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Blood ; 139(21): 3204-3221, 2022 05 26.
Artículo en Inglés | MEDLINE | ID: mdl-35259210

RESUMEN

Bone marrow-derived mesenchymal stem cells (BMSCs) support bone formation and constitute the stromal niche in regulating hematopoietic stem cells (HSCs). Stromal niche dysfunction affects HSC engraftment during transplantation; however, the underlying mechanisms remain elusive. In the present study, we found that all-trans retinoic acid (ATRA) and inflammation stress upregulated retinoic acid-inducible gene I (RIG-I) in BMSCs. Excess RIG-I expression damaged the clonogenicity, bone-forming ability of BMSCs and particularly their stromal niche function that supports HSC expansion in vitro and engraftment in vivo. Mechanistically, RIG-I elevation promoted the degradation of NRF2, a checkpoint for antioxidant cellular response, by altering the RIG-I-Trim25-Keap1-NRF2 complex, leading to reactive oxygen species (ROS) accumulation and BMSC damage. Genetic inhibition of RIG-I sustained NRF2 protein levels and reduced ROS levels in ATRA-treated BMSCs, thus preserving their clonogenicity, bone-forming ability, and stromal niche function in supporting HSC engraftment in mice. More importantly, RIG-I inhibition recovered the ATRA-treated stromal niche function to enhance HSC engraftment and emergency myelopoiesis for innate immunity against the bacterium Listeria monocytogenes during transplantation. Overall, we identified a noncanonical role of RIG-I in the regulation of the stromal niche for HSC transplantation.


Asunto(s)
Trasplante de Médula Ósea , Proteína 58 DEAD Box/metabolismo , Factor 2 Relacionado con NF-E2 , Animales , Células Madre Hematopoyéticas/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Ratones , Especies Reactivas de Oxígeno/metabolismo , Nicho de Células Madre/fisiología
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