Platelet-biased stem cells reside at the apex of the haematopoietic stem-cell hierarchy

被引：490

作者：

Sanjuan-Pla, Alejandra ^{[1
,2
,3
]}

Macaulay, Iain C. ^{[4
,5
]}

Jensen, Christina T. ^{[4
,5
]}

Woll, Petter S. ^{[4
,5
]}

Luis, Tiago C. ^{[4
,5
]}

Mead, Adam ^{[4
,5
]}

Moore, Susan ^{[1
,2
,3
]}

Carella, Cintia ^{[3
]}

Matsuoka, Sahoko ^{[4
,5
]}

Jones, Tiphaine Bouriez ^{[4
,5
]}

Chowdhury, Onima ^{[4
,5
]}

Stenson, Laura ^{[4
,5
]}

Lutteropp, Michael ^{[4
,5
]}

Green, Joanna C. A. ^{[4
,5
]}

Facchini, Raffaella ^{[4
,5
]}

Boukarabila, Hanane ^{[4
,5
]}

Grover, Amit ^{[4
]}

Gambardella, Adriana ^{[4
]}

Thongjuea, Supat ^{[4
]}

Carrelha, Joana ^{[4
,5
]}

Tarrant, Paul ^{[4
,5
]}

Atkinson, Deborah ^{[4
,5
]}

Clark, Sally-Ann ^{[4
,5
]}

Nerlov, Claus ^{[1
,2
,3
,4
]}

Jacobsen, Sten Eirik W. ^{[4
,5
]}

机构：

[1] Univ Edinburgh, Inst Stem Cell Res, Edinburgh EH9 16UU, Midlothian, Scotland

[2] Univ Edinburgh, MRC Ctr Regenerat Med, Edinburgh EH9 16UU, Midlothian, Scotland

[3] EMBL Mouse Biol Program, I-00015 Monterotondo, Italy

[4] Univ Oxford, Weatherall Inst Mol Med, MRC Mol Haematol Unit, Oxford OX3 9DS, England

[5] Univ Oxford, Weatherall Inst Mol Med, Haematopoiet Stem Cell Biol Lab, Oxford OX3 9DS, England

来源：

NATURE | 2013年 / 502卷 / 7470期

基金：

英国医学研究理事会;

关键词：

SELF-RENEWAL; IN-VIVO; DIFFERENTIATION; THROMBOPOIETIN; RECONSTITUTION; HETEROGENEITY; PROGENITORS; GENERATION;

D O I：

10.1038/nature12495

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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(1). Although it has become clear that distinct HSC subsets exist that are stably biased towards the generation of lymphoid or myeloid blood cells(2-4), 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(5-8) 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(9). 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.

引用

页码：232 / +

页数：17

共 28 条

[1]

Identification of Flt3+ lympho-myeloid stem cells lacking erythro-megakaryocytic potential:: A revised road map for adult blood lineage commitment [J].