The Role Of APC/C On Hematopoietic Stem Cells And Its Significance On Aplastic Anemia

The cell cycle profile of hematopoietic stem cell（HSC）is different.Most HSC remain quiescent for avoiding HSC exhaustion and only a few HSC enter into cell cycle for organism requirements.So cell cycle is necessary for maintenance of HSC characteristic status and function.APC/C is usually regarded as a key regulator of mitosis.As an E3 ubiquitin ligase,it regulates the mitosis process and conducts non-mitotic functions through degradation for the specific substrates.So this study researched on the role of APC/C on hematopoietic system and its significance on aplastic anemia.Thank to Apc2^flox/flox transgenic mouse and Mx1-Cre transgenic mouse,this study established an APC/C-function-loss mouse model(Apc2^flox/floxMx1-Cre transgenic mouse).Through this transgenic mouse,this study found that hematopoietic cells dramatically decreased and hepatocytes re-entered into cell cycle but arrested in metaphase after the absence of APC/C function,which caused the mouse dead.For avoiding the disturbance of abnormal liver founction,this study designed an Apc2^flox/floxMx1-Cre/WT BM-chimeric transgenic mouse,which also displayed that the peripheral blood cells derived from Apc2^flox/floxMx1-Cre greatly decreased after the abscence of APC/C function,suggesting that the abscence of APC/C function primarily resulting in bone marrow failure.This study analyzed the characteristics of hematopoietic cells derease in details and found that the cells firstly decreased at the metaphysis,gradually spreaded to diaphysis and almost disappeared at the seventh day after induction.What’s more,the LSK（Lin^-Sca-1⁺c-Kit⁺）cells disappeared at the third day after induction and they also lost their colony-forming ability after induction.These results revealed that APC/C was indispensible for HSC to maintain cell cycle.Besides,after the abscence of APC/C function,only a few c-Kit positive cells could be detected in the core area of diaphysis and no dorment HSC（d-HSC）could be detected in the whold bone.These findings as well as the phenomenon of increased mitotic hepatocytes suggested that APC/C helped HSC keep quiescence.The absence of APC/C function caused bone marrow failure in this study,suggesting APC/C may be related with bone marrow failure diseases such as aplastic anemia.So this study detected if APC2 was expressed in CD34 positive cells of aplastic anemia bone marrow biopsy section through immunohistochemistry double stain.The result showed that APC2 was negative in most of cases,suggesting that there exited the absence of APC/C function in aplastic anemia.In summary,this study revealed that APC/C was indispensible for HSC cell cycle and stabilized HSC quiescence.And it found that APC/C function may be related to the pathophysiological process of aplasitc anemia.All of these findings would shed new light on the pathogenic mechanism and therapy of bone marrow failure diseases.