Healing the unhealable: Wharton's jelly stem cell vesicles as a breakthrough for feline chronic skin ulcers

Abstract

Abstract Chronic skin wounds in companion animals, particularly cats, often persist due to a combination of impaired healing responses and underlying primary etiologies, such as trauma, post-surgical dehiscence, pressure ulcers, allekirgic dermatitis, or immune-mediated conditions. Effective management therefore requires both accurate diagnosis and treatment of these primary causes and the implementation of strategies to promote tissue repair and regeneration. While an acute wound typically heals within 4–6 weeks through orderly phases of hemostasis, inflammation, proliferation, and remodeling, a chronic wound remains unresolved beyond this period, often due to prolonged inflammation or disruption of one or more healing stages. This study evaluated the therapeutic efficacy of WJ-MSC-derived EVs in adult cats with chronic ulcers persisting for more than four weeks. These EVs support essential biological processes, including immune modulation, tissue regeneration, cellular homeostasis, anti-inflammatory actions, and anti-fibrotic activity. Twenty cats were divided into two groups: an EV-treated group receiving carboxymethyl cellulose (CMC) gel loaded loaded with Wharton's Jelly mesenchymal stem cell-derived extracellular vesicles (WJ-MSC-derived EVs) (100 μg EV protein/cm2 wound area) alongside standard care, and a control group receiving CMC gel (in house prepared 2% concentration) alone. EV treatment significantly accelerated ulcer healing, with markedly enhanced wound contraction and near-complete closure by Day 16 (92.4 ± 6.8%) compared with controls (58.3 ± 12.1% at Day 16). Histopathology revealed superior epithelialization, earlier collagen deposition, and better connective tissue organization in EV-treated wounds. Immunohistochemistry demonstrated increased α-SMA and CD31 expression, indicating active angiogenesis and tissue remodeling. Additionally, scratch assays showed improved cellular migration in response to EVs. Overall, In this pilot study of client-owned cats, WJ-MSC-derived EVs demonstrated beneficial effects on wound healing, with significantly accelerated contraction and improved histological organization compared to standard care alone. However, due to the small sample size, etiological and therapeutic heterogeneity, and study design limitations, external validity remains limited. These findings suggest WJ-MSC-derived EVs may represent a promising adjunctive therapy for feline chronic ulcers, but larger, etiology-stratified trials are needed before recommending this as an established alternative treatment. Further research should focus on standardizing treatment protocols, identifying optimal patient selection criteria, and evaluating long-term outcomes.