A lineage of diploid platelet-forming cells precedes polyploid megakaryocyte formation in the mouse embryo.

In this study, we test the assumption that the hematopoietic progenitor/colony-forming cells of the embryonic yolk sac (YS), which are endowed with megakaryocytic potential, differentiate into the first platelet-forming cells in vivo. We demonstrate that from embryonic day (E) 8.5 all megakaryocyte (MK) colony-forming cells belong to the conventional hematopoietic progenitor cell (HPC) compartment. Although these cells are indeed capable of generating polyploid MKs, they are not the source of the first platelet-forming cells. We show that proplatelet formation first occurs in a unique and previously unrecognized lineage of diploid platelet-forming cells, which develop within the YS in parallel to HPCs but can be specified in the E8.5 Runx1-null embryo despite the absence of the progenitor cell lineage.

[1]  J. Italiano,et al.  The incredible journey: From megakaryocyte development to platelet formation , 2013, The Journal of cell biology.

[2]  M. Marcos,et al.  Megakaryocytes promote hepatoepithelial liver cell development in E11.5 mouse embryos by cell‐to‐cell contact and by vascular endothelial growth factor A signaling , 2012, Hepatology.

[3]  J. Italiano,et al.  High-content live-cell imaging assay used to establish mechanism of trastuzumab emtansine (T-DM1)--mediated inhibition of platelet production. , 2012, Blood.

[4]  J. Pollard,et al.  A Lineage of Myeloid Cells Independent of Myb and Hematopoietic Stem Cells , 2012, Science.

[5]  Jhagvaral Hasbold,et al.  Activation-Induced B Cell Fates Are Selected by Intracellular Stochastic Competition , 2012, Science.

[6]  S. Rybtsov,et al.  Embryonic origin of the adult hematopoietic system: advances and questions , 2011, Development.

[7]  Jian Yang,et al.  Restoration of Runx1 Expression in the Tie2 Cell Compartment Rescues Definitive Hematopoietic Stem Cells and Extends Life of Runx1 Knockout Animals Until Birth , 2009, Stem cells.

[8]  Shin-Ichi Nishikawa,et al.  Continuous single-cell imaging of blood generation from haemogenic endothelium , 2009, Nature.

[9]  Satoru Takahashi,et al.  Runx1 is involved in primitive erythropoiesis in the mouse. , 2008, Blood.

[10]  K. McGrath,et al.  Primitive erythropoiesis and megakaryopoiesis in the yolk sac are independent of c-myb. , 2008, Blood.

[11]  R. Waugh,et al.  The megakaryocyte lineage originates from hemangioblast precursors and is an integral component both of primitive and of definitive hematopoiesis. , 2007, Blood.

[12]  Satoru Takahashi,et al.  Primitive erythropoiesis from mesodermal precursors expressing VE-cadherin, PECAM-1, Tie2, endoglin, and CD34 in the mouse embryo. , 2006, Blood.

[13]  Steve P. Watson,et al.  Regulation of proplatelet formation and platelet release by integrin αIIbβ3 , 2006 .

[14]  F. Buchholz,et al.  AML1 deletion in adult mice causes splenomegaly and lymphomas , 2006, Oncogene.

[15]  S. Ogawa,et al.  AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis , 2004, Nature Medicine.

[16]  P. Morrison,et al.  CD41 expression defines the onset of primitive and definitive hematopoiesis in the murine embryo , 2003, Development.

[17]  S. Orkin,et al.  Expression of CD41 marks the initiation of definitive hematopoiesis in the mouse embryo. , 2003, Blood.

[18]  Elaine Dzierzak,et al.  Runx1 expression marks long-term repopulating hematopoietic stem cells in the midgestation mouse embryo. , 2002, Immunity.

[19]  P. Marrack,et al.  Observation of antigen-dependent CD8+ T-cell/ dendritic cell interactions in vivo. , 2001, Cellular immunology.

[20]  S. Asano,et al.  Evidence for the presence of murine primitive megakaryocytopoiesis in the early yolk sac. , 2001, Blood.

[21]  J. Frampton,et al.  Initiation of adult myelopoiesis can occur in the absence of c-Myb whereas subsequent development is strictly dependent on the transcription factor , 2000, Oncogene.

[22]  S. Nishikawa,et al.  In vitro generation of lymphohematopoietic cells from endothelial cells purified from murine embryos. , 1998, Immunity.

[23]  W. Vainchenker,et al.  Effects of cytokines on platelet production from blood and marrow CD34+ cells. , 1998, Blood.

[24]  M. Marín‐Padilla,et al.  Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[25]  A. Koniski,et al.  Analysis of hematopoietic progenitors in the mouse embryo. , 2005, Methods in molecular medicine.