CXCL8 and CXCR1 Remodel the Vascular Niche to Promote Hematopoietic Stem and Progenitor Cell Colonization and Engraftment [wt vs kdrl:cxcr1]

The microenvironment is an important regulator of hematopoietic stem and progenitor cell (HSPC) biology. Interactions between the niche and stem cells have been difficult to track, but recent advances marking fluorescent HSPCs have allowed exquisite visualization in the caudal hematopoietic tissue (CHT) of the developing zebrafish. Sinusoidal endothelial cells interact closely with HSPCs as they colonize this niche. Here we show that the chemokine cxcl8 and its receptor, cxcr1, are abundantly expressed by zebrafish endothelial cells and we identify cxcl8/cxcr1 signaling as a positive regulator of HSPC colonization using genetic gain- and loss-of-function techniques. Single-cell tracking experiments demonstrated that this effect is due to an increase in HSPC “cuddling” by endothelial cells, thereby increasing CHT residency time and allowing more HSPC cell divisions to occur. Enhanced cxcl8/cxcr1 signaling was associated with an increase in the volume of the CHT and induction of cxcl12a expression, favoring HSPC colonization. Finally, using parabiotic zebrafish, we show that cxcr1 acts stem cell non-autonomously to improve the efficiency of donor HSPC engraftment. This work identifies a mechanism by which the hematopoietic niche remodels to promote HSPC engraftment and suggests that cxcl8/cxcr1 signaling is a potential therapeutic target in patients undergoing hematopoietic stem cell transplantation. Overall design: Kdrl:mcherry and kdrl:mcherry;kdrl:cxcr1 zebrafish were dissociated and endothelial cells purified by FACS. RNA-seq libraries were prepared from endothelial cells purified from two independent clutches of fish (four libraries total).

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Blaser BW, Moore JL, Hagedorn EJ, Li B, Riquelme R, Lichtig A, Yang S, Zhou Y, Tamplin OJ, Binder V, Zon LI