A genetic anemia disentangles the dual effect of chronically reduced thrombopoietin on hematopoietic stem cells and bone marrow niche
Aprile, A.; Malara, A.; Storto, M.; Gulino, A.; Cancila, V.; Morello, G.; Sighinolfi, S.; Raggi, L.; Beretta, S.; Merelli, I.; Marktel, S.; Ponzoni, M.; Tripodo, C.; Balduini, A.; Ferrari, G.
Show abstract
Many studies unraveled the reciprocal regulation between hematopoietic stem cells (HSC) and the bone marrow (BM) niche by using transgenic knock-out or reporter mice, often overlooking the pathophysiological relevance and the existence of compensatory mechanisms. Here, we exploit the th3 murine model of a genetic anemia, beta-thalassemia (BThal), to investigate the dual impact of chronically reduced thrombopoietin (TPO) production on HSC and megakaryocytic BM niche. Decreased systemic TPO downregulates stemness programs in HSC and impairs their commitment towards megakaryocytes (Mk). We uncover dysmegakaryopoiesis in the BM from BThal patients and mice with defective Mk maturation and reduced production of niche factors, altering the HSC-niche crosstalk. Notably, in vivo stimulation of the TPO signaling restores HSC quiescence, Mk maturation and niche support. These findings demonstrate that TPO regulates HSC through both direct and niche-mediated routes, underscoring the value of using a genetic disease model to disentangle general molecular mechanisms.
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