Hematopoietic stem cell deficiencies in mice lacking c-Mpl, the receptor for thrombopoietin
Hematopoietic stem cell deficiencies in mice lacking c-Mpl, the receptor for thrombopoietin
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DOI：
10.1073/pnas.95.3.1195
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发表时间：
1998-02-03
影响因子：
11.1
通讯作者：
Alexander, WS
中科院分区：
文献类型：
--
作者：
Kimura, S;Roberts, AW;Alexander, WS
血小板生成素 (TPO) 作为谱系特异性迟发因子，刺激巨核细胞和血小板形成，然而，对缺乏细胞因子或其受体 c-Mpl 的小鼠的分析也揭示了多个造血谱系的祖细胞的缺陷，表明 TPO 信号传导可能在造血干细胞的调节中发挥重要作用 隔间。为了研究这一假设，我们测定了脾脏前祖细胞和集落形成单位 (CFU-S) 的数量，并分析了 mpl(-/-) 小鼠骨髓细胞的长期造血再增殖能力。 mpl(-/-) 小鼠的前祖细胞比野生型小鼠少 4 至 12 倍。在受辐射的正常受体中，mpl(-/-) 骨髓产生的前祖细胞数量为 8 至 12 倍。 移植后第 8 天和第 12 天，脾脏集落数量比野生型骨髓少 10 倍。这种缺陷是移植造血细胞固有的，因为 mpl(-/-) 受体的微环境支持与野生型受体中观察到的类似的 CFU-S 生长。在干细胞功能的确定性测定中，mpl(-/-) 小鼠的骨髓细胞未能与正常细胞有效竞争受辐射造血器官的长期重建。 连续移植研究进一步表明，在 mpl(-/-) 小鼠中，干细胞的自我更新也可能受到损害。这些数据表明，通过 c-Mpl 发出信号的 TPO 在调节造血干细胞的产生和功能中发挥着至关重要的生理作用。
Thrombopoietin (TPO) acts as a lineage-specific late-acting factor to stimulate megakaryocyte and platelet formation, However, analysis of mice lacking either the cytokine or its receptor, c-Mpl, also revealed deficiencies in progenitor cells of multiple hematopoietic lineages, suggesting that TPO signaling may play an important role in the regulation of the hematopoietic stem cell compartment. To investigate this hypothesis, we determined preprogenitor and colony forming unit-spleen (CFU-S) numbers and analyzed the long-term hematopoietic repopulating capacity of bone marrow cells from mpl(-/-) mice.mpl(-/-) mice had 4- to 12-fold fewer preprogenitor cells than wild type mice, In irradiated normal recipients, mpl(-/-) bone marrow generated 8- to 10-fold fewer spleen colonies than wild-type marrow at both 8 and 12 days after transplantation. This defect was intrinsic to the transplanted hematopoietic cells, as the microenvironment of mpl(-/-) recipients supported similar CFU-S growth to that observed in wild-type recipients, In definitive assays of stem cell function, bone marrow cells from mpl(-/-) mice failed to compete effectively with normal cells for long-term reconstitution of the hematopoietic organs of irradiated recipients, even when transplanted in 10-fold excess, Serial transplantation studies further suggested that stem cell self-renewal also may be compromised in mpl(-/-) mice, These data imply that TPO, signaling through c-Mpl, plays a vital physiological role in the regulation of hematopoietic stem cell production and function.