Blood stem cell fate regulation by Delta-1-mediated rewiring of IL-6 paracrine signaling.
Increasing evidence supports the importance of cell extrinsic regulation in stem cell fate control. Hematopoietic stem cells (HSC) are responsive to local signals from their niche and to systemic feedback from progenitors and mature cells. The Notch ligand Delta-1 (DL1), a key component of the stem cell niche, regulates human hematopoietic lineage development in a dose-dependent manner and has been used clinically for primitive progenitor expansion. How DL1 acts to regulate HSC fate and whether these actions are related to its lineage skewing effects are poorly understood. Here we demonstrate that, although DL1 activates signal transducer and activator of transcription 3 signaling similarly to the gp130-activating cytokine interleukin-6 (IL-6), it has opposite effects on myeloid cell production. Mechanistically, these different outcomes are attributable to a DL1-mediated reduction in membrane (m)-bound IL-6 receptor (R) expression, converting progenitor cells from being directly IL-6 responsive to requiring both IL-6 and soluble (s) IL-6R for activation. Concomitant reduction of both mIL-6R (by DL1 supplementation) and sIL-6R (using dynamically fed cultures) reduced myeloid cell production and led to enhanced outputs of human HSCs. This work describes a new mode of cytokine action in which DL1 changes cytokine receptor distributions on hematopoietic cells, altering feedback networks and their impact on stem cell fate.
Institute for Biomaterials and Biomedical Engineering and.
Elizabeth
E
Csaszar
Weijia
W
Wang
Tatiana
T
Usenko
Wenlian
W
Qiao
Colleen
C
Delaney
Irwin D
ID
Bernstein
Peter W
PW
Zandstra
D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D019899:Paracrine Communication; D050796:STAT3 Transcription Factor / Q000378:metabolism
D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D050796:STAT3 Transcription Factor; C064045:delta protein; D053612:Janus Kinases