Megakaryocyte and platelet ontogeny

巨核细胞和血小板个体发育

基本信息

批准号：
9264520
负责人：
James Palis
金额：
$ 33.39万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9264520
关键词：
Activities of Daily Living Adult Adult Acute Lymphocytic Leukemia Agonist Alpha Granule Biological Assay Blood Cells Blood Platelet Disorders Blood Platelets CDKN1C gene Cell Cycle Cell Therapy Cell surface Cells Characteristics Coagulation Process Collaborations Down-Regulation Embryo Embryonic Development Embryonic Structures Erythrocytes Erythroid F2R gene Family Family member Foundations GATA1 gene Generations Growth Hematopoietic Hematopoietic stem cells Hemorrhage Hemostatic function Human Immunity In Vitro Inflammation Light Mediating Megakaryocytes Megakaryocytopoieses Mus Natural History Neonatal P-Selectin Platelet Activation Platelet Count measurement Property Radial Replacement Therapy Research Role Signal Transduction Source Specific qualifier value Stem cells Structure Testing Thrombin Thrombocytopenia Thrombopoiesis Thrombus Transcript Up-Regulation angiogenesis base blastomere structure clinical development differential expression embryonic stem cell fetal high risk in vivo induced pluripotent stem cell inhibitor/antagonist neonate public health relevance response stem

项目摘要

DESCRIPTION (provided by applicant): Platelets are anucleate cells derived from megakaryocytes (megs) that serve as critical components of hemostasis and thrombus formation, and mediate aspects of inflammation, immunity, and angiogenesis. In the adult, all platelets are derived from hematopoietic stem cells (HSCs). We previously discovered in the mouse embryo that the meg lineage is specified several days before HSC emergence as embryonic (pre- HSC) megakaryopoiesis. We have also determined that embryonic megs have limited polyploidization and generate extremely large platelets with small a-granules. Thrombopoiesis in human neonates is also characterized by limited polyploidization and rapid cytoplasmic maturation. Endoreplication is regulated in part by the Cip/Kip family of cell cycle inhibitors. Our preliminary studies indicate that embryonic, but not adult, platelets express high levels of p57 (Kip2). In Aim 1, we will further define the differences between embryonic, fetal and adult megakaryopoiesis and test the hypothesis that differences in meg endoreplication are regulated, in part, by the differential expression of Cip/Kip family members. Our preliminary studies of primary embryonic platelets indicate that they are effectively activated by thrombin but markedly less so by ADP. These functional studies correlate with the differential upregulation of PAR1 and down-regulation of P2Y12 in primary embryonic versus adult platelets. In Aim 2 studies, we will test the hypothesis that embryonic platelets have intrinsic functional differences in activation and clot formation when compared to their adult counterparts. An understanding of hematopoietic ontogeny is particularly relevant to the generation of blood cells from embryonic stem (ES) cells and induced pluripotent stem (iPS) cells, which carry the potential to serve as an important source of cell-based therapies. We hypothesize that ES cell-derived megs and platelets will have predominantly embryonic characteristics. This hypothesis will be tested by comparing ES cell-derived meg maturation and platelet function with that of primary embryonic cells. This proposed research builds upon our studies of meg ontogeny and platelet emergence in the murine embryo and establishes a foundation for the development of clinically useful cell-based therapies from ES/iPS cell sources.

描述（由申请人提供）：血小板是源自巨核细胞（megs）的无核细胞，作为止血和血栓形成的关键成分，并介导炎症、免疫和血管生成等方面。在成人中，所有血小板均源自造血干细胞 (HSC)。我们之前在小鼠胚胎中发现，meg谱系在HSC出现前几天被指定为胚胎（HSC前）巨核细胞生成。我们还确定，胚胎巨细胞的多倍化程度有限，并产生带有小α颗粒的极大血小板。人类新生儿的血小板生成还具有有限的多倍化和快速细胞质成熟的特征。内复制部分受到细胞周期抑制剂 Cip/Kip 家族的调节。我们的初步研究表明，胚胎而非成人血小板表达高水平的 p57 (Kip2)。在目标 1 中，我们将进一步定义胚胎、胎儿和成人巨核细胞生成之间的差异，并检验 meg 内复制差异部分受到 Cip/Kip 家族成员差异表达调节的假设。我们对初级胚胎血小板的初步研究表明，它们可以被凝血酶有效激活，但 ADP 的情况明显较少。这些功能研究与初级胚胎与成人血小板中 PAR1 的差异上调和 P2Y12 的下调相关。在目标 2 研究中，我们将检验胚胎血小板具有内在功能差异的假设与成人相比，在激活和凝块形成方面。对造血个体发育的理解与胚胎干 (ES) 细胞和诱导多能干 (iPS) 细胞生成血细胞特别相关，它们有可能成为细胞疗法的重要来源。我们假设 ES 细胞衍生的巨细胞和血小板将主要具有胚胎特征。该假设将通过将 ES 细胞衍生的 meg 成熟和血小板功能与原代胚胎细胞进行比较来检验。这项拟议的研究建立在我们对小鼠胚胎中 meg 个体发育和血小板出现的研究的基础上，并为从 ES/iPS 细胞来源开发临床上有用的细胞疗法奠定了基础。