Open the gates: vascular neurocrine signaling mobilizes hematopoietic stem and progenitor cells
Tomer Itkin, … , Jesús María Gómez-Salinero, Shahin Rafii
Tomer Itkin, … , Jesús María Gómez-Salinero, Shahin Rafii
Published November 13, 2017
Citation Information: J Clin Invest. 2017;127(12):4231-4234. https://doi.org/10.1172/JCI98323.
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Commentary

Open the gates: vascular neurocrine signaling mobilizes hematopoietic stem and progenitor cells

Abstract

Mobilization of hematopoietic stem and progenitor cells (HSPCs) from the bone marrow (BM) into the peripheral blood is a complex process that is enhanced dramatically under stress-induced conditions. A better understanding of how the mobilization process is regulated will likely facilitate the development of improved clinical protocols for stem cell harvesting and transplantation. In this issue of the JCI, Singh et al. (1) showed that the truncated cleaved form of neurotransmitter neuropeptide Y (NPY) actively promotes a breach of BM vascular sinusoidal portals, thereby augmenting HSPC trafficking to the circulation. The authors report a previously unrecognized axis, in which expression of the enzyme dipeptidylpeptidase-4 (DPP4)/CD26 by endothelial cells activates NPY-mediated signaling by increasing the bioavailability of the truncated form of NPY. These findings underscore the importance of and urgency to develop pharmacological therapies that target the vasculature and regulate diverse aspects of hematopoiesis, such as HSPC trafficking, in steady-state and stress-induced conditions.

Authors

Tomer Itkin, Jesús María Gómez-Salinero, Shahin Rafii

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Figure 1

Model of the mechanisms that promote G-CSF–induced HSPC mobilization.

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Model of the mechanisms that promote G-CSF–induced HSPC mobilization. G-...
G-CSF stimulation activates the redelivery of CXCL12 (red) from the BM to the vessel lumen by the endothelium-expressed CXCR4 receptor (pink), thereby favoring mobilization of HSPCs to the periphery. In parallel, CD26 (yellow) levels are increased on the ECs, promoting NPY cleavage into its truncated form (NPY3-36, dark green), which in turn binds with higher affinity to NPYR2/5 (blue). Stimulation of NPY receptors triggers VE-cadherin (purple) internalization and degradation, enhancing BM vascular permeability. Increasing the permeability of the vascular barrier further promotes HSPC activation by enhancing intracellular HSPC ROS levels, HSPC motility, and the HSPC-expressed CXCR4 response to the CXCL12 gradient. Thus, the CD26/NPY3-36/NPYR2/5 axis activates the vascular arm that favors the transendothelial migration of HSPCs into the peripheral blood. In the absence of CD26, NPY cryptic domain truncation is impaired, diminishing NPYR2/5 activation. As a consequence, in CD26-deficient mice, the vascular barrier retains the same steady-state permeability properties, preventing the full activation and translocation of BM HSPCs into the sinusoidal lumen.