# Modulating Cell-fate to Promote Regenerative Tendon Healing

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2021 · $447,703

## Abstract

Tendon injuries heal in a fibrotic manner via chronic deposition of excessive, disorganized extracellular matrix.
Myofibroblasts are a critical driver of fibrosis in many tissues, and emerging evidence demonstrates
myofibroblast heterogeneity. That is, myofibroblasts with unique molecular profiles that correspond to changes
in myofibroblast function. Importantly, the fibroblast lineage from which myofibroblasts are derived also plays a
major role in dictating myofibroblast function. However, very little is known about myofibroblast dynamics
during fibrotic tendon healing, including their fibroblast/tenocyte-lineage, how their functions change over time,
what the molecular profiles of these different myofibroblast subtypes are, and how myofibroblasts interact with
other cells, such as macrophages, to mediate healing and fibrosis. We have identified Scleraxis-lineage and
S100a4-lineage cells as the predominant myofibroblast precursor populations during tendon healing.
Interestingly, depletion of S100a4-cells impairs early tendon healing, while Scx-cell depletion improves late
tendon healing suggesting these cells may give rise to functionally distinct myofibroblast populations. In
addition, our preliminary data identifies macrophages as a critical driver of the tenocyte-myofibroblast
transition, and we observed prolonged macrophage presence during late healing, concomitant with NFB-
mediated pro-survival signaling in myofibroblasts. These data are consistent with a pro-fibrotic feedback loop
between macrophages and myofibroblasts to sustain fibrosis in many tissues. Thus, in the present study we
will use a murine model of acute tendon injury and repair to rigorously define tenocyte lineage-specific
contributions to myofibroblast fate and define myofibroblast heterogeneity during healing. We will test the
central hypothesis that inhibiting macrophage-mediated myofibroblast differentiation and NF-B-mediated
survival of lineage-specific myofibroblasts promotes regenerative tendon healing. We will test this hypothesis
through the following specific aims: Aim 1: Define the temporal and tenocyte lineage-dependent
immunophenotype of myofibroblasts during fibrotic tendon healing. Aim 2: Establish the requirement for
extrinsic macrophages in fibrotic healing via modulation of the tenocyte-myofibroblast transition and test the
translational potential of inhibiting macrophage recruitment. Aim 3: Demonstrate that disrupting myofibroblast
survival or macrophage persistence inhibits sustained fibrosis and promotes regenerative tendon healing.
Successful completion of these studies will establish myofibroblast lineage, molecular profile and activation
mechanisms over time during fibrotic healing and define disruption of persistent myofibroblasts and
macrophages as a novel means to improve tendon healing.

## Key facts

- **NIH application ID:** 10208209
- **Project number:** 1R01AR077527-01A1
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Alayna Loiselle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $447,703
- **Award type:** 1
- **Project period:** 2021-07-08 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10208209

## Citation

> US National Institutes of Health, RePORTER application 10208209, Modulating Cell-fate to Promote Regenerative Tendon Healing (1R01AR077527-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10208209. Licensed CC0.

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