Neuropeptide Y regulates a vascular gateway for hematopoietic stem and progenitor cells

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

“…Contrary to the prior hypothesis suggesting that CXCL12 cleavage by hematopoietic CD26 promotes HSPC migration out of the BM, Singh and colleagues showed that hematopoietic expression of CD26 is not essential for HSPC mobilization. Moreover, CD26 expression was reduced in mobilized HSPCs, and deletion of CD26 in murine HSPCs did not alter HSPC mobilization in a WT environment (1). These unexpected results align with recent reports indicating that CD26 truncates inflammatory cytokines into a nonactive form (18,19) and, as such, may interfere with the hematopoietic response during alert and stress conditions.…”

“…Singh et al provide important insight into the complex mechanism that regulates stem cell mobilization by molecularly eavesdropping on the crosstalk among blood, bone, and brain elements (1). Previous studies have shown the importance of the CXCL12/CXCR4 axis in regulating HSPC mobilization as the immediate response to alarm or stress (2).…”

“…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 NPYmediated signaling by increasing the bioavailability of the truncated form of NPY.…”

Peripheral Blood Stem Cell Mobilization: a Look Ahead

“…Recently, proof was provided that mobilization of repopulating HSC by G-CSF is in fact reduced by inhibition of DPP4/CD26, however, using chimeric mice created by transplanting bone marrow from wild-type or CD26 knockout mice into syngeneic wild-type or CD26 knockout recipient mice, it was found that HSPC-intrinsic CD26 expression was not required for HSPC egress in response to G-CSF but rather mobilization was dependent on CD26 expression on stromal cells [63]. Moreover, G-CSF associated degradation of SDF-1 occurred equally in wild-type and CD26 knockout mice or mice treated with a DPP4 enzyme inhibitor, as determined by MASS Spectrometry.…”

How to say NO to vascular disruption and stem cell mobilization

“…The microvasculature, in particular, has classically been associated with the control of HSC traffic [12]. Far from being a passive gateway, endothelial cells surrounding specialized vessels in the BM regulate HSC anchorage by producing a complex milieu of adhesion molecules, cytokines, growth factors, and extracellular matrix [13,14].…”