Prominent role of TGF-β1 in thrombopoietin-induced myelofibrosis in mice
Prominent role of TGF-β1 in thrombopoietin-induced myelofibrosis in mice
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DOI：
10.1182/blood-2002-04-1133
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发表时间：
2002-11-15
期刊：
影响因子：
20.3
通讯作者：
Wendling, F
中科院分区：
文献类型：
--
作者：
Chagraoui, H;Komura, E;Wendling, F
几项研究表明，在促进骨髓纤维化与造血系统恶性肿瘤，转化生长因子-β 1（TGF-β 1）的影响，但这种细胞因子的参与没有得到充分的调查。为了直接检测TGF-β 1在骨髓纤维化发病机制中的作用，用编码鼠血小板生成素（TPO）蛋白的逆转录病毒感染来自纯合TGF-β 1缺失（TGF-β 1（-/-））和野生型（WT）同窝仔的骨髓干细胞，并将其移植到致死性照射的野生型宿主中进行长期重建。在4个月的随访中，两组小鼠血浆中的TPO水平均显著升高，并且动物通常发展为骨髓增生综合征，其特征为血小板增多、白细胞增多、脾肿大、血液中祖细胞数量增加和髓外造血。在所有移植WT细胞的小鼠的脾脏和骨髓中观察到严重的纤维化。相比之下，在随访期间的任何时间，用TGF-β 1（-/-）细胞重新繁殖的小鼠（嵌合率>70%）都没有显示网硬蛋白纤维沉积。与纤维化的发展一致，移植WT细胞的小鼠脾的血浆和细胞外液中的潜伏TGF-β 1水平分别比正常宿主中的水平增加了6倍和4倍，而在接受TGF-β 1（-/-）细胞移植的动物中没有显示出超过基线水平的增加。这些数据提供了证据，证明造血细胞产生的TGF-β 1对于TPO过表达小鼠中发生的骨髓纤维化的发病机制至关重要。
Several studies suggest an implication of transforming growth factor-beta1 (TGF-beta1) in the promotion of myelofibrosis associated with hematopoietic malignancies, but the involvement of this cytokine is not fully investigated. To test directly the impact of TGF-beta1 in the pathogenesis of myelofibrosis, bone marrow stem cells from homozygous TGF-beta1 null (TGF-beta1(-/-)) and wild-type (WT) littermates were infected with a retrovirus encoding the murine thrombopoietin (TPO) protein and engrafted Into lethally irradiated wildtype hosts for long-term reconstitution. Over the 4 months of follow-up, TPO levels in plasma were markedly elevated in both groups of mice, and animals typically developed a myeloproliferative syndrome characterized by thrombocytosis, leukocytosis, splenomegaly, increased numbers of progenitors in blood, and extramedullary hematopoiesis. Severe fibrosis was observed in spleen and marrow from all the mice engrafted with WT cells. In contrast, none of the mice repopulated with TGF-beta1(-/-) cells (chimerism >70%) showed deposition of reticulin fibers at any time during the follow-up. In accordance with the development of fibrosis, latent TGF-beta1 levels in plasma and extracellular fluid of the spleen from mice engrafted with WT cells were increased 6-fold and 4-fold, respectively, over levels found in normal hosts, whereas no increase over baseline levels could be demonstrated in animals undergoing transplantation with TGF-beta1(-/-) cells. These data provide evidence that TGF-beta1 produced by hematopoietic cells is pivotal for the pathogenesis of myelofibrosis that develops in mice with TPO overexpression.