# Defining periosteal skeletal stem cells and novel migration mechanisms in bone regeneration and repair in vivo

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $415,284

## Abstract

PROJECT SUMMARY/ABSTRACT
Significant bone loss and defective bone healing in age-related bone diseases cause severe pain and high
morbidity and mortality, and are a major health issue in the U.S. Lifelong regeneration of bone and cartilage
requires skeletal stem cells (SSCs), and a skeletal stem/progenitor cell subset in periosteum (P-SSCs) has
been known to play an important role for bone repair. However, due to the wide tissue distribution of SSCs and
the lack of specific markers to distinguish rare P-SSCs in vivo, how endogenous P-SSCs respond to bone
injury and how they function in bone healing are unknown. Therefore, the goal of our proposal is to define the
in vivo identity and function of P-SSCs and the mechanisms that regulate P-SSCs in order to control bone
regeneration and repair under physiologic circumstances. We will also explore the induction of endogenous P-
SSC migration and proliferation with the goal of improving recovery from age-related bone injuries. Using
newly generated reporter mouse models in combination with intravital imaging technology, we recently
determined that a combination of SSC markers, myxovirus resistance-1 (Mx1) and alpha smooth muscle actin
(αSMAGFP) can selectively label endogenous P-SSCs that are exclusively present in the periosteal cambial
layer with Prx1GFP expression. In addition, sequential in vivo imaging revealed that Mx1 αSMAGFP P-SSCs,
rather than BM-SSCs, rapidly respond to the injury and continually supply new osteoblasts for injury repair in
vivo. These P-SSCs show higher expression of CCR3/CCR5, the receptors for chemokine (C-C motif) ligand 5
(CCL5), than BM-SSCs and other bone cells. Moreover, we found for the first time that periosteal
administration of CCL5 stimulates the real-time migration of these P-SSCs toward injury sites in vivo. Human
primary periosteal cells also express CCR5 and conduct CCL5-mediated migration. We thus hypothesize that
P-SSCs and their migration, upon CCL5 signaling, are necessary for bone repair, and that exogenous
CCL5 provision improves the healing of age-related bone defects. Our novel intravital imaging technology
and the various animal models enable us to track endogenous stem cells present in the periosteum and bone
marrow as well as their differentiation at the single-cell level in living animals. We thus plan to pursue the
following specific aims. In aim 1, we will determine whether inflammatory stimuli such as CCL5 are necessary
for P-SSC migration and bone healing by generating a conditional ablation of CCL5 in immune cells. We will
also examine if CCL5 is specific for P-SSC migration. In aim 2, we will determine whether P-SSCs and their
migration are required for injury repair by performing local ablation of P-SSCs and by generating a conditional
deletion of the CCR5 in P-SSCs. In aim 3, we will determine whether the local provision of exogenous CCL5
induces the migration and activation of endogenous P-SSCs early in the repair process, leading to accel...

## Key facts

- **NIH application ID:** 9970206
- **Project number:** 5R01AR072018-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Dongsu Park
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $415,284
- **Award type:** 5
- **Project period:** 2018-07-09 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970206

## Citation

> US National Institutes of Health, RePORTER application 9970206, Defining periosteal skeletal stem cells and novel migration mechanisms in bone regeneration and repair in vivo (5R01AR072018-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9970206. Licensed CC0.

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