Simon G Royce1,2, Krupesh P Patel1, WeiYi Mao1, Dandan Zhu3, Rebecca Lim3, Chrishan S Samuel1,4. 1. Cardiovascular Disease Program, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia. 2. Department of Medicine, Central Clinical School, Monash University, Clayton, Victoria, Australia. 3. The Ritchie Centre, Hudson Institute of Medical Research and Department of Obstetrics and Gynecology, Monash University, Clayton, Victoria, Australia. 4. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia.
Abstract
BACKGROUND AND PURPOSE: There is growing interest in stem cell-derived exosomes for their therapeutic and regenerative benefits given their manufacturing and regulatory advantages over cell-based therapies. As existing fibrosis impedes the viability and efficacy of stem cell/exosome-based strategies for treating chronic diseases, here we tested the effects of the anti-fibrotic drug, serelaxin, on the therapeutic efficacy of human amnion epithelial cell (AEC)-derived exosomes in experimental lung disease. EXPERIMENTAL APPROACH: Female Balb/c mice were subjected to either the 9.5-week model of ovalbumin and naphthalene (OVA/NA)-induced chronic allergic airway disease (AAD) or 3-week model of bleomycin (BLM)-induced pulmonary fibrosis; then administered increasing concentrations of AEC-exosomes (5 μg or 25μg), with or without serelaxin (0.5mg/kg/day) for 7-days. 1x106 AECs co-administered with serelaxin over the corresponding time-period were included for comparison in both models, as was pirfenidone-treatment of the BLM model. Control groups received saline/corn oil or saline, respectively. KEY RESULTS: Both experimental models presented with significant tissue inflammation, remodelling, fibrosis and airway/lung dysfunction at the time-points studied. While AEC-exosome (5 μg or 25μg)-administration alone demonstrated some benefits in each model, serelaxin was required for AEC-exosomes (25μg) to rapidly normalise chronic AAD-induced airway fibrosis and airway reactivity, and BLM-induced lung inflammation, epithelial damage and subepithelial/basement membrane fibrosis. Combining serelaxin with AEC-exosomes (25μg) also demonstrated broader protection compared to co-administration of serelaxin with 1x106 AECs or pirfenidone. CONCLUSIONS AND IMPLICATIONS: Serelaxin enhanced the therapeutic efficacy of AEC-exosomes in treating basement membrane-induced fibrosis and related airway dysfunction.
BACKGROUND AND PURPOSE: There is growing interest in stem cell-derived exosomes for their therapeutic and regenerative benefits given their manufacturing and regulatory advantages over cell-based therapies. As existing fibrosis impedes the viability and efficacy of stem cell/exosome-based strategies for treating chronic diseases, here we tested the effects of the anti-fibrotic drug, serelaxin, on the therapeutic efficacy of human amnion epithelial cell (AEC)-derived exosomes in experimental lung disease. EXPERIMENTAL APPROACH: Female Balb/c mice were subjected to either the 9.5-week model of ovalbumin and naphthalene (OVA/NA)-induced chronic allergic airway disease (AAD) or 3-week model of bleomycin (BLM)-induced pulmonary fibrosis; then administered increasing concentrations of AEC-exosomes (5 μg or 25μg), with or without serelaxin (0.5mg/kg/day) for 7-days. 1x106 AECs co-administered with serelaxin over the corresponding time-period were included for comparison in both models, as was pirfenidone-treatment of the BLM model. Control groups received saline/corn oil or saline, respectively. KEY RESULTS: Both experimental models presented with significant tissue inflammation, remodelling, fibrosis and airway/lung dysfunction at the time-points studied. While AEC-exosome (5 μg or 25μg)-administration alone demonstrated some benefits in each model, serelaxin was required for AEC-exosomes (25μg) to rapidly normalise chronic AAD-induced airway fibrosis and airway reactivity, and BLM-induced lung inflammation, epithelial damage and subepithelial/basement membrane fibrosis. Combining serelaxin with AEC-exosomes (25μg) also demonstrated broader protection compared to co-administration of serelaxin with 1x106 AECs or pirfenidone. CONCLUSIONS AND IMPLICATIONS: Serelaxin enhanced the therapeutic efficacy of AEC-exosomes in treating basement membrane-induced fibrosis and related airway dysfunction.
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