Investigating the role of ZMIZ1 in hematopoiesis 2688

Description Hematopoietic stem cells (HSCs) sustain blood cell production across all lineages throughout the lifespan. For HSCs to maintain this vital function, they must possess both self-renewal capacity and multipotent differentiation potential. Understanding the mechanisms that enable and regulate this process is crucial for advancing treatments for hematopoietic disorders and immunodeficiencies via HSC transplantation. This study investigates the mechanisms of HSC regulation through studying the role of ZMIZ1, a zinc finger protein that functions as a transcriptional co-regulator, in hematopoiesis. Using a global conditional Zmiz1 knockout model, we observed impaired B-cell lymphopoiesis, characterized by reductions of B cell populations in the bone marrow and spleen as well as reduced expression of B cell supportive cytokines. Specific depletion of ZMIZ1 in HSCs resulted in no observable phenotypic changes to the blood cell compartment under steady state conditions. However, competitive transplantation of these ZMIZ1-depleted HSCs into lethally irradiated mice, alongside wild-type HSCs, revealed a reduced reconstitution capacity in ZMIZ1-deficient HSCs. Despite this, B-cell compartments derived from these ZMIZ1-depleted HSCs exhibit no observable deficits. These findings support the hypothesis that ZMIZ1 plays an intrinsic role in promoting HSC self-renewal and an extrinsic role in the B-cell supportive niche within the bone marrow.