Huang Jinbo, Ge Meili, Lu Shihong, Shi Jun, Yu Wei, Li Xingxin, Wang Min, Zhang Jizhou, Feng Sizhou, Dong Shuxu, Cheng Xuelian, Zheng Yizhou
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, P.R. China.
PLoS One. 2016 Mar 1;11(3):e0149586. doi: 10.1371/journal.pone.0149586. eCollection 2016.
Aplastic anemia (AA) is a bone marrow failure syndrome that is caused largely by profound quantitative and qualitative defects of hematopoietic stem and progenitor cells. However, the mechanisms underlying these defects remain unclear. Under conditions of stress, autophagy acts as a protective mechanism for cells. We therefore postulated that autophagy in CD34+ hematopoietic progenitor cells (HPCs) from AA patients might be impaired and play a role in the pathogenesis of AA. To test this hypothesis, we tested autophagy in CD34+ cells from AA samples and healthy controls and investigated the effect of autophagy on the survival of adult human bone marrow CD34+ cells. We found that the level of autophagy in CD34+ cells from AA patients was significantly lower than in age/sex-matched healthy controls, and lower in cases of severe AA than in those with non-severe AA. Autophagy in CD34+ cells improved upon amelioration of AA but, compared to healthy controls, was still significantly reduced even in AA patients who had achieved a complete, long-term response. We also showed that although the basal autophagy in CD34+ cells was low, the autophagic response of CD34+ cells to "adversity" was rapid. Finally, impaired autophagy resulted in reduced differentiation and proliferation of CD34+ cells and sensitized them to death and apoptosis. Thus, our results confirm that autophagy in CD34+ cells from AA patients is impaired, that autophagy is required for the survival of CD34+ cells, and that impaired autophagy in CD34+ HPCs may play an important role in the pathogenesis of AA.
再生障碍性贫血（AA）是一种骨髓衰竭综合征，主要由造血干细胞和祖细胞在数量和质量上的严重缺陷引起。然而，这些缺陷背后的机制仍不清楚。在应激条件下，自噬作为细胞的一种保护机制。因此，我们推测AA患者CD34+造血祖细胞（HPCs）中的自噬可能受损，并在AA的发病机制中起作用。为了验证这一假设，我们检测了AA样本和健康对照中CD34+细胞的自噬，并研究了自噬对成人骨髓CD34+细胞存活的影响。我们发现，AA患者CD34+细胞中的自噬水平显著低于年龄/性别匹配的健康对照，重度AA患者低于非重度AA患者。AA病情改善后，CD34+细胞中的自噬有所改善，但与健康对照相比，即使是已实现完全长期缓解的AA患者，其自噬水平仍显著降低。我们还表明，尽管CD34+细胞中的基础自噬水平较低，但CD34+细胞对“逆境”的自噬反应迅速。最后，自噬受损导致CD34+细胞的分化和增殖减少，并使它们对死亡和凋亡敏感。因此，我们的结果证实，AA患者CD34+细胞中的自噬受损，CD34+细胞的存活需要自噬，并且CD34+ HPCs中的自噬受损可能在AA的发病机制中起重要作用。
