Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States.
CCR Collaborative Bioinformatics Resource, Office of Science and Technology Resources, National Cancer Institute, National Institutes of Health, Bethesda, United States.
Elife. 2024 Jul 9;12:RP92679. doi: 10.7554/eLife.92679.
Extramedullary erythropoiesis is not expected in healthy adult mice, but erythropoietic gene expression was elevated in lineage-depleted spleen cells from mice. Expression of several genes associated with early stages of erythropoiesis was elevated in mice lacking CD47 or its signaling ligand thrombospondin-1, consistent with previous evidence that this signaling pathway inhibits expression of multipotent stem cell transcription factors in spleen. In contrast, cells expressing markers of committed erythroid progenitors were more abundant in spleens but significantly depleted in spleens. Single-cell transcriptome and flow cytometry analyses indicated that loss of CD47 is associated with accumulation and increased proliferation in spleen of Ter119CD34 progenitors and Ter119CD34 committed erythroid progenitors with elevated mRNA expression of Kit, Ermap, and Tfrc. Induction of committed erythroid precursors is consistent with the known function of CD47 to limit the phagocytic removal of aged erythrocytes. Conversely, loss of thrombospondin-1 delays the turnover of aged red blood cells, which may account for the suppression of committed erythroid precursors in spleens relative to basal levels in wild-type mice. In addition to defining a role for CD47 to limit extramedullary erythropoiesis, these studies reveal a thrombospondin-1-dependent basal level of extramedullary erythropoiesis in adult mouse spleen.
健康成年小鼠的骨髓外红细胞生成是不会发生的，但在 CD47 缺失或其信号配体血小板反应蛋白-1 缺失的小鼠的谱系耗竭脾细胞中，红细胞生成基因表达升高。与之前的证据一致，该信号通路抑制脾中多能干细胞转录因子的表达，与红细胞生成早期相关的几个基因的表达在缺乏 CD47 的小鼠中升高。相比之下，在 小鼠的脾脏中，表达定型红细胞祖细胞标记的细胞更为丰富，但在 小鼠的脾脏中则明显减少。单细胞转录组和流式细胞术分析表明，CD47 的缺失与脾中 Ter119CD34 祖细胞和 Ter119CD34 定型红细胞祖细胞的积累和增殖增加有关，这些细胞的 Kit、Ermap 和 Tfrc 的 mRNA 表达升高。定型红细胞前体的诱导与 CD47 限制衰老红细胞吞噬清除的已知功能一致。相反，血小板反应蛋白-1 的缺失会延迟衰老红细胞的周转，这可能是 小鼠脾脏中定型红细胞前体相对于野生型小鼠基础水平的抑制的原因。这些研究除了确定 CD47 限制骨髓外红细胞生成的作用外，还揭示了成年小鼠脾脏中血小板反应蛋白-1 依赖性的基础水平骨髓外红细胞生成。
