Retinoid X receptor promotes hematopoietic stem cell fitness and quiescence and preserves hematopoietic homesotasis [Single Cells]

Hematopoietic stem cells (HSCs) balance self-renewal and differentiation to maintain hematopoietic fitness throughout life. In steady-state conditions, HSC exhaustion is prevented 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. Here, we show that dual deficiency for hematopoietic RXRa and RXRb induces HSC exhaustion, myeloid cell/megakaryocyte differentiation, and myeloproliferative-like disease. RXRa and RXRb maintain HSC quiescence, survival, and chromatin compaction; moreover, transcriptome changes in RXRa;RXRb-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 RXRa;RXRb-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. snRNA-seq of mouse LSKs using 10x Genomics 3' v2.

造血干细胞（Hematopoietic stem cells, HSCs）通过调控自我更新与分化的动态平衡，终生维持造血适配功能。稳态条件下，多数HSCs处于静息状态，仅偶有细胞进入细胞周期，从而避免造血干细胞耗竭。造血干细胞的静息状态受核维甲酸X受体（nuclear retinoid X receptor, RXR）家族转录因子的维甲酸类与脂肪酸配体调控。本研究发现，造血系统中RXRα与RXRβ的双缺陷会诱导造血干细胞耗竭、髓系细胞/巨核细胞分化异常以及类骨髓增生性疾病。RXRα与RXRβ可维持造血干细胞的静息状态、存活能力及染色质致密性；此外，RXRα;RXRβ缺陷型造血干细胞的转录组变化包括过早获得衰老样造血干细胞特征、MYC通路激活以及RNA内含子滞留。MYC基因单倍剂量不足可阻断RXRα;RXRβ缺陷型造血干细胞的适配能力丧失，以及伴随出现的转录组与剪接异常。本研究揭示了RXR家族在维持造血干细胞适配能力以及抵御其过早衰老过程中的关键作用。本研究采用10x Genomics 3' v2试剂盒对小鼠LSK细胞开展单细胞核RNA测序（snRNA-seq）。