Subclinical mastitis is an inflammatory disease that affects the milk production, fertility, and lifespan of animals, leading to significant losses to dairy industry. Antibiotics therapies are resulting in suboptimal benefits in treating subclinical mastitis due to prevalent antibiotic resistance in dairy herds. In a quest to develop alternative therapy, umbilical cord-derived mesenchymal stem cells (UCB-MSCs) and its extracellular vesicles (UCB-MSC-EVs) are used, in the present study, to validate its safety and efficacy as potential therapy for treatment of subclinical mastitis in dairy cows with respect to conventional antibiotic therapy (ABT). We isolated, in vitro cultured, and characterized the UCB-MSCs as well as UCB-MSC-EVs. The repeated infusions of low dose MSCs and EVs were delivered in healthy animals for safety analysis, followed by the same administrations in infected animals for therapeutic efficacy analysis. UCB-MSCs and UCB-MSC-EVs were found to be safe at 2 doses with 7-day gap of 5 × 107 cells/injection and EV equivalent to 500 μg protein in DPBS, respectively. Efficacy trials demonstrated significantly decreased somatic cell count to safe levels in milk samples of UCB-MSCs and UCB-MSC-EVs treated groups compared to antibiotic group. The leucocytes expression of anti-inflammatory cytokines, anti-microbial peptides, and angiogenic genes were significantly upregulated in UCB-MSCs and UCB-MSC-EVs treated groups as compared to antibiotic therapy group. Antibiotic therapy and UCB-MSC-EV groups failed to significantly decrease the gene expression of pro-inflammatory cytokine. In conclusion, the administration of UCB-MSCs and UCB-MSC-EVs through intravenous and local routes was found to be safe and efficacious for alleviating subclinical mastitis in dairy cows.
Keywords: Dairy cow; Extracellular vesicles; Mesenchymal stem cells; Stem cell therapy; Subclinical mastitis.
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