Exosomes derived from miR‐181‐5p‐modified adipose‐derived mesenchymal stem cells prevent liver fibrosis via autophagy activation

Abstract

Proliferating hepatic stellate cells (HSCs) respond to liver damage by secreting collagens that form fibrous scar tissue, which can lead to cirrhosis if in appropriately regulated. Advancement of microRNA (miRNA) hepatic therapies has been hampered by difficulties in delivering miRNA to damaged tissue. However, exosomes secreted by adipose‐derived mesenchymal stem cells (ADSCs) can be exploited to deliver miRNAs to HSCs. ADSCs were engineered to overexpress miRNA‐181‐5p (miR‐181‐5p‐ADSCs) to selectively home exosomes to mouse hepatic stellate (HST‐T6) cells or a CCl4‐induced liver fibrosis murine model and compared with non‐targeting control Caenorhabditis elegans miR‐67 (cel‐miR‐67)‐ADSCs. In vitro analysis confirmed that the transfer of miR‐181‐5p from miR‐181‐5p‐ADSCs occurred via secreted exosomal uptake. Exosomes were visualized in HST‐T6 cells using cyc3‐labelled pre‐miRNA‐transfected ADSCs with/without the exosomal inhibitor, GW4869. The effects of miRNA‐181‐5p overexpression on the fibrosis associated STAT3/Bcl‐2/Beclin 1 pathway and components of the extracellular matrix were assessed. Exosomes from miR181‐5p‐ADSCs down‐regulated Stat3 and Bcl‐2 and activated autophagy in the HST‐T6 cells. Furthermore, the up‐regulated expression of fibrotic genes in HST‐T6 cells induced by TGF‐β1 was repressed following the addition of isolated miR181‐5p‐ADSC exosomes compared with miR‐67‐ADSCexosomes. Exosome therapy attenuated liver injury and significantly down‐regulated collagen I, vimentin, α‐SMA and fibronectin in liver, compared with controls. Taken together, the effective anti‐fibrotic function of engineered ADSCs is able to selectively transfer miR‐181‐5p to damaged liver cells and will pave the way for the use of exosome‐ADSCs for therapeutic delivery of miRNA targeting liver disease.

Mesenchymal Stem Cells Reduce Corneal Fibrosis and Inflammation via Extracellular Vesicle-Mediated Delivery of miRNA

“…These results suggest a role for miRNA in the anti‐inflammatory/regenerative function displayed by the CSSC EVs. Such a function is consistent with a number of recent studies that have linked miRNA delivery by EVs to regenerative, antifibrotic, and immune suppressive properties of the vesicles . Some authors have suggested that the small amount of miRNA in EVs makes it more likely that a protein cargo is involved in their biological properties .…”

Exosomes from MiR-126-Overexpressing Adscs Are Therapeutic in Relieving Acute Myocardial Ischaemic Injury

“…The proteins and/or miRNAs carried by ADSC exosomes may be associated with the promotion of cell protection and angiogenesis. It has been reported that exosomes from ADSCs have therapeutic effects in many diseases, including AMI [22-27]. …”

Exosomal biomarkers in Down syndrome and Alzheimer's disease

“…On the other hand, potential future therapies for DS-AD could be to actively deliver certain miRNAs to the brain, to activate autophagy and remove AD pathology. This approach has been studied for different types of cancer (Qu et al 2017), but has not, to our knowledge, been applied to neurodegenerative conditions and may represent an exciting and novel use for exosomes. Thus, there is a strong connection between autophagy and oxidative stress, which in turn have significant direct and/or indirect effects on exosome cargo and on exosome secretion.…”