USP10 is an essential deubiquitinase for hematopoiesis and inhibitsapoptosis of long-term hematopoietic stem cells

Masaya Higuchi, et al.

Stem Cell Reports. 2016; 7(6):1116-1129.

Speaker: Yi-Ju Chen (陳奕如)                                      Time: 14:00~15:00, May. 10, 2017

Commentator: Dr. Li-Jin Hsu (徐麗君老師)               Place: Room 601

Abstract

Hematopoietic stem cells (HSCs) are the cells that give rise to all other blood cells via the process of hematopoiesis, bestowing with the ability of both self-renewal and differentiation. Developmental studies in mouse reveals that HSCs first appear in aorta-gonad-mesonephros and placenta on embryonic day 11 and then migrate to fetal liver (FL), residing there until birth [1]. In general, after the birth, HSCs house in the bone marrow (BM) compartment, a specialized microenvironment called niche. Cells in the niche are thought to produce cytokines supporting key HSC properties. However, HSCs need to overcome apoptosis induced by fluctuation of cytokines during the migration from one niche to another, such as from placenta to FL. Ubiquitin-specific peptidase 10 (USP10) has been shown to be an anti-stress factor under several conditions [2]. In this study, the authors generated USP10-knockout (KO) mice to investigate the correlation between USP10 and HSCs development. They observed that USP10-KO mice failed to develop BM coupled with pancytopenia resulting from enhanced apoptosis in hematopoietic stem/progenitor cells (HSPCs), especially thelong-term HSCs (LT-HSCs). To dissect the HSC activity in USP10-KO mice is either caused by defects in HSCs or by the environment, the authors transplanted USP10-competent BM cells into USP10-KO mice. Their results suggested that the transplanted materials efficiently reconstituted multi-lineage hematopoiesis in recipient USP10-KO mice. Since studies have indicated that hematopoietic cells can grow and expand in HSC growth-promoting cytokines [3], the authors then cultured HSCs from USP10-KO cells in cytokine-low medium to examine if cytokine-deprivation could induce cell death. Their data showed that cytokine deprivation induced higher levels of apoptosis in HSCs from USP10-KO mice, but the apoptosis could be overcome by transduction of the USP10-WT gene, but not by a deubiquitinase-defective mutant. In summary, USP10 is an essentialdeubiquitinase in hematopoiesis and functions by inhibiting apoptosis of HSPC including LT-HSCs.

References

1.    Mikkola, H.K. and S.H. Orkin, The journey of developing hematopoietic stem cells. Development, 2006. 133(19): p. 3733-44.

2.    Takahashi, M., et al., HTLV-1 Tax oncoprotein stimulates ROS production and apoptosis in T cells by interacting with USP10. Blood, 2013. 122(5): p. 715-725.

3.    Sauvageau, G., N.N. Iscove, and R.K. Humphries, In vitro and in vivo expansion of hematopoietic stem cells. Oncogene, 2004. 23(43): p. 7223-7232.