Paracrine signaling gradients regulate leukocyte recruitment to injury, infection or tumor sites during chemotaxis. Leukocytes detect concentration gradients of chemotactic signals and migrate to the source. It is becoming increasingly evident from work in whole animal tissues that contact guidance from physical structures within the surrounding environment (e.g. cells, ECM) is important to orient migrating cells towards their target. This suggests that both diffusive chemotactic signals and a permissive tissue environment must be in place to permit rapid leukocyte migration to reestablish tissue homeostasis. Our preliminary results, using intravital imaging in a Zebrafish wound detection model, demonstrate that wounding triggers adjacent epithelial cell rearrangements and that leukocytes utilize these tissue modifications for migration to the wound. These preliminary findings support the hypothesis that, in addition to direct leukocyte chemotaxis in vivo, paracrine signals derived from an injury site produce structural changes in surrounding tissue architecture that promote cell migration. Using the Zebrafish wounding model, we will address the following aims: (1) the wound-induced signals regulating epithelial architecture;(2) the cell-autonomous mechanisms of cell rearrangements in epithelia;and (3) the role of epithelial architecture on leukocyte migration kinetics. We will focus on signaling pathways that have been linked to inflammation in addition to the regulation of tissue architecture. To address the cell biological basis of tissue structural changes, we will analyze the spatiotemporal dynamics of cell junction proteins. Finally, we will determine the physiological relevance of cell rearrangement by analyzing the dynamics of leukocyte migration through epithelial upon inhibition of the cell rearrangement. Upon completion, this proposal will broaden our understanding of the wound response to include a novel modification to surrounding epithelial architecture and the effects on cell migration. Importantly, defining the effects of tissue structural changes on migration will led to advances in our understanding of cell migration in pathological contexts, such as cancer metastasis. These new insights will likely lead to a new generation of therapeutic applications that will modulate cell migration through affecting the permeability of the surrounding tissue environment.
Immune response to injury, infection or tumor growth require that immune cells move through dense regions of the body to clear the danger and protect the well being of the entire animal. Using a live Zebrafish animal model to study how immune cells move through their surroundings, our research will provide a foundation to better understand how all cells, from immune cells to cancer cells, can transit from one part of the body to another. It is our hope that understanding how cell movements occur within a complex organism will promote the identification of new drug treatment strategies to control pathologies such as hyperinflammation and cancer.