Biology Group, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Say Li
authors.initials: SL
authors.lastname: Kong
authors.affiliation: Stem Cell and Regenerative Biology Group, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Michael Lingzi
authors.initials: ML
authors.lastname: Chin
authors.affiliation: Stem Cell and Regenerative Biology Group, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Wei Yin
authors.initials: WY
authors.lastname: Ling
authors.affiliation: Stem Cell and Regenerative Biology Group, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Edwin Kok Hao
authors.initials: EK
authors.lastname: Lim
authors.affiliation: Department of Molecular Pharmacology &Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Hu
authors.initials: H
authors.lastname: Li
authors.affiliation: Stem Cell and Regenerative Biology Group, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Tara
authors.initials: T
authors.lastname: Huber
authors.affiliation: Department of Developmental Biology, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Loh
authors.affiliation: Epigenetics and Cell Fates Laboratory, Institute of Molecular and Cell Biology, Singapore 138673, Singapore.|Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore.
authors.forename: Yuin-Han
authors.initials: YH
authors.lastname: Loh
authors.affiliation: Stem Cell and Regenerative Biology Group, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Bing
authors.initials: B
authors.lastname: Lim
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D065150:Cellular Reprogramming; D048049:Extracellular Signal-Regulated MAP Kinases; D005347:Fibroblasts / Q000502:physiology*; D005786:Gene Expression Regulation; D023281:Genomics; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D008533:Megakaryocytes / Q000502:physiology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D022423:Myeloid Cells / Q000502:physiology; D010586:Phagocytes / Q000502:physiology; D040081:Protein Array Analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D019485:Bone Morphogenetic Proteins; D014157:Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D000110:Acetylcholinesterase