# Coordinated resident macrophage-tenocyte signaling in tendon formation

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2024 · $200,874

## Abstract

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.

## Key facts

- **NIH application ID:** 10886827
- **Project number:** 5R21AR081564-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Nathaniel A. Dyment
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $200,874
- **Award type:** 5
- **Project period:** 2023-08-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10886827

## Citation

> US National Institutes of Health, RePORTER application 10886827, Coordinated resident macrophage-tenocyte signaling in tendon formation (5R21AR081564-02). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10886827. Licensed CC0.

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