Retinoid X receptor promotes hematopoietic stem cell fitness and quiescence and preserves hematopoietic homeostasis

Hematopoietic stem cells (HSCs) balance self-renewal and differentiation to maintain hematopoietic fitness throughout life. In steady-state conditions, HSC exhaustion is pre-vented by the maintenance of most HSCs in a quiescent state, with cells entering the cell cycle only occasionally. HSC quiescence is regulated by retinoid and fatty-acid ligands of transcriptional factors of the nuclear retinoid X receptor (RXR) family. Herein, we show that dual deficiency for hematopoietic RXR alpha and RXR beta induces HSC exhaustion, myeloid cell/megakaryocyte differentiation, and myeloproliferative-like disease. RXR alpha and RXR beta maintain HSC quiescence, survival, and chromatin compaction; moreover, transcriptome changes in RXR alpha;RXR beta-deficient HSCs include premature acquisition of an aging-like HSC signature, MYC pathway upregulation, and RNA intron retention. Fitness loss and associated RNA transcriptome and splicing alterations in RXR alpha;RXR beta-deficient HSCs are prevented by Myc haploinsufficiency. Our study reveals the critical importance of RXRs for the maintenance of HSC fitness and their protection from premature aging.

Automated summary

Hematopoietic stem cells (HSCs) maintain hematopoietic fitness by balancing self-renewal and differentiation, with retinoid X receptor (RXR) family transcription factors regulating HSC quiescence. Dual deficiency of hematopoietic RXR alpha and RXR beta leads to HSC exhaustion, myeloid cell/megakaryocyte differentiation, and myeloproliferative-like disease. RXR alpha and RXR beta maintain HSC quiescence, survival, and chromatin compaction, and their deficiency causes transcriptome changes and premature acquisition of an aging-like HSC signature in HSCs. Myc haploinsufficiency prevents fitness loss and transcriptome/splicing alterations in RXR alpha;RXR beta-deficient HSCs. This study highlights the critical importance of RXRs in maintaining HSC fitness and preventing premature aging.