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dc.contributor.advisorZhang, Chengcheng "Alec"en
dc.creatorHuynh, Hoang Dinhen
dc.date.accessioned2011-08-26T17:34:47Z
dc.date.available2011-08-26T17:34:47Z
dc.date.issued2011-08-10
dc.identifier.urihttps://hdl.handle.net/2152.5/882
dc.description.abstractSuccessful hematopoietic stem cell (HSC) transplantation is often limited by the numbers of HSCs, and robust methods to expand HSCs ex vivo are needed. We previously showed that angiopoietin-like proteins (Angptls), a group of growth factors isolated from a fetal liver HSC supportive cell population, improved ex vivo expansion of HSCs. Here we demonstrate that insulin-like growth factor binding protein 2 (IGFBP2), secreted by a tumorigenic cell line, also enhanced ex vivo expansion of mouse HSCs. As measured by competitive repopulation analyses, there was a 48-fold increase in numbers of long-term repopulating mouse HSCs after 21 days of culture. This is the first demonstration that IGFBP2 stimulates expansion or proliferation of murine stem cells. Our finding also suggests that certain cancer cells synthesize proteins that can stimulate HSC expansion. To further study the function of IGFBP2 in vivo, 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, downregulated expression of anti-apoptotic factor Bcl-2, and upregulated 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.en
dc.language.isoenen
dc.subjectHematopoietic Stem Cell Transplantationen
dc.subjectInsulin-Like Growth Factor Binding Protein 2en
dc.subjectCell Divisionen
dc.titleInsulin-Like Growth Factor-Binding Protein 2 Supports Hematopoietic Stem Cell Expansion: From In Vitro to In Vivoen
dc.typeThesisen
dc.type.materialTexten
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.nameDoctor of Philosophyen
thesis.degree.levelDoctoralen
thesis.degree.disciplineImmunologyen
thesis.date.available2013-08-10
dc.identifier.oclc758975971


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