Maria Rosa Lidonnici, Giulia Chianella, Nicole Mende et al. Imbalanced TGF-beta signalling and autophagy drive erythroid priming of hematopoietic stem cells in Beta-thalassemia.
Maria Rosa Lidonnici, Giulia Chianella, Nicole Mende et al. **Imbalanced TGF-beta signalling and autophagy drive erythroid priming of hematopoietic stem cells in Beta-thalassemia.**
The hematopoietic stem cell and multipotent progenitor (HSC/MPP) pool dynamically responds to stress to adapt blood output to specific physiological demands. In beta-thalassemia (Bthal), the severe anemia and the ineffective erythropoiesis generate expansion of erythroid precursors and a chronic stress status in the bone marrow (BM) microenvironment. However, the response to the BM altered status at the level of the HSC/MPP compartment in terms of lineage commitment has not been investigated. Bulk and single-cell RNA-sequencing reveal that Bthal HSCs/MPPs are expanded and activated with an enhanced priming along the whole Ery differentiation trajectory. Consistently, HSC/MPP showed an altered TGFβ expression and autophagy transcriptional signatures along with a declined dormancy state. We discovered that the altered TGF signalling fosters the Ery potential of HSCs by reducing their autophagic activity and in vivo stimulation of autophagy is sufficient to rescue the imbalance of the HSC compartment. Our findings identify the interplay between TGFß and HSC autophagy as a key driver in the context of non-malignant hematopoiesis.
