# Cellular and molecular mechanisms driving regeneration and fibrosis of the tendon-bone attachment

> **NIH NIH K99** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $105,737

## Abstract

Project Summary
 Injuries to the tendon-bone attachment, or enthesis, are common and challenging to treat clinically, with
re-rupture rates of up to 94% in patients. The enthesis is composed of a special cellular and matrix composition
which is uniquely tailored to transmit force from tendon to bone, enabling movement. While the mammalian
enthesis can heal, its distinctive structure cannot be restored after injury. Even with existing treatments, healing
forms disorganized scar tissue with compromised function, leading to a higher likelihood of both re-injury and
developing joint degenerative diseases, ultimately impacting patient quality of life. As current treatment options
are limited and highly variable in efficacy, better clinical strategies are needed.
 Unlike mammals, zebrafish can fully regenerate their tendon-bone attachments. Notably, following injury,
preliminary data indicate that endogenous scleraxis a (scxa)-expressing tendon cells in zebrafish proliferate and
migrate to regenerate the enthesis, while their mammalian Scx+ counterparts remain quiescent. The
mechanisms underlying these divergent scxa/Scx+ tendon cell responses after enthesis injury remain unknown
yet may be key to redirecting fibrotic responses into regenerative outcomes in mammals.
 The goal of this proposal is to identify molecular and cellular mechanisms which control cell activation
after injury by employing a combination of multiphoton imaging, chemical, genetic, and cross-species
comparative genomic approaches in both zebrafish and mice. During the mentored K99 phase, mechanisms
that are required and sufficient for tendon cell proliferation and recruitment after enthesis injury will be identified
(Aims 1 and 2). In the independent R00 phase, Dr. Tsai will investigate the role of surrounding cell populations
in enthesis regeneration and elucidate how their injury-responsive signaling interactions with tendon cells diverge
between zebrafish and mammals to drive regeneration or scarring (Aim 3). These findings will not only uncover
instructive cues directing regenerative and fibrotic responses which may be leveraged to inspire novel strategies
to treat enthesis injuries, but also expose basic principles underlying scarring which may extend to other tissues.
The extensive training plan in the K99 phase will be conducted under the mentorship of Dr. Jenna Galloway and
co-mentor Dr. Jayaraj Rajagopal at the Center for Regenerative Medicine at MGH, a collaborative and
intellectually vibrant research community with ample opportunities for scientific and professional skill
development. In addition to boosting grant writing and leadership skills, Dr. Tsai will also acquire scientific
expertise in new areas with the aid of her advisory committee and collaborators. These include enthesis healing
and biomechanics (Dr. Elazar Zelzer, Dr. Stavros Thomopoulos), single cell ATAC-sequencing (Dr. Mansi
Shrivastava, Dr. Rajagopal), and cross-species comparative genomics (Dr. Bo Wang)...

## Key facts

- **NIH application ID:** 10948604
- **Project number:** 1K99AR084574-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Stephanie L Tsai
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $105,737
- **Award type:** 1
- **Project period:** 2024-07-05 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10948604

## Citation

> US National Institutes of Health, RePORTER application 10948604, Cellular and molecular mechanisms driving regeneration and fibrosis of the tendon-bone attachment (1K99AR084574-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10948604. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*