Our findings directly interface with the role of CXCL SDF

Our findings directly interface with the role of CXCL12 (SDF1)/CXCR4 signaling in adult HSPC migration: CXCL12 levels increase in response to stress and inflammation, and influence HSPC mobilization and extravasation within the adult BM (Dar et al., 2006). As hematopoietic niches are hypoxic during HSPC specification, budding, and migration and recently shown to be under inflammatory regulation, our discovery that Mmp9-mediated modulation of Cxcl12 signaling is necessary to ensure proper HSPC maturation in the faah inhibitors illustrates functional parallels between embryonic and adult niches, despite differing cellular components. The CXCL12/CXCR4 axis has previously been therapeutically exploited to improve HSC transplantation: the CXCR4 inhibitor plerixafor (AMD3100), which prevents CXCL12 binding, is administered before BM donation to increase HSPC mobilization (Dar et al., 2006). The HSPC mobilizing agent Me6Tren also promotes HSPC migration by inducing MMP9, leading to disruption of CXCL12/CXCR4 signaling (Zhang et al., 2013). This shows the therapeutic relevance of our characterization of the relationship between chemokine signaling, MMP9, and HSPC migration, and raises the possibility that administration of CXCL12/CXCR4 modulators with known inducers of HSPC specification and expansion, such as PGE2, may ensure that HSPCs can correctly home to and seed the recipient BM niche. Taken together, our data and the previously described roles of MMP2 and MMP9 in tissue remodeling (Giannandrea and Parks, 2014), cytokine regulation (Parks et al., 2004), and cell migration/localization (Zhang et al., 2013) suggest a model whereby these enzymes provide HSPCs with physical “permission” to leave the niches and move to other hematopoietic sites, likely affecting their maturation, expansion, or function. The wide variety of substrates cleaved by MMPs and their expression throughout embryonic development and in the adult suggests that MMP2 and MMP9 are part of a larger mechanism by which the niche provides instructive cues affecting organ development and homeostasis. Further understanding of the intersections between inflammatory signaling, ECM remodeling, and hematopoiesis could be exploited to improve in vitro and in vivo HSPC expansion efforts, as well as HSC mobilization and transplantation. Here, we find that via a combination of direct and indirect mechanisms, including ECM degradation and regulation of chemokine activity, Mmp2 and Mmp9 work to maintain HSPC equilibrium within embryonic hematopoietic niches. This work furthers our understanding of the biophysical details underlying embryonic HSPC production and function in vivo.
Experimental Procedures
Author Contributions
Introduction Hematopoietic stem cells (HSCs) are a distinct population of multipotent cells that can self-renew and differentiate into various types of blood cells and thus are responsible for maintenance and homeostasis of a healthy hematopoietic system (Morrison et al., 1995; Orford and Scadden, 2008; Orkin and Zon, 2008). HSCs are exposed daily to internal and external stresses which in turn lead to DNA damage. Accumulation of DNA damage in hematopoietic stem and progenitor cells (HSPCs) during the cell\'s life span is a factor of hematopoietic system aging and degeneration, and likely contributes to transformation and cancer development (Rossi et al., 2008). Accelerated bone marrow (BM) degeneration leading to BM failure and high risks of leukemia development is frequently observed in diseases with a deficiency in DNA repair pathways such as Fanconi anemia (FA) (Taniguchi and D\'Andrea, 2006). FA is an inherited disease caused by mutations in any of 17 already identified FA DNA repair pathway genes (FANCA-S) (Kottemann and Smogorzewska, 2013; Sawyer et al., 2015). FA proteins have been mainly studied for their role in genomic DNA repair and genome integrity. Upon DNA damage, eight of the FA proteins (FANCA, -B, -C, -E, -F, -G, -L, and -M) interact to form the FA core complex responsible for FANCD2 and FANCI activation by mono-ubiquitination (Kottemann and Smogorzewska, 2013). FANCD2 activation is essential for genome integrity maintenance upon double DNA strand break or interstrand crosslinking by favoring the homologous recombination (HR) DNA repair pathway.