MD, University of Antwerp
PhD, University of Antwerp
, Antwerp University Hospital
, Mount Sinai School of Medicine
Quantitative genetics of hematopoietic stem cells
The best-characterized stem cells are hematopoietic stem cells (HSC) in the bone marrow, which are responsible for the lifelong production of blood cells HSC can give rise to at least eight lineages of mature cells and can self-renew. As they differentiate, HSC progressively lose their self-renewal capacity, and generate multipotential progenitor cells, which become increasingly lineage restricted and give rise in turn to mature cells. A tight balance between the self renewal of HSC and their differentiation to specific blood cell lineages is critical for the production of normal numbers of blood cells throughout our life span. Defining the signaling pathways and transcriptional machinery regulating these events is essential to understand the control of lineage commitment within the hematopoietic system and ultimately to enable the manipulation of these decisions in HSCs both in culture and in vivo.
One way to approach the study of the regulation of HSC is quantitative genetics. We and others have shown that the HSC compartment of the mouse is subject to extensive quantitative genetic variation among inbred mouse strains. Individual variation in the quality of bone marrow donors, and in the hematopoietic response to chemotherapeutic agents suggest that the same may be true in humans. These finding raises two questions: one, what are the regulatory pathways and underlying genes that cause genetic variation in the HSC compartment, and two, what are its organismal consequences. We have shown that signaling by transforming growth factor-beta2 (TGF-b2) in HSC plays a role in the quantitative genetic variation in HSC function and is determined by locus on quantitative trait locus on chr. 4. The signaling mechanism of TGF-b2 in HSC clearly differs from that of other TGF-b isoforms, as its biological effects in stem cells are different and even opposite. Furthermore, we are testing the hypothesis that genetic variation in the kinetics of HSC may affect aging of the hematopoietic system, in particular thymic involution, and perhaps organismal aging.
Generation of thymic epithelial cells from embryonic stem (ES) cells
ES cells are derived from the inner cell mass of the blastocyst and can be maintained in a pluripotent state in defined conditions in both human and mouse. The capacity of embryonic stem (ES) cells to differentiate and generate diverse cell types in culture together with the access to virtually unlimited numbers of tissue-specific progenitors in these differentiation cultures provides a novel source of cells for cell replacement therapy. Furthermore, the recent discovery that adult, somatic cells can be reprogrammed using a relatively simple procedure to a pluripotent state (induced pluripotent cells, or iPS cells) opens the way for the generation of patient-specific ES cells, which would overcome rejection problems associated with transplantation of ES cell-derived tissues. The thymus is required for the development of T cells from very early hematopoietic precursors, which continuously seed this organ from the bone marrow. Before and during adolescence, the thymus begins to involute, and the production of naive T cells decreases. While thymic involution in young individuals is likely under evolutionary selection and therefore probably beneficial, further thymic involution in old individuals may be detrimental to health, and perhaps to longevity. It is widely hypothesized that improving thymic function in the elderly will increase health, and perhaps extend life span. We are therefore developing approaches to generate functional thymic tissue from embryonic stem cells.
B cell development
Because many of studies on the genetic regulation of HSCs suggested a strong genetic link between function of HSCs and aging, we developed an interest in B cell development, and into how B cell development changes with age. The aged immune system is characterized by a state of immune dysregulation, decreased cellular immune responses, vaccine failure, high titers of autoantibodies, vigourous humoral immune responses that produce antibodies of lower affinity than in young individuals, and a typical spectrum of hematological malignancies including B-chronic lymphocytic leukemia and multiple myeloma. We have identified a novel B cell development program that becomes predominant with age and are in the process of determining to what extent the age-associated B cell development program may explain age-related changes in B cell development and function.
Avagyan S, Glouchkova L, Choi Y, Snoeck HW. A quantitative trait locus on chr.4 affects cycling of hematopoietic stem and progenitor cells through regulation of transforming growth factor-beta 2 responsiveness. J. Immunol 2008;.
Ginhoux F, Collin MP, Bogunovic M, Abel M, Leboeuf M, Helft J, Ochando J, Kissenpfennig A, Malissen B, Grisotto M, Snoeck H, Randolph G, Merad M. Blood-derived dermal langerin+ dendritic cells survey the skin in the steady state. J Exp Med 2007; 204: 3133-3146.
Langer JL, Kumar R, Snoeck HW. Age-related accumulation of a novel CD44+CD25low gd T cell population in the hematopoietic organs of the mouse. J Gerontol A Biol Sci 2006; 61(6): 568-571.
Kumar R, Langer JC, Snoeck HW. Transforming growth factor-beta2 is involved in quantitative genetic variation in thymic involution. Blood 2006; 107: 1974-1979.
Langer JC, Henckaerts E, Orenstein J, Snoeck HW. Quantitative trait analysis reveals transforming growth factor-beta2 as a positive regulator of early hematopoietic progenitor and stem cell function.. J Exp Med 2004 Jan; 199(1): 5-14.
Henckaerts E, Langer JC, Snoeck HW. Quantitative genetic variation in the hematopoietic stem cell and progenitor cell compartment and in lifespan are closely linked at multiple loci in BXD recombinant inbred mice.. Blood 2004 Jul; 104(2): 374-9.
Henckaerts E, Langer JC, Orenstein J, Snoeck HW. The positive regulatory effect of TGF-beta2 on primitive murine hemopoietic stem and progenitor cells is dependent on age, genetic background, and serum factors. J Immunol 2004 Aug; 173(4): 2486-93.