# Spatiotemporal regulation of digit regeneration by sensory nerves

> **NIH NIH R21** · TULANE UNIVERSITY OF LOUISIANA · 2022 · $244,262

## Abstract

Specific Aims
The regeneration of the mammalian skeleton requires the action of both intrinsic and extrinsic inductive factors
from multiple cell types which function in a hierarchical and temporal fashion to control skeletal progenitor cell
proliferation and differentiation. Sensory nerves have been shown to be an integral part of the bone fracture
repair process, driving the processes of vascularization, ossification, and mineralization of bone. In contrast to
the bone repair process, regeneration, where new growth replaces both the amputated bone and surrounding
soft tissue varies widely in vertebrates. In mammals, regeneration is restricted to only the distal phalangeal
element. More proximal amputations result in the formation of a hypertrophic callus and failed regeneration.
Significant efforts have been placed on dissecting out the distinguishing signaling pathways differentiating
regenerative versus non-regenerative amputations. Beyond the desire to promote full regeneration, unraveling
these processes could allow us to leverage regenerative mechanisms during repair and tissue-engineering
based bone therapeutic approaches. A handful of prior studies have implicated innervation as an essential
component of regeneration, however they relied on complete sciatic nerve resection, making it impossible to
distinguish nerve-specific regenerative outcomes from mechanical loading-induced effects, and the relationship
between innervation and regeneration remains unclear.
Using transgenic mouse models and pharmacological inhibition, our preliminary results point to a severe delay
in digit regeneration following inhibition of sensory nerve tropomycin receptor kinase A (TrkA). In the context of
previous literature, we propose that sensory nerve TrkA signaling is necessary for proper digit regeneration.
Specifically, we propose that: i) sensory nerves are recruited to the amputation site early in the healing process
through the nerve growth factor (NGF)-TrkA signaling axis established in our lab, ii) sensory nerve-derived
signals play an essential role in promoting blastema formation and maintaining cells in a proliferative,
osteogenically primed state, and thus, iii) disruption of sensory nerve signaling through transgenic and/or
pharmacological inhibition severely impairs digit bone regeneration.
Specific Aim 1: Define the spatiotemporal patterning of sensory innervation and characterize the effects of
sensory nerve TrkA signaling disruption during digit regeneration
Hypothesis: Sensory nerve outgrowth and signaling coincides with wound closure, blastema formation and
proliferation, initiating overall digit regeneration.
Preliminary results using a transgenic knockin mouse model (TrkAF592A), demonstrate a substantial deficit in digit
regeneration. In Aim 1 we will first conduct a comprehensive study on the temporal and spatial patterning of
neurotrophin expression and sensory innervation during early and late stages of digit regeneration. Here, we wil...

## Key facts

- **NIH application ID:** 10452887
- **Project number:** 1R21HD106162-01A1
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Mimi C Sammarco
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $244,262
- **Award type:** 1
- **Project period:** 2022-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10452887

## Citation

> US National Institutes of Health, RePORTER application 10452887, Spatiotemporal regulation of digit regeneration by sensory nerves (1R21HD106162-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10452887. Licensed CC0.

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