Coordinated resident macrophage-tenocyte signaling in tendon formation

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Summary Despite the vast knowledge of the structure and mechanical function of mature tendons, the understanding of tenogenic cell differentiation during development and how cell types from non-tenogenic origins, such as macrophages, influence tenogenesis is limited. Tissue resident macrophages play key roles in the development of several tissues and colony stimulating factor 1 receptor (CSF1R) signaling is essential for their differentiation and survival. The source of ligands that act on CSF1R (CSF1 being the most common) often originate from adjacent resident cells. In addition to CSF1R signaling acting on the macrophages, macrophages often produce trophic factors that act on the adjacent resident cells to regulate aspects of tissue development. In exciting new data, we demonstrate that CSF1R-expressing resident macrophages are situated adjacent to CSF1-expressing tenocytes within linear arrays in the tendon fascicle from initial formation (E15.5) into adulthood, these resident macrophages rapidly accumulate to nearly 10% of the total cell population within tendons during early postnatal growth, and CSF1 produced by tenogenic cells is required for their survival. Additionally, these macrophages internalize collagen in situ, which may indicate a potential role in matrix remodeling during growth and development. Despite their relative abundance and presumed communication with adjacent tenocytes, our limited understanding of the role of resident macrophages in tendon growth and development and potential trophic signaling to tenocytes are significant gaps in knowledge. As macrophages are critical to the development and repair of numerous tissues, defining their role in tendon development will provide insight into signaling mechanisms that could be leveraged in future therapies to improve repair outcomes, which is an unmet clinical need. To address these gaps in knowledge, this proposal will define the ontogeny, distribution, and phenotypic profile of resident macrophages and establish their cross-talk with tenocytes to regulate tendon formation during growth and development. Our central hypothesis is that stable macrophage-tenocyte cross-talk exists and this communication is necessary for tendon formation. Aim 1 will define the ontogeny, abundance, and distribution of resident macrophages with respect to Csf1-expressing tenocytes and the phenotypic profile of these cells at multiple stages of growth and development. Aim 2 will then establish the cross-talk between macrophages and adjacent tenocytes and its role in tendon formation and growth. In this proposal, we will elucidate the importance of stable macrophage-tenocyte cross-talk in promoting cell differentiation and tendon formation in growth and development, thus providing new and critical insight to tendon cell biology that will inform future regenerative strategies.