Cellular and Molecular Pathways Governing Hematopoietic Stem Cell Fate
Research output: Thesis › Doctoral Thesis (compilation)
Hematopoietic Stem Cells (HSCs) have been defined to have abilities of both self-renewal and multi-lineage differen-tiation. The balance between these abilities is rigorously controlled under steady-state status (homeostasis) and when the normal processes of self-renewal and differentiation become deregulated, a disorder of blood system (such as leukemias) can occur. HSCs are enriched in lineage negative (Lin-), SCA-1 positive and c-KIT positive (LSK) cells in mouse bone marrow (BM), as well as in the Lin(-)CD34(+) cells in human BM or cord blood. However, the LSK compartment is heterogeneous, containing long-term (LT) and short-term (ST) self-renewing HSCs as well as non-self-renewing multipotent progen-itors (MPPs) and demanding further subfractionation of this population to allow for detailed functional investiga-tions. Even though these different subpopulations are phenotypically and functionally characterized, it is still poorly understood how LT-HSCs make a cell fate decision to differentiate into ST-HSCs and further to MPPs, as well as how the cellular and molecular pathways regulate HSC fate decisions. In this thesis, we identified two distinct subpopulations within BM and fetal liver LSK compartment: ST-HSC population identified as LSKCD34(+/hi)FLT3(-) cells and lymphoid primed multipotent progenitors (termed LMPPs) represented by LSKCD34(+)FLT3(hi) cells. LSKCD34(+/hi)FLT3(-) cells are capable of rapid but short-term reconstitution, high colony-forming units-spleen (CFU-S) and radio-protective activities while LSKCD34(+)FLT3(hi) cells can give rise to lymphoid and myeloid cells but have no self-renewal activity and little or no megakaryocytic-erythrocytic (MkE) potentials. This was further supported by gene expression analysis revealing a modulation of genetic programs in the transition from the ST-HSC to the LMPP, with down-regulation of MkE and up-regulation of lymphoid gene programs. The work has also investigated the regulatory roles of extrinsic modulators on HSC function. We found that HSC self-renewal is negatively regulated by activation of the IFN-gamma and Fas pathways, through the promotion of HSC differentiation.
|Research areas and keywords||
Subject classification (UKÄ) – MANDATORY
|Award date||2006 Jan 21|
|Publication status||Published - 2006|
Defence details Date: 2006-01-21 Time: 10:00 Place: Segerfalksalen, BMC, Lund External reviewer(s) Name: Spangrude, Gerald Title: Professor Affiliation: University of Utah School of Medicine, USA ---
L Yang, D Bryder, J Adolfsson, J Nygren, R Mansson, M Sigvardsson and SEW Jacobsen. 2005. Identification of Lin-Sca1+kit+ CD34+Flt3- short-term hematopoietic stem cells capable of rapidly reconstituting and rescuing myeloablated recipients. Blood, vol 105 pp 2717-23.
J Adolfsson, R Mansson, NB Vidas, A Hultquist, K Liuba, CT Jensen, D Bryder, L Yang, OJ Borge, L Thoren, K Andersson, E Sitnicka, Y Sasaki, M Sigvardsson and SEW Jacobsen. 2005. Identification of Flt3+ lympho-myeloid stem cells lacking erythro- megakaryocytic potential: A revised road map for adult blood lineage commitment. Cell, vol 121 pp 295-306.
L Yang, A Hultquist, R Mansson, S Luc, K Liuba, L Thoren, J Adolfsson, N Buza-Vidas, Q Hong, T Enver, M Sigvardsson and SEW Jacobsen. . Biological and genetic evidence for a hierarchical organisation of lineage potentials conserved in fetal and adult hematopoietic stem cells. (manuscript)
L Yang, I Dybedal, D Bryder, L Nilsson, E Sitnicka, Y Sasaki and SEW Jacobsen. 2005. Interferon-gamma negatively modulates self-renewal of repopulating human hematopoietic stem cells. J Immunol, vol 174 pp 752-7.
I Dybedal, L Yang, D Bryder, I Aastrand-Grundstrom, K Leandersson and SEW Jacobsen. 2003. Human reconstituting hematopoietic stem cells up-regulate Fas expression upon active cell cycling but remain resistant to Fas-induced suppression. Blood, vol 102 pp 118-26.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)