Mice lacking transcription factor NF-E2 provide in vivo validation of the proplatelet model of thrombocytopoiesis and show a platelet production defect that is intrinsic to megakaryocytes
Mice lacking transcription factor NF-E2 provide in vivo validation of the proplatelet model of thrombocytopoiesis and show a platelet production defect that is intrinsic to megakaryocytes
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DOI：
10.1182/blood.v92.5.1608.417k27_1608_1616
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发表时间：
1998-09-01
期刊：
影响因子：
20.3
通讯作者：
Shivdasani, RA
中科院分区：
文献类型：
--
作者：
Lecine, P;Villeval, JL;Shivdasani, RA
哺乳动物巨核细胞产生和释放血小板的机制尚不清楚。我们使用了血小板减少基因敲除小鼠来更好地了解这些过程。原血小板是终末分化的巨核细胞的丝状延伸，被认为是血小板释放的一种机制；然而，这些结构在培养细胞中已被广泛识别，体内的血小板生成与原血小板的形成之间没有相关性。缺乏转录因子NF-E2的小鼠巨核细胞成熟迟缓，导致严重的血小板减少。与正常巨核细胞产生大量的前血小板不同，这些小鼠的细胞从来不会产生前血小板，即使在c-MPI配体的长期刺激下也是如此。同样，带有转录因子GATA-1谱系选择性缺失的血小板减少症小鼠的巨核细胞很少产生前血小板。这些发现建立了血小板生成和原血小板形成之间的显著相关性，并提示后者代表了血小板释放的一种生理机制。我们进一步证明，正常巨核细胞形成的原血小板及其在缺乏核因子-内啡肽的细胞中的缺失与与贴壁(间质)细胞的相互作用无关。同样，核因子-E2(-/-)小鼠的血小板减少反映了巨核细胞谱系的内在缺陷。这些观察结果提高了我们对血小板生成的理解，并验证了对前血小板的研究在探索潜在机制方面的作用。(C)1998年由美国血液病学会主办。
Mechanisms of platelet production and release by mammalian megakaryocytes are poorly understood. We used thrombocytopenic knockout mice to better understand these processes. Proplatelets are filamentous extensions of terminally differentiated megakaryocytes that are thought to represent one mechanism of platelet release; however, these structures have largely been recognized in cultured cells and there has been no correlation between thrombocytopoiesis in vivo and proplatelet formation. Mice lacking transcription factor NF-E2 have a late arrest in megakaryocyte maturation, resulting in profound thrombocytopenia. In contrast to normal megakaryocytes, which generate abundant proplatelets, cells from these mice never produce proplatelets, even after prolonged stimulation with c-MpI ligand. Similarly, megakaryocytes from thrombocytopenic mice with lineage-selective loss of transcription factor GATA-1 produce proplatelets very rarely. These findings establish a significant correlation between thrombocytopoiesis and proplatelet formation and suggest that the latter represents a physiologic mechanism of platelet release. We further show that proplatelet formation by normal megakaryocytes and its absence in cells lacking NF-EP are independent of interactions with adherent (stromal) cells. Similarly, thrombocytopenia in NF-E2(-/-) mice reflects intrinsic defects in the megakaryocyte lineage. These observations improve our understanding of platelet production and validate the study of proplatelets in probing the underlying mechanisms. (C) 1998 by The American Society of Hematology.