title: Ectopic miR-125a Expression Induces Long-Term Repopulating Stem Cell Capacity in Mouse and Human Hematopoietic Progenitors.
abstract: Umbilical cord blood (CB) is a convenient and broadly used source of hematopoietic stem cells (HSCs) for allogeneic stem cell transplantation. However, limiting numbers of HSCs remain a major constraint for its clinical application. Although one feasible option would be to expand HSCs to improve therapeutic outcome, available protocols and the molecular mechanisms governing the self-renewal of HSCs are unclear. Here, we show that ectopic expression of a single microRNA (miRNA), miR-125a, in purified murine and human multipotent progenitors (MPPs) resulted in increased self-renewal and robust long-term multi-lineage repopulation in transplanted recipient mice. Using quantitative proteomics and western blot analysis, we identified a restricted set of miR-125a targets involved in conferring long-term repopulating capacity to MPPs in humans and mice. Our findings offer the innovative potential to use MPPs with enhanced self-renewal activity to augment limited sources of HSCs to improve clinical protocols.
authors.affiliation: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Antonius Deusinglaan 1, 9700 AV Groningen, the Netherlands.
authors.forename: Edyta E
authors.initials: EE
authors.lastname: Wojtowicz
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: Karin G
authors.initials: KG
authors.lastname: Hermans
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Erwin M
authors.initials: EM
authors.lastname: Schoof
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: The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Ruth
authors.initials: R
authors.lastname: Isserlin
authors.affiliation: Departments of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
authors.forename: Peter A
authors.initials: PA
authors.lastname: van Veelen
authors.affiliation: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Antonius Deusinglaan 1, 9700 AV Groningen, the Netherlands.
authors.forename: Mathilde J C
authors.initials: MJ
authors.lastname: Broekhuis
authors.affiliation: Departments of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
authors.forename: George M C
authors.initials: GM
authors.lastname: Janssen
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Aaron
authors.initials: A
authors.lastname: Trotman-Grant
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Dobson
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Krivdova
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Jantje
authors.initials: J
authors.lastname: Elzinga
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Kennedy
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Olga I
authors.initials: OI
authors.lastname: Gan
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Ankit
authors.initials: A
authors.lastname: Sinha
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ignatchenko
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kislinger
authors.affiliation: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Antonius Deusinglaan 1, 9700 AV Groningen, the Netherlands.
authors.forename: Bertien
authors.initials: B
authors.lastname: Dethmers-Ausema
authors.affiliation: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Antonius Deusinglaan 1, 9700 AV Groningen, the Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Weersing
authors.affiliation: Department of Hematology, Erasmus University Medical Center Cancer Institute, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
authors.forename: Mir Farshid
authors.initials: MF
authors.lastname: Alemdehy
authors.affiliation: Department of Hematology, Erasmus University Medical Center Cancer Institute, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
authors.forename: Hans W J
authors.initials: HW
authors.lastname: de Looper
authors.affiliation: The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bader
authors.affiliation: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Antonius Deusinglaan 1, 9700 AV Groningen, the Netherlands.
authors.forename: Martha
authors.initials: M
authors.lastname: Ritsema
authors.affiliation: Department of Immunology, Erasmus University Medical Center, Wytemaweg 80, 3015CN Rotterdam, the Netherlands.
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Erkeland
authors.affiliation: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Antonius Deusinglaan 1, 9700 AV Groningen, the Netherlands.
authors.forename: Leonid V
authors.initials: LV
authors.lastname: Bystrykh
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: jdick@uhnres.utoronto.ca.
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
authors.affiliation: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Antonius Deusinglaan 1, 9700 AV Groningen, the Netherlands. Electronic address: g.de.haan@umcg.nl.
authors.forename: Gerald
authors.initials: G
authors.lastname: de Haan
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D049109:Cell Proliferation; D000066673:Cell Self Renewal / Q000235:genetics; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D015203:Reproducibility of Results; D013997:Time Factors
chemical_list: D018952:Antigens, CD34; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; D051997:ADP-ribosyl Cyclase 1