title: Reduced lymphoid lineage priming promotes human hematopoietic stem cell expansion.
abstract: The hematopoietic system sustains regeneration throughout life by balancing self-renewal and differentiation. To stay poised for mature blood production, hematopoietic stem cells (HSCs) maintain low-level expression of lineage-associated genes, a process termed lineage priming. Here, we modulated expression levels of Inhibitor of DNA binding (ID) proteins to ask whether lineage priming affects self-renewal of human HSCs. We found that lentiviral overexpression of ID proteins in cord blood HSCs biases myeloerythroid commitment at the expense of lymphoid differentiation. Conversely, reducing ID2 expression levels increases lymphoid potential. Mechanistically, ID2 inhibits the transcription factor E47 to attenuate B-lymphoid priming in HSCs and progenitors. Strikingly, ID2 overexpression also results in a 10-fold expansion of HSCs in serial limiting dilution assays, indicating that early lymphoid transcription factors antagonize human HSC self-renewal. The relationship between lineage priming and self-renewal can be exploited to increase expansion of transplantable human HSCs and points to broader implications for other stem cell populations.
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: van Galen
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Antonija
authors.initials: A
authors.lastname: Kreso
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Erno
authors.initials: E
authors.lastname: Wienholds
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Elisa
authors.initials: E
authors.lastname: Laurenti
authors.affiliation: Department of Pediatrics, McGill University and the Research Institute of the McGill University Health Centre, Westmount, QC H3Z 2Z3, Canada.
authors.forename: Kolja
authors.initials: K
authors.lastname: Eppert
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Lechman
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Nathan
authors.initials: N
authors.lastname: Mbong
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Karin
authors.initials: K
authors.lastname: Hermans
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dobson
authors.affiliation: Illumina, San Diego, CA 92122, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: April
authors.affiliation: Illumina, San Diego, CA 92122, USA.
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Fan
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada. Electronic address: jdick@uhnres.utoronto.ca.
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058127:Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D015415:Biomarkers; C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2; D012333:RNA, Messenger; D058127:Transcription Factor 3