title: The TLR1/2 agonist PAM(3)CSK(4) instructs commitment of human hematopoietic stem cells to a myeloid cell fate.
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/EBPalpha 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.
authors.affiliation: INSERM, U851, 21 Avenue Tony Garnier, Lyon, France.
authors.forename: K
authors.initials: K
authors.lastname: De Luca
authors.forename: V
authors.initials: V
authors.lastname: Frances-Duvert
authors.forename: M-J
authors.initials: MJ
authors.lastname: Asensio
authors.forename: R
authors.initials: R
authors.lastname: Ihsani
authors.forename: E
authors.initials: E
authors.lastname: Debien
authors.forename: M
authors.initials: M
authors.lastname: Taillardet
authors.forename: E
authors.initials: E
authors.lastname: Verhoeyen
authors.forename: C
authors.initials: C
authors.lastname: Bella
authors.forename: S
authors.initials: S
authors.lastname: Lantheaume
authors.forename: L
authors.initials: L
authors.lastname: Genestier
authors.forename: T
authors.initials: T
authors.lastname: Defrance
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D019070:Cell Lineage / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics; D005312:Fetal Blood / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects*; D006801:Humans; D055666:Lipopeptides / Q000494:pharmacology*; D038041:Lymphopoiesis / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology*; D017154:Stromal Cells / Q000166:cytology; D051194:Toll-Like Receptor 1 / Q000819:agonists* / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D018952:Antigens, CD34; D004268:DNA-Binding Proteins; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; C499308:Rag2 protein, mouse; C495342:TLR2 protein, human; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2