# The role of Nerve-fibroblast communication in EDS pain

> **NIH NIH R21** · RUSH UNIVERSITY MEDICAL CENTER · 2024 · $351,223

## Abstract

Classic Ehlers Danlos Syndrome (cEDS) is characterized by skin hyperextensibility and fragility, wound
healing problems, and joint hypermobility. cEDS is caused by genetic defects in genes that encode type V
collagen (COL5A1 and COL5A2). Chronic widespread pain is one of the most common and intractable, yet
barely studied, complaints in all EDS patients, and cEDS patients are in great need of new non-opioid pain
therapies. Research into the characteristics and mechanisms of pain in EDS is exceedingly limited. A unique
collaboration between the Chicago Center on Musculoskeletal Pain (C-COMP) and the Center for Medical
Genetics at Ghent University (Belgium) has uncovered critical, novel observations in cEDS patients and in
Col5a1 haploinsufficient (Col5a1+/-) mice, a validated model of cEDS. Quantitative sensory testing in cEDS
patients revealed mechanical pain hypersensitivity. Likewise, Col5a1+/- mice manifest widespread mechanical
allodynia, accompanied by abnormal skin innervation by nociceptors. Fibroblasts are the principal source of
abnormal type V collagen, and cEDS fibroblasts show transcriptome-wide changes, including genes related to
cell proliferation, migration, wound healing, and axonal guidance. While it has been recognized that fibroblasts
may contribute to peripheral sensitization of nociceptors through secretion of sensitizing molecules, in depth
studies into how fibroblasts communicate with the nociceptive system in peripheral tissues to initiate and/or
potentiate pain are surprisingly scant. Here, we will address this critical knowledge gap; we propose that cEDS
provides an excellent model for investigating how fibroblast-nociceptor interactions drive pain in cEDS and other
pain syndromes. We hypothesize that fibroblast-neuron interactions may cause hyperexcitability and/or
abnormal growth of nociceptors in the skin, two of the defining features of cEDS. We are in an unparalleled
position to examine this idea, owing to the unique, complementary resources and state-of-the-art techniques
present in our groups. In Aim 1, we will determine the innervation and cellular transcriptome in skin tissues of
cEDS vs control patients through immunohistochemistry and Visium. To do this, we will leverage the unique
cohort of molecularly and phenotypically characterized cEDS patients available through the Center for Medical
Genetics in Ghent, Belgium. In Aim 2, we will use a neuron-fibroblast microfluidic co-culture system to assess
the effect of Col5a1 mutant fibroblasts on neuronal excitability and neuronal growth/sprouting. In Subaim 2.1,
we will use murine cells to examine the effects of fibroblasts harboring a type V collagen defect on DRG neurons
in co-cultures. In Subaim 2.2, findings will be validated in human microfluidic co-cultures, using human iPSC-
derived sensory neurons with fibroblasts derived from cEDS patients or controls. We anticipate that the findings
generated from the proposed experiments will advance our knowledge of mec...

## Key facts

- **NIH application ID:** 11036741
- **Project number:** 1R21AR085242-01
- **Recipient organization:** RUSH UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Anne-Marie Malfait
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $351,223
- **Award type:** 1
- **Project period:** 2024-09-23 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11036741

## Citation

> US National Institutes of Health, RePORTER application 11036741, The role of Nerve-fibroblast communication in EDS pain (1R21AR085242-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/11036741. Licensed CC0.

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