The TLR1/2 agonist PAM3CSK4 instructs commitment of human hematopoietic stem cells to a myeloid cell fate

K De Luca, V Frances-Duvert, MJ Asensio, R Ihsani… - Leukemia, 2009 - nature.com
K De Luca, V Frances-Duvert, MJ Asensio, R Ihsani, E Debien, M Taillardet, E Verhoeyen…
Leukemia, 2009nature.com
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 long-term cultures of HSCs,
HPCs and stromal cells, most TLR-L profoundly inhibited B-cell development while …
Abstract
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 long-term 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/EBPα 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.
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