Department of Pathology and Laboratory Medicine, and.
Center for Pediatric Biomedical Research, Department of Pediatrics, University of Rochester Medical Center, Rochester NY.
Blood Adv. 2019 Jan 8;3(1):72-82. doi: 10.1182/bloodadvances.2018020859.
Platelets are essential for hemostasis; however, several studies have identified age-dependent differences in platelet function. To better understand the origins of fetal platelet function, we have evaluated the contribution of the fetal-specific RNA binding protein in the megakaryocyte/platelet lineage. Because activated fetal platelets have very low levels of P-selectin, we hypothesized that the expression of platelet P-selectin is part of a fetal-specific hematopoietic program conferred by Lin28b. Using the mouse as a model, we find that activated fetal platelets have low levels of P-selectin and do not readily associate with granulocytes in vitro and in vivo, relative to adult controls. Transcriptional analysis revealed high levels of and in fetal, but not adult, megakaryocytes. Overexpression of in adult mice significantly reduces the expression of P-selectin in platelets, and therefore identifies as a negative regulator of P-selectin expression. Transplantation of fetal hematopoietic progenitors resulted in the production of platelets with low levels of P-selectin, suggesting that the developmental regulation of P-selectin is intrinsic and independent of differences between fetal and adult microenvironments. Last, we observe that the upregulation of P-selectin expression occurs postnatally, and the temporal kinetics of this upregulation are recapitulated by transplantation of fetal hematopoietic stem and progenitor cells into adult recipients. Taken together, these studies identify as a new intrinsic regulator of fetal platelet function.
血小板对于止血至关重要；然而，有几项研究已经确定了血小板功能与年龄相关的差异。为了更好地了解胎儿血小板功能的起源，我们评估了在巨核细胞/血小板谱系中胎儿特异性 RNA 结合蛋白 的作用。由于激活的胎儿血小板中 P-选择素的水平非常低，我们假设血小板 P-选择素的表达是由 Lin28b 赋予的胎儿特异性造血程序的一部分。我们使用小鼠作为模型，发现与成年对照组相比，激活的胎儿血小板中 P-选择素的水平较低，并且在体外和体内不易与粒细胞结合。转录分析显示，胎儿巨核细胞中 和 的水平较高，但成年巨核细胞中则不然。在成年小鼠中过表达 可显著降低血小板中 P-选择素的表达，因此鉴定出 是 P-选择素表达的负调节剂。胎儿造血祖细胞的移植导致产生 P-选择素水平较低的血小板，这表明 P-选择素的发育调控是内在的，独立于胎儿和成年微环境之间的差异。最后，我们观察到 P-选择素表达的上调发生在出生后，并且通过将胎儿造血干祖细胞移植到成年受者中可以再现这种上调的时间动力学。综上所述，这些研究确定 是胎儿血小板功能的新内在调节因子。
