# Psychosocial Stress Effects on Regenerative Medicine Therapies for Lower Urinary Tract Disorders in Nonhuman Primates

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2022 · $676,122

## Abstract

This proposal is a response to PAS-19-241, Stimulating Urology Interdisciplinary Team 
Opportunity Research, the aim of which is to promote innovative, high-quality, 
interdisciplinary research relevant to the NIDDK. Importantly, this PAS and a prior 
workshop identified psychosocial factors in women with urinary incontinence as an important 
knowledge gap. To this end, we bring together experts from behavioral sciences, urology, molecular 
 pathology, and regenerative medicine to explore further our initial findings that 
socially subordinate female monkeys do not respond as well to cell therapy for urinary incontinence 
as their dominant counterparts. We now propose a more comprehensive approach to assess (a) 
sympathetic nervous system (SNS) arousal, hypothalamic-pituitary-adrenal (HPA) activation, and 
 impaired ovarian function in socially housed monkeys; and (b) the likely pathways by 
which social subordination stress affects structural and functional regeneration within 
the urinary sphincter. Two likely pathways through which social subordination stress may 
modulate these processes are cortisol and SNS effects on tissue and cell damaging inflammation and 
estrogen-deficiency-associated inhibition of cell mobilization. These processes are not mutually 
exclusive and may involve the CXCL12/CXCR4 signaling pathway. Based on our previous 
studies and the published literature, our central hypothesis is that psychosocial stress 
inhibits the regenerative effects of cell therapy by reducing the mobilization of tissue 
healing bone marrow progenitor cells, and increasing the presence of hematopoietic tissue 
damaging inflammatory cells in the urinary sphincter. This hypothesis will be tested in a 
prospective, randomized, nonhuman primate preclinical trial using our well-characterized female 
cynomolgus monkey model of psychosocial stress due to social subordination, and our model of 
intrinsic urinary sphincter deficiency. Our Specific Aims are to determine the effect of 
 social status on: 1) the structural (cellular, acellular, vascular, innervation) and 
functional (urinary sphincter and bladder) effects of autologous skMPC therapy in female 
primates with ISD; 2) The injected lenti-M-cherry+ skMPC cell retention in, and lenti GFP+ labeled 
bone marrow cell mobilization to, the urinary sphincter of dominant and subordinate monkeys; 3) The 
effect of social subordination stress on abundance and polarization of inflammatory 
cells and associated molecules in the urinary sphincter; and 4) Whether social status 
effects on cell therapy-induced tissue regeneration are mediated by behavioral stress, SNS, 
HPA, or ovarian function. The results of this translational research will promote understanding 
of limitations and potential future regenerative medicine strategies for women with urinary 
incontinence.

## Key facts

- **NIH application ID:** 10375461
- **Project number:** 5R01DK124639-03
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Carol A. Shively
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $676,122
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375461

## Citation

> US National Institutes of Health, RePORTER application 10375461, Psychosocial Stress Effects on Regenerative Medicine Therapies for Lower Urinary Tract Disorders in Nonhuman Primates (5R01DK124639-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10375461. Licensed CC0.

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