The TLR1/2 agonist PAM3CSK4 instructs commitment of human hematopoietic stem cells to a myeloid cell fate
The TLR1/2 agonist PAM3CSK4 instructs commitment of human hematopoietic stem cells to a myeloid cell fate
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DOI：
10.1038/leu.2009.155
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发表时间：
2009-11-01
期刊：
影响因子：
11.4
通讯作者：
Defrance, T.
中科院分区：
文献类型：
--
作者：
De Luca, K.;Frances-Duvert, V.;Defrance, T.
Toll样受体（TLR）是一类非多态性的受体家族，主要参与病原体的识别。在这项工作中，我们探讨了TLR配体（TLR-L）对人造血干细胞（HSC）和造血祖细胞（HPC）的影响。我们发现，造血干细胞和造血干细胞具有相似的TLR转录本表达模式，其特征在于TLR 1、-2、-3、-4和-6占优势。在HSC、HPC和基质细胞的长期培养中，大多数TLR-L深刻地抑制B细胞发育，同时保持或增强骨髓细胞的产生。在短期培养中，TLR 1/2配体PAM（3）CSK（4）诱导大部分HPC表达骨髓单核细胞谱系的标志物。PAM（3）CSK（4）仅诱导HSC上髓系标志物的边缘表达，但促进其髓系定型，如通过其获得多能和双能髓系祖细胞的表型以及通过上调转录因子PU. 1、C/EBP α和加塔-1所揭示的。我们的研究结果表明，TLR激动剂可以偏向人类造血干细胞的谱系承诺，并转移谱系承诺的祖细胞的分化，有利于骨髓细胞的淋巴样B细胞的发展为代价。Leukemia（2009）23，2063-2074; doi：10.1038/leu.2009.155; 2009年7月30日在线发表
Toll-like receptors (TLRs) constitute a family of nonpolymorphic receptors that are devoted to pathogen recognition. In this work, we have explored the impact of TLR ligands (TLR-L) on human hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). We show that HSCs and HPCs have a comparable pattern of expression of TLR transcripts characterized by the predominance of TLR1, -2, -3, -4 and -6. In longterm cultures of HSCs, HPCs and stromal cells, most TLR-L profoundly inhibited B-cell development while preserving or enhancing the production of myeloid cells. In short-term cultures, the TLR1/2 ligand PAM(3)CSK(4) induced a large proportion of HPCs to express markers of the myelomonocytic lineage. PAM(3)CSK(4) induced only marginal expression of myeloid lineage markers on HSCs but promoted their myeloid commitment as revealed by their acquisition of the phenotype of multi-and bipotential myeloid progenitors and by upregulation of the transcription factors PU.1, C/EBP alpha and GATA-1. Our results suggest that TLR agonists can bias the lineage commitment of human HSCs and shift the differentiation of lineage-committed progenitors to favor myelopoiesis at the expense of lymphoid B-cell development. Leukemia (2009) 23, 2063-2074; doi: 10.1038/leu.2009.155; published online 30 July 2009