Regulation of Hematopoietic Stem and Progenitor Cells by Bone Marrow Niche Components
Research output: Thesis › Doctoral Thesis (compilation)
Throughout the lifespan of an individual, enormous numbers of mature blood cells are generated by hematopoietic stem cells (HSCs) in the bone marrow (BM). The HSC is a cell that can self-renew to maintain the HSC pool and differentiate into all types of mature blood cells. HSCs can also be mobilized out of the BM into blood and can be isolated from different sources including mobilized blood, umbilical cord blood, BM and fetal liver for clinical and experimental purposes. HSCs are widely used as an effective therapy for treatment of hematopoietic and some non-hematopoietic diseases. HSCs reside and develop in the BM in specialized microenvironments, termed niches. However, specific niche components and the molecular mechanisms underlying the regulation of HSC self-renewal, differentiation and migration by the niche remain poorly defined. In the present thesis, we have analysed the interactions of hematopoietic stem and progenitor cells (HSPCs) with niche components and their role in the regulation of HSC migration, self-renewal and differentiation. Specifically, the functional role of integrin receptors in HSPC migration and the role of the blood cell growth factor thrombopoietin (THPO) in HSC maintenance during hematopoietic cell development and after transplantation have been studied. By using both function-blocking antibodies and integrin alpha6 gene-deleted embryos in a mouse transplantation model, we have found that integrin alpha6 receptor, highly expressed on HSPCs, is important for homing of adult HSCs and HPCs to BM in vivo. Furthermore, we have shown that integrin alpha6 receptor is not involved in fetal liver HSC homing and engraftment, whereas it plays a role in fetal liver HPC homing. Importantly, alpha4 was found to be essential for both adult BM and fetal liver HSC and HPC homing. By using functional assays and phenotypic HSC analysis of Thpo-/- mice, we demonstrated that THPO is critically involved in postnatal and post-transplantation HSC maintenance. The distinct role of THPO in postnatal HSC maintenance was accompanied by accelerated HSC cell cycle kinetics in Thpo-/- mice and reduced expression of cyclin-dependent kinases p57Kip2 and p19INK4D. Taken together, we have for the first time provided the evidence that integrin alpha6 functions as a homing receptor for BM HSPCs and fetal liver HPCs, and that THPO regulates the maintenance of postnatal quiescent HSCs, of critical importance to avoid postnatal HSC exhaustion. Notably, our studies on functions of integrin alpha6 and THPO in HSCs emphasize ontogeny related differences in HSC regulation.
|Research areas and keywords||
Subject classification (UKÄ) – MANDATORY
|Award date||2007 Jun 13|
|Publication status||Published - 2007|
Defence details Date: 2007-06-13 Time: 13:00 Place: Segerfalk lecture hall, BMC, Lund External reviewer(s) Name: Lapidot, Tsvee Title: professor Affiliation: The Weizmann Institute of Science,Israel ---
Hong Qian, Karl Tryggvason, Sten Eirik Jacobsen and Marja Ekblom. 2006. Contribution of alpha6-integrins to hematopoietic stem and progenitor cell homing to bone marrow and collaboration with alpha4-integrins, Blood, vol 107 pp 3503-3510.
Hong Qian, Elisabeth Georges-labouesse, Anna Domogatskaya, Karl Tryggvason, Sten Eirik W Jacobsen and Marja Ekblom. 2007. Distinct roles of integrins alpha6 and alpha4 in fetal liver hematopoietic stem and progenitor cell homing. Blood, (submitted)
Hong Qian, Natalija Buza-Vidas, Jennifer Antonchuk, Robert Månsson, Lina A Thoren, Marja Ekblom and Sten Eirik W Jacobsen. 2007. Critical role of thrombopoietin in maintaining postnatal quiescent HSCs. (submitted)The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Hematopoietic Stem Cell Laboratory (013022012)