The Role of Inflammation and Inflammatory Mediators in Hematopoiesis

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Abstract: The immune response is intimately linked to the dynamics of hematopoietic stem and progenitor cell (HSPCs) regulation, including their production, migration and lineage commitment. We, and others, recently showed that inflammatory signaling upregulates overall HSPC formation in the developing vertebrate embryos. Further, primitive myeloid cells, which act as the first inflammatory intermediates, appear to play an unexpected role in regulating the specification and production of embryonic HSPCs; however, the cellular interactions and biophysical mechanisms downstream of inflammatory stimulation that modulate HSPC number and function remain unknown. Pro-inflammatory matrix metalloproteinases (MMPs) are a group of extracellular matrix (ECM)-remodeling enzymes expressed in response to immune stimuli. Of the 25 known MMPs, MMP2 and MMP9, which comprise the “gelatinase” family, are tightly associated with inflammation and secreted by adult HSPCs to break down bone marrow endothelium, allow for cell migration, and promote angiogenesis. Additionally, MMP2/9 double knockout mice have dysregulated immune biology, suggesting a potential intersection between inflammatory signaling and MMP-induced niche remodeling that may function to control HSPC emergence, migration and differentiation. HSPCs are born from hemogenic endothelium in the aorta-gonad mesonephros (AGM) region of the embryo, and migrate to/expand in the fetal liver (caudal hematopoietic tissue (CHT) in zebrafish) before colonizing the thymus and marrow. Chemical or genetic inhibition of MMP2, expressed in the endothelial niche during HSPC emergence, retained runx1+ cells in the zebrafish AGM, delaying migration to the CHT; preliminary data indicates this may be due to MMP2-mediated ECM digestion. In contrast, loss of MMP9 did not affect HSPC budding, but instead resulted in aberrant HSPC expansion within the CHT. Our preliminary data suggests that effect is due to MMP9-dependent modulation of SDF1/CXCR4 chemokine signaling, induced downstream of inflammatory stimuli like prostaglandin-E2 (PGE2). Importantly, inhibition of either MMP2 or MMP9 led to abnormal colonization of the thymus, a process dependent on normal HSPC production and function, demonstrating these enzymes are necessary throughout developmental hematopoiesis. Therefore, our central hypothesis is that matrix metalloproteinases, specifically MMP2 and MMP9 regulate the production and migration of HSPCs during developmental hematopoiesis. Our proposed studies will reveal whether MMP2/9 serve as the effector of primitive myeloid cells and inflammatory signaling in controlling HSPCs form and function the hemogenic niche.