Narrative review of bovine milk exosomes as a potential therapeutic option for hepatic fibrosis

Background and Objective: Exosomes and their microRNAs (miRNAs) are in the focus of recent research as they modify the homeostasis of hepatic stellate cells (HSCs) and play key roles in liver fibrogenesis as well as the resolution of hepatic fibrosis (HF). At present, no effective therapy of HF exists. Exosomes and their miRNA cargo are involved in the pathogenesis and resolution of HF. It is the intention of this narrative review to provide basic research evidence for oral administration of bovine milk-derived exosomes (BMEX) as a new treatment option of HF. Methods: English literature published between 2000–2021 were searched using the PubMed database focusing on publications including HF, exosomes, miRNAs, fibrogenic and anti-fibrogenic miRNAs has been performed and related to known effects BMEX and their miRNAs. Key Content and Findings: BMEX and their miRNAs accumulate in the liver after oral administration, are able to transit vascular endothelial cells and may thus reach the space of Disse, where HSCs reside. Dominant BMEX-derived miRNAs (miRNA-148a, miRNA-29s and let-7 family) are known suppressors of fibrogenic transcription factors and signaling components including DNMT1, DNMT3A, DNMT3B, TLR4, NF-κB, USP4, SMADs, PDGFB, CTGF, CCKBR, PTHLH, Hedgehog signaling, ATG7 and BECN1. Anti-fibrogenic effects of BMEX may be augmented by co-administration of metformin, a known suppressor of the miRNA sponge lncRNA-H19 further increasing the expression of anti-fibrogenic miRNA-148a, miRNA-29b and let-7 and suppressing the fibrogenic and oncogenic miRNA-21. Conclusions: Presented basic research evidence suggests promising anti-fibrogenic effects of BMEX either alone or combined with other drugs increasing the expression of anti-fibrogenic miRNAs in the treatment of HF. Our narrative review should stimulate future experimental and clinical research.