Roles of Bile-Derived Exosomes in Hepatobiliary Disease

Table 1

Mechanism of action of exosomes from various humoral sources.

Source	Disease type	Related molecule	Signalling pathway	Function	Ref.
Bile	Normal physiology	miR-15A	ERK	Exosomes in bile interact with primary cilia to reduce the proliferation of bile duct cells through the ERK pathway and miR-15A.	[28]
	Normal physiology	ALV-J	—	Biliary exosomes promote the proliferation of CD4^+ and CD8^+ T cells and monocytes in the liver, and can inhibit ALV-J.	[32]
Bile, cell line	Cholangiocarcinoma	circ-CCAC1	circ-CCAC1/miR-514a-5p/YY1/CAMLG axis; EZH2/SH3GL2/ZO-1/occludin	The circ-CCAC1-carrying EVs released by cholangiocarcinoma cells were absorbed by endothelial cells. circ-CCAC1 was able to destroy vascular barrier and angiogenesis via the regulation of EZH2/SH3GL2/ZO-1/occludin.	[30]
Serum, cell line	Prostate cancer	PKM2, CXCL12	HIF-1α	Exosome-mediated PKM2 upregulated BMSC CXCL12 by HIF-1α-dependent fashion to complete bone metastasis of prostate cancer.	[69]
	Liver fibrosis	lncRNA-H19	—	Exosomal lncRNA-H19 promotes cholestatic liver fibrosis by promoting the differentiation and activation of HSCs.	[70]
	Cholestatic liver injury	lncRNA-H19	ERK1/2, AMPK, SHP	Uptake of H19-carrying exosomes from cholangiocytes suppresses SHP expression by inhibiting promotor activity and destabilizing SHP mRNA in hepatocytes. Downregulation of SHP expression results in increase of bile acid synthesis and eventually causes cholestatic liver injury.	[71]
	Bladder tumour	lncRNA-UCA1	EMT	Hypoxic exosomal lncRNA-UCA1 promoted tumour growth and progression in vitro and in vivo through EMT.	[72]
Tissue, cell line	Hepatocellular carcinoma	LOXL4	FAK/Src pathway	Exosome-mediated secretion of LOXL4 by modulating the FAK/Src pathways and angiogenesis in HCC, plays the role of tumour metastasis.	[73]
	Gastric cancer	HMGB1/TLR4	NF-κB pathway	Gastric cancer-derived exosomes carry high mobility group box-1 (HMGB1), which interacts with Toll-like receptor 4 (TLR4) to activate NF-κB and induce neutrophil autophagy, thereby promoting gastric cancer cell migration.	[74]
	Inflammatory bowel disease	ANXA1	FPR1 and FPR2/ALX	Endogenous annexin A1 (ANXA1) is released as a component of intestinal epithelial EVs that activate wound repair circuits.	[75]
Cell line	Clear cell renal cell carcinoma	miR-19b-3p, PTEN, CD103, E-cadherin, N-cadherin, vimentin, twist	EMT	CSC exosomes transport miR-19b-3p to CCRCC cells and initiate EMT to promote metastasis. CD103 enables tumour to target lung.	[76]
	Osteochondral defects	CD73, IL-1β, TNF-α	AKT, ERK	MSC exosomes achieve osteochondral regeneration through coordinated mobilization of multiple cell types and activation of multiple cellular processes.	[77]
Urine	Diabetes	DMBT1	/	USC-exos may promote angiogenesis by transferring DMBT1 protein.	[78]
Breast	Breast cancer	TGFβ2, E-cadherin, alpha-smooth muscle actin (α-SMA), filamentous- (F-) actin, vimentin	EMT	Breast exosomes with high TGFβ2 expression can induce changes in benign and malignant breast epithelial cells.	[79]