ALBERT

Description: The blood system is maintained by a small pool of haematopoietic stem cells (HSCs), which are required and sufficient for replenishing all human blood cell lineages at millions of cells per second throughout life. Megakaryocytes in the bone marrow are responsible for the continuous production of platelets in the blood, crucial for preventing bleeding--a common and life-threatening side effect of many cancer therapies--and major efforts are focused at identifying the most suitable cellular and molecular targets to enhance platelet production after bone marrow transplantation or chemotherapy. Although it has become clear that distinct HSC subsets exist that are stably biased towards the generation of lymphoid or myeloid blood cells, we are yet to learn whether other types of lineage-biased HSC exist or understand their inter-relationships and how differently lineage-biased HSCs are generated and maintained. The functional relevance of notable phenotypic and molecular similarities between megakaryocytes and bone marrow cells with an HSC cell-surface phenotype remains unclear. Here we identify and prospectively isolate a molecularly and functionally distinct mouse HSC subset primed for platelet-specific gene expression, with enhanced propensity for short- and long-term reconstitution of platelets. Maintenance of platelet-biased HSCs crucially depends on thrombopoietin, the primary extrinsic regulator of platelet development. Platelet-primed HSCs also frequently have a long-term myeloid lineage bias, can self-renew and give rise to lymphoid-biased HSCs. These findings show that HSC subtypes can be organized into a cellular hierarchy, with platelet-primed HSCs at the apex. They also demonstrate that molecular and functional priming for platelet development initiates already in a distinct HSC population. The identification of a platelet-primed HSC population should enable the rational design of therapies enhancing platelet output.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sanjuan-Pla, Alejandra -- Macaulay, Iain C -- Jensen, Christina T -- Woll, Petter S -- Luis, Tiago C -- Mead, Adam -- Moore, Susan -- Carella, Cintia -- Matsuoka, Sahoko -- Bouriez Jones, Tiphaine -- Chowdhury, Onima -- Stenson, Laura -- Lutteropp, Michael -- Green, Joanna C A -- Facchini, Raffaella -- Boukarabila, Hanane -- Grover, Amit -- Gambardella, Adriana -- Thongjuea, Supat -- Carrelha, Joana -- Tarrant, Paul -- Atkinson, Deborah -- Clark, Sally-Ann -- Nerlov, Claus -- Jacobsen, Sten Eirik W -- G0701761/Medical Research Council/United Kingdom -- G0900892/Medical Research Council/United Kingdom -- G84/6443/Medical Research Council/United Kingdom -- H4RPLK0/Medical Research Council/United Kingdom -- England -- Nature. 2013 Oct 10;502(7470):232-6. doi: 10.1038/nature12495. Epub 2013 Aug 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Stem Cell Research and MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH9 16UU, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23934107" target="_blank"〉PubMed〈/a〉

Description: Blood cells derive from hematopoietic stem cells through stepwise fating events. To characterize gene expression programs driving lineage choice, we sequenced RNA from eight primary human hematopoietic progenitor populations representing the major myeloid commitment stages and the main lymphoid stage. We identified extensive cell type-specific expression changes: 6711 genes and 10,724 transcripts, enriched in non-protein-coding elements at early stages of differentiation. In addition, we found 7881 novel splice junctions and 2301 differentially used alternative splicing events, enriched in genes involved in regulatory processes. We demonstrated experimentally cell-specific isoform usage, identifying nuclear factor I/B (NFIB) as a regulator of megakaryocyte maturation-the platelet precursor. Our data highlight the complexity of fating events in closely related progenitor populations, the understanding of which is essential for the advancement of transplantation and regenerative medicine.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254742/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254742/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Lu -- Kostadima, Myrto -- Martens, Joost H A -- Canu, Giovanni -- Garcia, Sara P -- Turro, Ernest -- Downes, Kate -- Macaulay, Iain C -- Bielczyk-Maczynska, Ewa -- Coe, Sophia -- Farrow, Samantha -- Poudel, Pawan -- Burden, Frances -- Jansen, Sjoert B G -- Astle, William J -- Attwood, Antony -- Bariana, Tadbir -- de Bono, Bernard -- Breschi, Alessandra -- Chambers, John C -- BRIDGE Consortium -- Choudry, Fizzah A -- Clarke, Laura -- Coupland, Paul -- van der Ent, Martijn -- Erber, Wendy N -- Jansen, Joop H -- Favier, Remi -- Fenech, Matthew E -- Foad, Nicola -- Freson, Kathleen -- van Geet, Chris -- Gomez, Keith -- Guigo, Roderic -- Hampshire, Daniel -- Kelly, Anne M -- Kerstens, Hindrik H D -- Kooner, Jaspal S -- Laffan, Michael -- Lentaigne, Claire -- Labalette, Charlotte -- Martin, Tiphaine -- Meacham, Stuart -- Mumford, Andrew -- Nurnberg, Sylvia -- Palumbo, Emilio -- van der Reijden, Bert A -- Richardson, David -- Sammut, Stephen J -- Slodkowicz, Greg -- Tamuri, Asif U -- Vasquez, Louella -- Voss, Katrin -- Watt, Stephen -- Westbury, Sarah -- Flicek, Paul -- Loos, Remco -- Goldman, Nick -- Bertone, Paul -- Read, Randy J -- Richardson, Sylvia -- Cvejic, Ana -- Soranzo, Nicole -- Ouwehand, Willem H -- Stunnenberg, Hendrik G -- Frontini, Mattia -- Rendon, Augusto -- 082961/Wellcome Trust/United Kingdom -- 082961/Z/07/Z/Wellcome Trust/United Kingdom -- 084183/Z/07/Z/Wellcome Trust/United Kingdom -- 095908/Wellcome Trust/United Kingdom -- 100140/Wellcome Trust/United Kingdom -- C45041/A14953/Cancer Research UK/United Kingdom -- FS/12/27/29405/British Heart Foundation/United Kingdom -- MC_UP_0801/1/Medical Research Council/United Kingdom -- MR/J011711/1/Medical Research Council/United Kingdom -- MR/K006584/1/Medical Research Council/United Kingdom -- MR/K023489/1/Medical Research Council/United Kingdom -- RG/09/012/28096/British Heart Foundation/United Kingdom -- RG/09/12/28096/British Heart Foundation/United Kingdom -- RP-PG-0310-1002/British Heart Foundation/United Kingdom -- RP-PG-0310-1002/Department of Health/United Kingdom -- WT091310/Wellcome Trust/United Kingdom -- WT098051/Wellcome Trust/United Kingdom -- Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Sep 26;345(6204):1251033. doi: 10.1126/science.1251033.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. ; Department of Molecular Biology, Radboud University, 6525 GA Nijmegen, Netherlands. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. ; Sanger Institute-EBI Single-Cell Genomics Centre, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Medical Research Council Biostatistics Unit, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK. ; Department of Haematology, University College London Cancer Institute, London WC1E 6DD, UK. The Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free NHS Trust, London NW3 2QG, UK. ; CHIME Institute, University College London, Archway Campus, London NW1 2DA, UK. Auckland Bioengineering Institute, University of Auckland, Auckland 1010, New Zealand. ; Centre for Genomic Regulation and University Pompeu Fabra, 08002 Barcelona, Spain. ; Imperial College Healthcare NHS Trust, DuCane Road, London W12 0HS, UK. Ealing Hospital NHS Trust, Southall, Middlesex UB1 3HW, UK. ; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. ; Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Australia. ; Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. ; Assistance Publique-Hopitaux de Paris, INSERM U1009, 94805 Villejuif, France. ; Biomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK. ; Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium. ; The Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free NHS Trust, London NW3 2QG, UK. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge B2 0QQ, UK. ; Department of Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London W12 0HS, UK. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Department of Twin Research & Genetic Epidemiology, Genetics and Molecular Medicine Division, St Thomas' Hospital, King's College, London SE1 7EH, UK. ; School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK. ; Department of Oncology, Addenbrooke's Cambridge University Hospital NHS Trust, Cambridge Biomedical Campus, Cambridge CB2 0RE, UK. Cancer Research UK, Cambridge Institute, Cambridge Biomedical Campus, Cambridge CB2 0RE, UK. ; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. ; School of Clinical Sciences, University of Bristol, Bristol BS2 8DZ, UK. ; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. ; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. Genome Biology and Developmental Biology Units, European Molecular Biology Laboratory, 69117 Heidelberg, Germany. Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK. ; Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK. ; Medical Research Council Biostatistics Unit, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. ar506@cam.ac.uk mf471@cam.ac.uk. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Medical Research Council Biostatistics Unit, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK. ar506@cam.ac.uk mf471@cam.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25258084" target="_blank"〉PubMed〈/a〉