Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing, China.
Department of Histology and Embryology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China.
J Mol Histol. 2024 Oct;55(5):661-673. doi: 10.1007/s10735-024-10219-z. Epub 2024 Jul 6.
Conventional treatments exhibit various side effects on chronic stress anemia. Extramedullary stress erythropoiesis is a compensatory mechanism, which may effectively counteract anemia. Angelica sinensis polysaccharides (ASP) are the main active ingredient found in Angelica sinensis and exhibit antioxidant and hematopoietic effects. However, the effects of ASP on extramedullary stress erythropoiesis remain to be unclear. Here, we demonstrated the protective effects of ASP on chemotherapeutic drug 5-fluorouracil (5-FU)-induced decline in peripheral blood parameters such as RBC counts, HGB, HCT, and MCH, and the decline of BFU-E colony enumeration in the bone marrow. Meanwhile, ASP promoted extramedullary erythropoiesis, increasing cellular proliferation in the splenic red pulp and cyclin D1 protein expression, abrogating phase G0/G1 arrest of c-kit cells in mouse spleen. RT-qPCR and immunohistochemistry further revealed that ASP increased macrophage chemokine Ccl2 genetic expression and the number of F4/80 macrophages in the spleen. The colony-forming assay showed that ASP significantly increased splenic BFU-E. Furthermore, we found that ASP facilitated glycolytic genes including Hk2, Pgk1, Pkm, Pdk1, and Ldha via PI3K/Akt/HIF2α signaling in the spleen. Subsequently, ASP declined pro-proinflammatory factor IL-1β, whereas upregulating erythroid proliferation-associated genes Gdf15, Bmp4, Wnt2b, and Wnt8a. Moreover, ASP facilitated EPO/STAT5 signaling in splenic macrophages, thus enhancing erythroid lineage Gata2 genetic expression. Our study indicated that ASP may improve glycolysis, promoting the activity of splenic macrophages, subsequently promoting erythroid progenitor cell expansion. Additionally, ASP facilitates erythroid differentiation via macrophage-mediated EpoR/STAT5 signaling; suggesting it might be a promising strategy for stress anemia treatment.
常规治疗对慢性应激性贫血表现出各种副作用。骨髓外应激性红细胞生成是一种代偿机制，可有效对抗贫血。当归多糖（ASP）是当归中的主要活性成分，具有抗氧化和造血作用。然而，ASP 对骨髓外应激性红细胞生成的影响尚不清楚。在这里，我们证明了 ASP 对化疗药物 5-氟尿嘧啶（5-FU）诱导的外周血参数（如 RBC 计数、HGB、HCT 和 MCH）下降以及骨髓中 BFU-E 集落计数下降的保护作用。同时，ASP 促进了骨髓外红细胞生成，增加了脾红髓中细胞的增殖和周期蛋白 D1 蛋白的表达，消除了小鼠脾中 c-kit 细胞的 G0/G1 期阻滞。RT-qPCR 和免疫组织化学进一步表明，ASP 增加了巨噬细胞趋化因子 Ccl2 的基因表达和脾中 F4/80 巨噬细胞的数量。集落形成实验表明，ASP 显著增加了脾 BFU-E。此外，我们发现 ASP 通过 PI3K/Akt/HIF2α 信号通路促进了包括 Hk2、Pgk1、Pkm、Pdk1 和 Ldha 在内的糖酵解基因的表达。随后，ASP 降低了促炎前因子 IL-1β，而上调了与红细胞增殖相关的基因 Gdf15、Bmp4、Wnt2b 和 Wnt8a。此外，ASP 促进了脾巨噬细胞中的 EPO/STAT5 信号通路，从而增强了红细胞谱系 Gata2 的基因表达。我们的研究表明，ASP 可能通过改善糖酵解来促进脾巨噬细胞的活性，从而促进红细胞祖细胞的扩增。此外，ASP 通过巨噬细胞介导的 EpoR/STAT5 信号通路促进红细胞分化；这表明它可能是治疗应激性贫血的一种有前途的策略。
