Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL; School of Life Science, Zhengzhou University, Zhengzhou, Henan, China.
Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL.
Exp Hematol. 2019 Oct;78:21-34.e3. doi: 10.1016/j.exphem.2019.09.021. Epub 2019 Sep 25.
Mouse models are widely used to study human erythropoiesis in vivo. One important caveat using mouse models is that mice often develop significant extramedullary erythropoiesis with anemia, which could mask important phenotypes. To overcome this drawback in mice, here we established in vitro and in vivo rat models for the studies of stress erythropoiesis. Using flow cytometry-based assays, we can monitor terminal erythropoiesis in rats during fetal and adult erythropoiesis under steady state and stress conditions. We used this system to test rat erythropoiesis under phenylhydrazine (PHZ)-induced hemolytic stress. In contrast to mice, rats did not have an increased proportion of early-stage erythroid precursors during terminal differentiation in the spleen or bone marrow. This could be explained by the abundant bone marrow spaces in rats that allow sufficient erythroid proliferation under stress. Consistently, the extent of splenomegaly in rats after PHZ treatment was significantly lower than that in mice. The level of BMP4, which was significantly increased in mouse spleen after PHZ treatment, remained unchanged in rat spleen. We further demonstrated that the bone marrow c-Kit positive progenitor population underwent a phenotype shift and became more CD71 positive and erythroid skewed with the expression of maturing erythroid markers under stress in rats and humans. In contrast, the phenotype shift to an erythroid-skewed progenitor population in mice occurred mainly in the spleen. Our study establishes rat in vitro and in vivo erythropoiesis models that are more appropriate and superior for the study of human stress erythropoiesis than mouse models.
小鼠模型广泛用于研究体内人类红细胞生成。使用小鼠模型的一个重要注意事项是，小鼠常因贫血而发生显著的骨髓外红细胞生成，这可能掩盖重要的表型。为了克服小鼠模型中的这一缺陷，我们在这里建立了体外和体内大鼠模型，用于研究应激性红细胞生成。通过基于流式细胞术的检测，我们可以在稳态和应激条件下监测大鼠胎儿和成年期红细胞生成过程中的终末红细胞生成。我们使用该系统测试了苯肼（PHZ）诱导的溶血性应激下大鼠的红细胞生成。与小鼠不同，大鼠在脾或骨髓中的终末分化过程中，早期红系前体细胞的比例没有增加。这可以用大鼠骨髓空间丰富来解释，在应激下允许足够的红细胞增殖。一致地，PHZ 处理后大鼠的脾肿大程度明显低于小鼠。PHZ 处理后小鼠脾脏中 BMP4 的水平显著增加，但在大鼠脾脏中保持不变。我们进一步证明，在大鼠和人类中，骨髓 c-Kit 阳性祖细胞群体在应激下经历表型转变，变得更 CD71 阳性和红细胞偏向，表达成熟的红细胞标记物。相比之下，小鼠中向红细胞偏向祖细胞群体的表型转变主要发生在脾脏中。我们的研究建立了大鼠体外和体内红细胞生成模型，这些模型比小鼠模型更适合和优越，可用于研究人类应激性红细胞生成。
