Complementary and Independent Function for Hoxb4 and Bmi1 in HSC Activity

Self-renewal implies the coordination between cell division and fate such that for at least one progeny, cell differentiation, proliferative senescence, and apoptosis are excluded.In contrast to mouse embryonic stem cells that undergo symmetrical self-renewal divisions in response to leukemia inhibitory factor (LIF) and bone morphogenetic protein (BMP) signaling, most adult stem cells have the capacity to undergo two distinct types of self-renewal divisions: symmetrical and asymmetrical (Shen et al. 2002).In the hematopoietic system, HSCs undergo at least two rounds of mobilization that largely overlap with changes in proliferative status: Indeed, most HSCs are in cycle and symmetrically self-renew (thus expand) at a specific time in the mouse fetal liver (FL) and they then switch to a more quiescent program later in the bone marrow environment where the population is maintained for the entire life of the animal (no expansion, but maintenance of the population).Whether this maintenance phase is established by a balance between symmetrical self-renewal and stem cell loss, by asymmetric self-renewal division, or a combination of these processes remains unclear.In adult mice, HSC symmetrical self-renewal divisions can be experimentally triggered (reactivation of an embryonic program?) under specific conditions such as during the early phase following HSC transplantation (Pawliuk et al. 1996;Antonchuk et al. 2001), and this can be dramatically enhanced upon the engineered overexpression of the Hoxb4 transcription factor or other homeobox genes (Sauvageau et al. 1995;Thorsteinsdottir et al. 1999Thorsteinsdottir et al. , 2002;;Antonchuk et al. 2001Antonchuk et al. , 2002;;Krosl et al. 2003;Cellot et al. 2007;Ohta et al. 2007).Recent studies have documented that at least two different stem cell populations with more or less equal dif-ferentiation potential can be prospectively isolated.These include the long-term repopulating hematopoietic stem cells (LTR-HSCs) that supply hematopoiesis for the life span of the animal and the short-term repopulating HSCs (STR-HSCs) that contribute to repopulation for up to 3 months after transplantation (Morrison et al. 1997;Christensen and Weissman 2001;Wognum et al. 2003).Until recently, however, this property of short-term versus long-term repopulation was limited to phenotypically defined populations, but new studies have validated, at the single-cell level, the concept that the HSC compartment is highly heterogeneous and includes STR-HSCs and LTR-HSCs (Dykstra et al. 2007; N.N.Iscove, pers.comm.).In these studies, single STR-HSCs could provide multilineage reconstitution for up to 3-4 months posttransplantation, whereas LTR-HSCs contributed to lifelong repopulation.This level of blood cell production, estimated at above 10 12 progeny per STR-HSC, argues that these cells can extensively self-renew, thus introducing the notion (of N.N.Iscove) that it is the ability to sustain self-renewal rather than self-renewal itself that distinguishes LTR-HSCs from STR-HSCs.Together, these data suggest the existence of two mandatory components that define self-renewal (SR) in LTR-HSCs: one that coordinates fate with cell division (referred to as "execution of SR") and one that ensures the sustainability of this execution through cell divisions (referred to as "sustainability of SR").Several observations suggest that although Hoxb4 overexpression enhances the execution of SR in defined conditions, the Polycomb group (PcG) gene Bmi1 may be critical for regulating the sustainability of this process.Indeed, by phenotypical analysis, Bmi1 -/-HSCs are present in normal Complementary and Independent Function for Hoxb4 and Bmi1 in HSC Activity

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