title: MicroRNA-125 family members exert a similar role in the regulation of murine hematopoiesis.
abstract: MicroRNAs (miRNAs) are crucial for proper functioning of hematopoietic stem and progenitor cells (HSPCs). Members of the miRNA-125 family (consisting of miR-125a, miR-125b1, and miR-125b2) are known to confer a proliferative advantage on cells upon overexpression, to decrease the rate of apoptosis by targeting proapoptotic genes, and to promote differentiation toward the myeloid lineage in mice. However, many distinct biological effects of the three miR-125 species have been reported as well. In the current study, we set out to assess whether the three miRNA-125s that carry identical seed sequences could be functionally different. Our data show that overexpression of each of the three miR-125 family members preserves HSPCs in a primitive state in vitro, results in a competitive advantage upon serial transplantation, and promotes skewing toward the myeloid lineage. All miR-125 family members decreased the pool of phenotypically defined Lin(-)Sca(+)Kit(+)CD48(-)CD150(+) long-term hematopoietic stem cells, simultaneously increasing the self-renewal activity upon secondary transplantation. The downregulation of miR-125s in hematopoietic stem cells abolishes these effects and impairs long-term contribution to blood cell production. The introduction of a point mutation within the miRNA-125 seed sequence abolishes all abovementioned effects and leads to the restoration of normal hematopoiesis. Our results show that all miR-125 family members are similar in function, they likely operate in a seed-sequence-dependent manner, and they induce a highly comparable hematopoietic phenotype.
authors.affiliation: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands. Electronic address: e.wojtowicz@umcg.nl.
authors.forename: Edyta E
authors.initials: EE
authors.lastname: Wojtowicz
authors.affiliation: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Marta A
authors.initials: MA
authors.lastname: Walasek
authors.affiliation: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Mathilde J C
authors.initials: MJ
authors.lastname: Broekhuis
authors.affiliation: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Weersing
authors.affiliation: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Martha
authors.initials: M
authors.lastname: Ritsema
authors.affiliation: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Albertina
authors.initials: A
authors.lastname: 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, Groningen, The Netherlands.
authors.forename: Leonid V
authors.initials: LV
authors.lastname: Bystrykh
authors.affiliation: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands. Electronic address: g.de.haan@umcg.nl.
authors.forename: Gerald
authors.initials: G
authors.lastname: de Haan
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002455:Cell Division; D019070:Cell Lineage; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D005260:Female; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016297:Mutagenesis, Site-Directed; D038042:Myelopoiesis / Q000235:genetics; D009841:Oligonucleotides / Q000494:pharmacology; D017354:Point Mutation; D011828:Radiation Chimera; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; D009841:Oligonucleotides; D011993:Recombinant Fusion Proteins