Institute of Cardiovascular Physiology, University Medical Center Göttingen, Georg-August-University Göttingen, 37073 Goettingen, Germany.
Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Göttingen, Georg-August-University Göttingen, 37075 Goettingen, Germany.
Cells. 2022 Feb 21;11(4):753. doi: 10.3390/cells11040753.
Inhibition of the prolyl-4-hydroxylase domain (PHD) enzymes, leading to the stabilization of hypoxia-inducible factor (HIF) α as well as to the stimulation of erythropoietin (Epo) synthesis, is the functional mechanism of the new anti-anemia drug roxadustat. Little is known about the effects of roxadustat on the Epo-producing cell pool. To gain further insights into the function of PHD inhibitors, we characterized the abundance of mesenchymal stem cell (MSC)-like cells after roxadustat treatment of mice. The number of Sca-1 mesenchymal cells following roxadustat treatment increased exclusively in the kidneys. Isolated Sca-1 cells demonstrated typical features of MSC-like cells, including adherence to tissue culture plates, trilineage differentiation potential, and expression of MSC markers. Kidney-derived Sca-1 MSC-like cells were cultured for up to 21 days. Within the first few days in culture, cells stabilized HIF-1α and HIF-2α and temporarily increased Epo production upon incubation in hypoxia. In summary, we have identified a Sca-1 MSC-like cell population that is involved in renal Epo production and might contribute to the strong anti-anemic effect of the PHD inhibitor roxadustat.
脯氨酰-4-羟化酶结构域（PHD）酶的抑制作用导致缺氧诱导因子（HIF）α的稳定以及促红细胞生成素（Epo）合成的刺激，这是新型抗贫血药物罗沙司他的功能机制。关于罗沙司他对 Epo 产生细胞池的影响知之甚少。为了更深入地了解 PHD 抑制剂的功能，我们对罗沙司他处理小鼠后间充质干细胞（MSC）样细胞的丰度进行了特征描述。在罗沙司他治疗后，肾脏中 Sca-1 间充质细胞的数量仅增加。分离出的 Sca-1 细胞表现出典型的 MSC 样细胞特征，包括对组织培养板的黏附性、三系分化潜能和 MSC 标志物的表达。肾脏来源的 Sca-1 MSC 样细胞培养长达 21 天。在培养的最初几天内，细胞稳定 HIF-1α 和 HIF-2α，并在低氧孵育时暂时增加 Epo 的产生。总之，我们已经确定了一个 Sca-1 MSC 样细胞群，它参与肾脏 Epo 的产生，并可能有助于 PHD 抑制剂罗沙司他的强烈抗贫血作用。
