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Effects of Congenital Erythrocytosis Related HIF2α Mutants on In Vitro Erythroid Differentiation of CD34+ Hematopoietic Stem and Progenitor Cells
Zhao Huijuan, Wang Wentian, Li Yuan, Wei Xiaojing, Yang Yang, Niu Lin, Duan Yongjuan, Hu Xiao*
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China
Abstract: The direct effects of congenital erythrocytosis related hypoxia-inducibel factor HIF2α mutations on erythroid differentiation of human hematopoietic stem and progenitor cells (HSPCs) is not clear yet， to investigate this question， we have constructed the lentiviral vectors of human HIF2α CDS and two disease related HIF2α mutants， M535V and G537R， and a reported HIF2α gain of function mutant P531A. The umbilical cord blood-derived HSPCs were infected with lentivirus carrying different HIF2α genes and induced into erythroid differentiation under 21% O2 and 5% O2 culture condition respectively. The progression of erythroid differentiation was measured by the expression of CD71 and CD235a via FACS. The results demonstrated that lentiviral vectors for HIF2α and individual mutants were successfully constructed， forced expression of HIF2α and its mutants in the CD34+ HSPCs had no detectable effect on the progression of in vitro erythroid differentiation. On the other hand， the expression of HIF2α downstream genes， such as EPOR and VEGFA， was increased modestly. We concluded that forced expression of HIF2α and the erythrocytosis related mutants does not directly enhancing in vitro erythroid differentiation， the cellular and molecular mechanisms resulting in overproducing erythroid cells in the patients require further systematic research.
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