Transcription factor Nkx2-3 maintains the self-renewal of hematopoietic stem cells by regulating mitophagy.

Hematopoietic stem cells (HSCs) reside at the top of the hematopoietic hierarchy, exhibiting a unique capacity to self-renew and differentiate into all blood cells throughout the lifetime. However, how to prevent HSC exhaustion during long-term hematopoietic output is not fully understood. Here, we show that the homeobox transcription factor Nkx2-3 is required for HSC self-renewal by preserving metabolic fitness. We found that Nkx2-3 is preferentially expressed in HSCs with excessive regenerative potential. Mice with conditional deletion of Nkx2-3 displayed a reduced HSC pool and long-term repopulating capacity as well as increased sensitivity to irradiation and 5-flurouracil treatment due to impaired HSC quiescence. In contrast, overexpression of Nkx2-3 improved HSC function both in vitro and in vivo. Furthermore, mechanistic studies revealed that Nkx2-3 can directly control the transcription of the critical mitophagy regulator ULK1, which is essential for sustaining metabolic homeostasis in HSCs by clearing activated mitochondria. More importantly, a similar regulatory role of NKX2-3 was observed in human cord blood-derived HSCs. In conclusion, our data demonstrate an important role of the Nkx2-3/ULK1/mitophagy axis in regulating the self-renewal of HSCs, therefore providing a promising strategy to improve the function of HSCs in the clinic. © 2023. The Author(s), under exclusive licence to Springer Nature Limited.

Citation

Mengjia Hu, Naicheng Chen, Mo Chen, Fang Chen, Yukai Lu, Yang Xu, Lijing Yang, Hao Zeng, Mingqiang Shen, Xuehong Chen, Shilei Chen, Fengchao Wang, Song Wang, Junping Wang. Transcription factor Nkx2-3 maintains the self-renewal of hematopoietic stem cells by regulating mitophagy. Leukemia. 2023 Jun;37(6):1361-1374

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PMID: 37095209

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