# Dynamics and Regulations of Bone Stem Cells in Vivo

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $370,500

## Abstract

PROJECT SUMMARY/ABSTRACT
Bone disorders and deformities are prevalent in children and young adults. Due to lack of effective modalities
to regenerate growing bones, these young patients often undergo multiple surgical interventions, posing a
significant burden on them, their family and society. During bone growth, chondrocytes and osteoblasts are
continuously generated to make bones bigger and stronger. Endogenous bone stem cells that serve as the
source of these cells have not been completely understood. Fundamental knowledge of how these bone stem
cells coordinate the two processes of endochondral and intramembranous ossification is essential to develop a
reliable approach to regenerate growing bones. In this project, the characteristics of distinct types of bone stem
cells that actively promote bone growth will be identified. We hypothesize that a subset of resting chondrocytes
in the postnatal growth plate behave as growth-associated bone stem cells, and become a source of
mesenchymal stromal progenitor cells in bone marrow; these two types of bone stem/progenitor cells
concertedly promote proper bone growth and maintenance. Identifying characteristics and molecular
regulations of bone stem cells will facilitate our endeavor to reproduce these cells through regenerative
engineering. In Aim1, we will identify molecular mechanisms regulating properties and fates of resting
chondrocytes. The working hypothesis is that resting chondrocytes of the postnatal growth plate exhibit unique
characteristics as growth-associated bone stem cells, whose properties and fates are regulated by Hedgehog
signaling. We will first identify a self-renewing multipotent subpopulation of resting chondrocytes using in vitro
colony-forming assays and in vivo transplantation of isolated growth plate cells. We will second identify the
unique gene expression profiles of self-renewing colony-forming resting chondrocytes. We will further define
roles of Hedgehog signaling in determining self-renewal and differentiation of resting chondrocytes by
modulating its signaling components, while simultaneously tracing their behavior both in vivo and in vitro. In
Aim2, we will define formation and fates of bone marrow mesenchymal stromal progenitors in growing bones.
The working hypothesis is that growth plate chondrocytes undergo hypertrophy and transform into Cxcl12-
abundant reticular (CAR) cells in bone marrow that behave as regional and reactive mesenchymal stromal
progenitor cells. We will first define differentiation potentials of CAR cells into osteoblasts and adipocytes in
vivo through intermittent PTH administration and a high-fat diet containing rosiglitazone. We will second
determine CAR cells' response to injury using a semistabilized tibial fracture model. We will also identify effects
of these manipulations on CAR cells' expression levels of key transcription factors that regulate cell fate choice.
We will third define the properties of CAR cells as mesenchymal stromal...

## Key facts

- **NIH application ID:** 9841374
- **Project number:** 5R01DE026666-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Noriaki Ono
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $370,500
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841374

## Citation

> US National Institutes of Health, RePORTER application 9841374, Dynamics and Regulations of Bone Stem Cells in Vivo (5R01DE026666-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9841374. Licensed CC0.

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