CXCR2 modulates bone marrow vascular repair and haematopoietic recovery post‐transplant

Haematopoietic stem and progenitor cells (HSPCs) are responsible for the generation and maintenance of all the blood cells in the body. In adults, the major site of haematopoiesis is the bone marrow, a structure which houses cellular components that form specialized micro‐environmental niches, which tightly control the quiescence, self‐renewal and differentiation of HSPCs (Wolf & Trentin, 1968; Schofield, 1978; Wilson & Trumpp, 2006; Sacchetti et al, 2007; Morrison & Spradling, 2008; Sugiyama & Nagasawa, 2012; Ding & Morrison, 2013). Studies in mice have demonstrated that pre‐conditioning regimes prior to bone marrow transplantation (BMT) can significantly affect the integrity of the bone marrow vasculature and that vascular repair of this niche following pre‐conditioning is an essential pre‐requisite for successful HSPC engraftment (Rafii et al, 2003; Avecilla et al, 2004; Kopp et al, 2005; Hooper et al, 2009; Butler et al, 2010; Kobayashi et al, 2010). Slayton et al (2007) also showed that the regenerated bone marrow sinusoidal endothelium following pre‐conditioning is host‐derived. These studies highlight the importance of the vascular niche in BMT and warrant further research focused on modulating the repair of this niche for therapeutic intervention. Although a role for positive regulators of murine bone marrow angiogenesis, such as Angiopoietin 1 (ANGPT1) and vascular endothelial growth factor A (VEGFA), has started to emerge (Avecilla et al, 2004; Kopp et al, 2005; Hooper et al, 2009), studies on the human bone marrow endothelial niche have been hampered by a lack of suitable tissue‐specific in vitro models. Chemokine (C‐X‐C motif) ligand 8 (CXCL8), a chemokine produced by various cells, is widely associated with inflammation and neutrophil recruitment, but is also a potent human pro‐angiogenic factor (Heidemann et al, 2003; Kimura et al, 2011; Singh et al, 2011; Roubelakis et al, 2013). Additionally, the CXCL8/chemokine (C‐X‐C motif) receptor 2 (CXCR2) pathway can be targeted to inhibit tumour angiogenesis (Singh et al, 2010; Nannuru et al, 2011). However, the role of this chemokine and receptor in supporting bone marrow angiogenesis and haematopoietic recovery following myeloablation is novel and has not been previously investigated. In this study, we found that the CXCL8/CXCR2 pathway modulated bone marrow angiogenesis and therefore haematopoiesis. These results may be relevant both clinically and in strategies aimed at improving HSPC reconstitution.