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SRC-3 is involved in maintaining hematopoietic stem cell quiescence by regulation of mitochondrial metabolism in mice

Mengjia Hu, Hao Zeng, Shilei Chen, Yang Xu, Song Wang, Yong Tang, Xinmiao Wang, Changhong Du, Mingqiang Shen, Fang Chen, Mo Chen, Cheng Wang, Jining Gao, Fengchao Wang, Yongping Su and Junping Wang

Key points

  • SRC-3 deficiency causes reduced quiescence and functional impairment of HSCs.

  • SRC-3 participates in HSC quiescence maintenance by regulating mitochondrial metabolism.

Abstract

Quiescence maintenance is an important property of hematopoietic stem cells (HSCs), while the regulatory factors and underlying mechanisms involved in HSC quiescence maintenance are not fully uncovered. Here, we show that steroid receptor coactivator 3 (SRC-3) is highly expressed in HSCs, and SRC-3-deficient HSCs are less quiescent and more proliferative, resulting in increased sensitivity to chemotherapy and irradiation. Moreover, the long-term reconstituting ability of HSCs is markedly impaired in the absence of SRC-3, and SRC-3 knockout (SRC-3-/-) mice exhibit a significant disruption of hematopoietic stem and progenitor cell homeostasis. Further investigations show that SRC-3 deficiency leads to enhanced mitochondrial metabolism, accompanied by overproduction of reactive oxygen species (ROS) in HSCs. Notably, the downstream target genes of peroxisome proliferator-activated receptor-coactivators 1 alpha (PGC-1α) involved in the regulation of mitochondrial metabolism are significantly upregulated in SRC-3-deficient HSCs. Meanwhile, a significant decrease in the expression of histone acetyltransferase GCN5 accompanied by downregulation of PGC-1α acetylation is observed in SRC-3-null HSCs. Conversely, overexpression of GCN5 can inhibit SRC-3 deficiency-induced mitochondrial metabolism enhancement and ROS overproduction, thereby evidently rescuing the impairment of HSCs in SRC-3-/- mice. Collectively, our findings demonstrate that SRC-3 plays an important role in HSC quiescence maintenance by regulating mitochondrial metabolism.

  • Submitted February 12, 2018.
  • Accepted June 25, 2018.