Mafb Restricts M-CSF Instructed Lineage Choice in HSC

Abstract SCI-15

HSC need to enter the cycle to continuously regenerate mature blood cells in a correctly balanced ratio or to replenish the stem cell pool under stress conditions. Cell division of HSC may thus result in self-renewal divisions or the production of more differentiated progeny. Although such downstream progenitors still retain a high degree of multi-potency, recent advances in their characterization also suggest that early diversification into cells with distinct lineage bias can occur at the most primitive stem and precursor cell level. Whereas multiple cellular regulators have been identified that affect self-renewal of HSC, regulators that selectively control lineage specific commitment divisions of HSC are only beginning to be elucidated. Both transcription factor and cytokine signaling may play important roles in lineage engagement but it has been a long-standing debate, whether cytokine signaling has instructive or permissive effects on lineage commitment. In this context we reported that deficiency for the monocytic transcription factor MafB specifically sensitized HSC populations to M-CSF induced cell division and myeloid lineage commitment. We observed that MafB deficiency resulted in a specific up-regulation of the early myeloid transcription factor PU.1 and a dramatically enhanced myeloid specific repopulation activity that did not affect self-renewal or differentiation into other lineages. Our results point to a role for MafB in the maintenance of a balanced lineage potential of HSC by selectively restricting myeloid commitment divisions that give rise to PU.1⁺ progenitors in response to M-CSF signaling. Together this suggests that the potential of stem cells to produce differentiated progeny of a specific lineage bias can be subject to control by integrated cytokine/transcription factor circuits, where variation in cell intrinsic sensitivity limits like those set by MafB can render external cues such as M-CSF instructive.

Stem cell self renewal or differentiation is associated with two different types of cell divisions, namely symmetric divisions that generate two identical daughter cells, or asymmetric divisions that produce a daughter cell with maintained stem cell properties and a daughter cell committed to a specific differentiation pathway. Our observation that reduced MafB levels specifically increased M-CSF stimulated asymmetric divisions giving rise to PU.1⁻/PU.1⁺ daughter pairs provides a conclusive explanation why increased myeloid commitment of MafB^−/− HSC does not come at the expense of self-renewal or other lineages. The micro-environment can play a critical role in specifying the symmetry of cell divisions, but so far, investigations have focused on niche micro-environments that support HSC self-renewal. It is unknown whether environments also exist that support HSC commitment to specific lineages by enabling asymmetric divisions at the niche border. Using video-imaging approaches and genetic manipulation of the stem cell and stromal cell compartments we explore how cues from the microenvironment can affect asymmetric HSC division and lineage commitment.