title: IGF binding protein 2 supports the survival and cycling of hematopoietic stem cells.
abstract: The role of IGF binding protein 2 (IGFBP2) in cell growth is intriguing and largely undefined. Previously we identified IGFBP2 as an extrinsic factor that supports ex vivo expansion of hematopoietic stem cells (HSCs). Here we showed that IGFBP2-null mice have fewer HSCs than wild-type mice. While IGFBP2 has little cell-autonomous effect on HSC function, we found decreased in vivo repopulation of HSCs in primary and secondary transplanted IGFBP2-null recipients. Importantly, bone marrow stromal cells that are deficient for IGFBP2 have significantly decreased ability to support the expansion of repopulating HSCs. To investigate the mechanism by which IGFBP2 supports HSC activity, we demonstrated that HSCs in IGFBP2-null mice had decreased survival and cycling, down-regulated expression of antiapoptotic factor Bcl-2, and up-regulated expression of cell cycle inhibitors p21, p16, p19, p57, and PTEN. Moreover, we found that the C-terminus, but not the RGD domain, of extrinsic IGFBP2 was essential for support of HSC activity. Defective signaling of the IGF type I receptor did not rescue the decreased repopulation of HSCs in IGFBP2-null recipients, suggesting that the environmental effect of IGFBP2 on HSCs is independent of IGF-IR mediated signaling. Therefore, as an environmental factor, IGFBP2 supports the survival and cycling of HSCs.
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Hoangdinh
authors.initials: H
authors.lastname: Huynh
authors.forename: Junke
authors.initials: J
authors.lastname: Zheng
authors.forename: Masato
authors.initials: M
authors.lastname: Umikawa
authors.forename: Chaozheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Robert
authors.initials: R
authors.lastname: Silvany
authors.forename: Satoru
authors.initials: S
authors.lastname: Iizuka
authors.forename: Martin
authors.initials: M
authors.lastname: Holzenberger
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Cheng Cheng
authors.initials: CC
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002452:Cell Count; D002453:Cell Cycle; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D018971:Insulin-Like Growth Factor Binding Protein 2; D019253:Proto-Oncogene Proteins c-bcl-2; D017526:Receptor, IGF Type 1; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse