# Examining Skeletal Stem Cell Diversity and its Role in Intervertebral Disc Regeneration

> **NIH NIH F31** · STANFORD UNIVERSITY · 2022 · $35,074

## Abstract

Project Summary/Abstract.
The intervertebral disc (IVD) is a highly specialized, fibrocartilaginous structure that deteriorates at a rate faster
than any other connective tissue in the body. This condition is commonly referred to as IVD degeneration and a
critical challenge for IVD repair is the development of effective treatments that reverses the fibrocartilage
damage. Due to their cell intrinsic properties of self-renewal and differentiation, the utilization of tissue resident
stem cells holds promise as a stem cell-based approach to combat IVD degeneration. Our lab was the first to
identify, isolate and functionally characterize bona fide skeletal stem cells (SSCs) and their committed
downstream progenitors that give rise strictly to bone, cartilage, and marrow stroma in mice and humans32,33.
SSCs are distinct from mesenchymal stromal cells which represent highly heterogenous mixtures of cell types57.
We’ve since have leveraged our knowledge of SSCs to understand degenerative skeletal conditions including
osteoarthritis, non-unions and age-related osteoporosis46,58,59. More recently, we used our isolation methods to
discover tissue resident SSCs within mouse and human IVDs. In this proposal, the overarching objective is to
identify the intrinsic cues that dictate SSC fate into IVD tissue as well as examine the extrinsic cues that may
guide IVD regeneration using a novel microfracture surgical model in the mouse caudal IVD. Our preliminary
data suggests that IVD SSCs are distinctly more chondrogenic than femur SSCs in their differentiation capacity
both in vitro and in vivo. Additionally, we found that mouse IVD SSCs exclusively express HOXA4 and their
skeletal fate decisions can be dictated by the addition of morphogens FGF2, SHH and WNT3A in vitro. We also
found that acute microfracture injury of caudal IVDs in the mouse tail does not amplify resident IVD SSCs and
transplantation of IVD SSCs into microfractured IVD fail to generate fibrocartilage, thus suggesting they may
require the guidance of additional factors for cartilage differentiation in vivo. In this proposal, our overall
hypothesis is that HOXA4 is an intrinsic regulator, while FGF2 is an extrinsic regulator of IVD tissue fate,
and that modulating these pathways in IVD SSCs can be used as a potential stem cell-targeting therapy
for combating IVD degeneration. In Aim 1, we will address this hypothesis by modulating HOXA4 expression
in IVD and femur (control) SSCs via lentiviral transduction and subsequently perform in vitro and in vivo
differentiation assays to assess their cartilagenic IVD output. In Aim 2, we will test if the injection of morphogens
FGF2, SHH and WNT3A can change the fate decision of microfractured resident SSCs to regenerate damaged
IVD tissue in vivo. Ultimately, this set of basic and pre-clinical proposed experiments will further define the
concept the SSC diversity and set the foundation for the clinical translation of stem cell-based therapies for
preventing...

## Key facts

- **NIH application ID:** 10537672
- **Project number:** 1F31AR079265-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Malachia Hoover
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $35,074
- **Award type:** 1
- **Project period:** 2022-08-16 → 2024-08-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10537672

## Citation

> US National Institutes of Health, RePORTER application 10537672, Examining Skeletal Stem Cell Diversity and its Role in Intervertebral Disc Regeneration (1F31AR079265-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10537672. Licensed CC0.

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