# Pulp fibroblast-mediated inferior alveolar nerve regeneration

> **NIH NIH R03** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2021 · $159,900

## Abstract

Project Summary/Abstract
 The dental pulp is composed of a supporting reticular matrix containing blood vessels, nerves, stromal
fibroblasts and few specific stem cells. Regenerative medicine has focused on the dental pulp stem cell as a
ready source of multipotential adult stem cells. However, the dental pulp fibroblast also may provide important
cues for the functioning dental pulp. Included is the dental pulp fibroblast’s support of nerve repair. This project
adopts an innovative and alternative approach to regenerative sciences by leveraging the neurotrophic features
of dental pulp fibroblasts, potentially for nerve regeneration therapies. Here we explore ways of enhancing this
neurotropic function of pulp fibroblasts via a novel C5L2 pathway involving p38 map kinase (p38) signaling. We
recently studied the complement C5a receptor (C5aR) as one of the initial events that control the brain-derived
neurotrophic factor (BDNF) secretion. This resultant BDNF secretion induces neurite outgrowth towards the
injury site. Whereas C5a is known to interact with its G-coupled protein receptor C5aR, another controversial
C5a receptor has been cloned. The C5L2 was considered as a non-functional decoy receptor of C5a signaling,
thus has received much less attention than C5aR. Preliminary data demonstrate that C5L2 inhibition by siRNA
significantly increases the pulp fibroblast-mediated BDNF secretion and neurite outgrowth. We provide further
evidence that p38 plays a key role in the pulp fibroblast-mediated BDNF modulation. Based on our observations,
we hypothesize that pulp fibroblasts enhance nerve regeneration by a paracrine function of secreted
neurotrophic factors via the C5L2 and p38 pathways. In this proposal, we will characterize the mechanisms of
C5L2 action in the pulp fibroblast-mediated nerve outgrowth in vitro. We will use an axon investigation system
device (AXIS) to identify the interaction with C5L2 and p38, and whether C5L2 function is dependent or
independent of C5a/C5aR. We will further determine, in vivo, whether C5L2 acts on pulp fibroblast functions to
control IAN regeneration using our mouse IAN regeneration model by transplantation of the C5L2-silenced pulp
fibroblasts. In our follow-on R01, we will investigate how pulp fibroblast-mediated nerve regeneration and C5L2
signaling impact functional plasticity: (a) whether the gene knockout approaches demonstrate nerve regenerative
potential using in vivo IAN regeneration model, (b) whether the transplantation of engineered pulp fibroblasts
and dental pulp stem cells that constitutively express and BDNF into the IAN denervation model can enhance
nerve regeneration, (c) the consequence of nerve regeneration regarding pulp and dentin healing, and (d) the
consequence of nerve regeneration regarding a behavioral (i.e., pain) effect. The results obtained from this
project will shed new light onto cellular and molecular events which orchestrate initial steps of nerve regeneration
by linking the...

## Key facts

- **NIH application ID:** 10169408
- **Project number:** 5R03DE028637-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Seung Chung
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $159,900
- **Award type:** 5
- **Project period:** 2020-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169408

## Citation

> US National Institutes of Health, RePORTER application 10169408, Pulp fibroblast-mediated inferior alveolar nerve regeneration (5R03DE028637-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10169408. Licensed CC0.

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