Blood stem cell fate regulation by Delta-1 mediated rewiring of IL-6 paracrine signaling.

Publication Type:

Journal Article

Source:

Blood (2013)

Keywords:

2013, Clinical Research Division, December 2013

Abstract:

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, is poorly understood. Herein we demonstrate that although DL1 activates STAT3 signaling similarly to the gp130-activating cytokine 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-6R expression, converting progenitor cells from being directly IL-6 responsive, to requiring both IL-6 and the soluble (s) IL-6R for activation. Concomitant reduction of both mIL-6R (by DL1 supplementation) and sIL6R (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 wherein DL1 changes cytokine receptor distributions on hematopoietic cells, altering feedback networks and their impact on stem cell fate.