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Imbalanced TGFβ signalling and autophagy drive erythroid priming of hematopoietic stem cells in β-thalassemia

Maria Rosa Lidonnici (), Giulia Chianella, Nicole Mende, Hugo P. Bastos, Matteo Barcella, Ivan Merelli, Mariangela Storto, Valentina Romeo, Francesca Tiboni, Samantha Scaramuzza, Claudia Rossi, Laura Raggi, Annamaria Aprile, Stefania Crippa, Deena Iskander, Irene Roberts, Anastasios Karamiditris, Julia Keith, Christophe Lechauve, Mitchell J. Weiss, Nicola K. Wilson, Berthold Göttgens, Maria Ester Bernardo, Fabio Ciceri, Alessandro Aiuti, Sarah Marktel, Elisa Laurenti and Giuliana Ferrari ()
Additional contact information
Maria Rosa Lidonnici: IRCCS San Raffaele Scientific Institute
Giulia Chianella: IRCCS San Raffaele Scientific Institute
Nicole Mende: University of Cambridge
Hugo P. Bastos: University of Cambridge
Matteo Barcella: IRCCS San Raffaele Scientific Institute
Ivan Merelli: National Research Council
Mariangela Storto: IRCCS San Raffaele Scientific Institute
Valentina Romeo: IRCCS San Raffaele Scientific Institute
Francesca Tiboni: IRCCS San Raffaele Scientific Institute
Samantha Scaramuzza: IRCCS San Raffaele Scientific Institute
Claudia Rossi: IRCCS San Raffaele Scientific Institute
Laura Raggi: IRCCS San Raffaele Scientific Institute
Annamaria Aprile: IRCCS San Raffaele Scientific Institute
Stefania Crippa: IRCCS San Raffaele Scientific Institute
Deena Iskander: Imperial College London
Irene Roberts: University of Oxford
Anastasios Karamiditris: Imperial College London
Julia Keith: St. Jude Children’s Research Hospital
Christophe Lechauve: St. Jude Children’s Research Hospital
Mitchell J. Weiss: St. Jude Children’s Research Hospital
Nicola K. Wilson: University of Cambridge
Berthold Göttgens: University of Cambridge
Maria Ester Bernardo: IRCCS San Raffaele Scientific Institute
Fabio Ciceri: IRCCS San Raffaele Scientific Institute
Alessandro Aiuti: IRCCS San Raffaele Scientific Institute
Sarah Marktel: IRCCS San Raffaele Scientific Institute
Elisa Laurenti: University of Cambridge
Giuliana Ferrari: IRCCS San Raffaele Scientific Institute

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract The hematopoietic stem cell and multipotent progenitor (HSC/MPP) pool dynamically responds to stress to adapt blood output to specific physiological demands. In β-thalassemia (Bthal), severe anemia and 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 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 TGFβ signaling fosters the Ery potential of HSCs by reducing their autophagic levels, and in vivo stimulation of autophagy is sufficient to rescue the imbalance of the HSC compartment. Our findings identify the interplay between TGFβ and HSC autophagy as a key driver in the context of non-malignant hematopoiesis.

Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60676-7

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DOI: 10.1038/s41467-025-60676-7

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