Role of mesenchymal stem cell derived extracellular vesicles in autoimmunity: A systematic review

Table 1 Immune modulation of extracellular vesicles in autoimmune related diseases

Disease	EVs	Expression	MSC-EVs source/ Target molecules	Target immune cells	Pathway(s) involved	Ref.
RA	MSC derived exosomal miR-150-5p	Down	Bone marrow derived MSC-EVs/MMP 14 and VEGF	Macrophages	TGF-β pathway	Chen et al[80]
	Exosome-encapsulated miR-548a-3p	Down	TLR4	Macrophages	MiR-548a-3p/TLR4/NF-κB axis	Wang et al[81]
	Exosome-encapsulated miR-6089	Down	TLR4	Macrophages	TLR4/NF-κB signaling pathway	Xu et al[82]
	Exosome-derived lncRNA Hotair	Up	MMP-2 and MMP-13	Macrophages	-	Song et al[83]
	Exosomal miR-17	Up	TGFBR II	T cells	-	Wang et al[84]
	MicroRNA-155	Up	SHIP-1	Macrophages	-	Kurowska-Stolarska et al[85]
	MicroRNA-146	Up	-	Macrophages, T cells, B cells	-	Nakasa et al[86]
SLE	Exosomal miR-26a	Up	Podocyte proteins, actin family members, and intermediate filaments	Podocytes	-	Ichii et al[99]
	Exosomal miRNA-146a	Up	-	-	Interferon-γ pathway	Perez-Hernandez et al[100]
pSS	EV derived LCN2	Up	TNF-α	B cells	TNF-α signaling	Aqrawi et al[107]
	EV derived APMAP	Up	TNF-α	B cells	TNF-α signaling	Aqrawi et al[107]
	EV derived CPNE1	Up	TNF-α	B cells	TNF-α signaling	Aqrawi et al[107]
IBD	MSC-EVs	Up	Bone marrow derived MSC-EVs	Macrophages	JAK1/STAT1/STAT6 signaling pathway	Cao et al[113]
Breast cancer	Exosomal PD-L1	Down	PD-1	T cells	PD-L1/ PD-1 pathway	Yang et al[120]
Lung cancer	EV derived miR-103a	Up	Lung cancer cell derived EVs/PTEN	Macrophages	PI3K/ AKT and STAT3 axis	Hsu et al[121]
Pancreatic cancer	Exosomal miR-301a-3p	Up	PTEN	Macrophages	PI3Kγ signaling pathway	Wang et al[122]
GVHD	MSC-EVs	Up	T cell derived EVs	-	-	Park et al[126]

RA: Rheumatoid arthritis; SLE: Systemic lupus erythematosus; pSS: Primary Sjgren's syndrome; IBD: Inflammatory bowel diseases; GVHD: Graft-versus-host disease; MSC: mesenchymal stem cell; EV: Extracellular vesicle; MSC-EV: Mesenchymal stem cell derived extracellular vesicle; MMP: Matrix metalloproteinase; VEGF: Vascular endothelial growth factor; TGFBR II : Transforming growth factor beta receptor II; SHIP-1: Src homology 2-containing inositol phosphatase-1; PD-1: Programmed death-1; PD-L1: PD-1 ligand; LCN2: Neutrophil gelatinase-associated lipocalin; APMAP: Adipocyte plasma membrane-associated protein.

Table 2 Therapeutic potential of extracellular vesicles

Disease	EVs	Experimental sample	Therapeutic potential	Ref.
RA	MSC derived exosomal miR-150-5p	Collagen induced arthritis mouse model	MiR-150-5p could reduce joint destruction by inhibiting synoviocyte hyperplasia and angiogenesis	Chen et al[80]
	Exosome-encapsulated miR-548a-3p	Macrophage-like cells	MiR-548a-3p could inhibit the proliferation and activation of pTHP-1 cells via the TLR4/NF-κB signaling pathway	Wang et al[81]
	Exosome-encapsulated miR-6089	Macrophage-like cells	MiR-6089 could regulate LPS/TLR4-mediated inflammatory response	Xu et al[82]
	Exosome-derived lncRNA Hotair	Blood mononuclear cells	Hotair may contribute to the dissolution of bone and cartilage matrix through activation of MMP-2 and MMP-13 in osteoclasts and RA synoviocytes. Hotair is more stable and easily detected in body fluid	Song et al[83]
	Exosomal miR-17	Blood mononuclear cells	MiR-17 can suppress regulatory T cell differentiation by inhibiting the expression of TGFBR II	Wang et al[84]
	MicroRNA-155	MiR-155–deficient mice	MiR-155–deficient mice are resistant to collagen-induced arthritis, and antigen-specific Th17 cell and autoantibody responses are suppressed markedly to reduce articular inflammation	Kurowska-Stolarska et al[85]
	MicroRNA-146	Human RA synovial fibroblasts	MiR-146a is expressed in the superficial and sublining layers of synovial tissue, like synovial fibroblasts, macrophages, T cells, and B cells	Nakasa et al[86]
SLE	Exosomal miR-26a	Female B6.MRLc1 and C57BL/6 mice; C57BL/6 (9 mo of age)	Podocytes mainly expresse miR-26a in mouse kidneys. Glomerular miR-26a expression in B6.MRLc1 mice correlates negatively with the urinary albumin levels and podocyte specific gene expression	Ichii et al[99]
	Exosomal miRNA-146a	Urine sample of SLE patients	Up-regulated exosomal miRNA-146a is found in the presence of active lupus nephritis	Perez-Hernandez et al[100]
pSS	EV derived LCN2	Saliva and tear samples from pSS patients and healthy controls	EV derived LCN2 is over-expressed in pSS patients	Aqrawi et al[107]
	EV derived APMAP	Saliva and tear samples from pSS patients and healthy controls	EV derived APMAP is over-expressed in pSS patients	Aqrawi et al[107]
	EV derived CPNE1	Saliva and tear samples from pSS patients and healthy controls	EV derived CPNE1 is over-expressed in pSS patients	Aqrawi et al[107]
IBD	MSC-EVs	LPS treated macrophages and an in vivo DSS induced mouse model	EVs promote the up-regulation of pro-inflammatory factors (TNF-α, IL-6, and IL-12) and down-regulation of the anti-inflammatory factor IL-10 in LPS-induced macrophages. EVs promote polarization of M1-like macrophages to an M2-like state	Cao et al[113]
Breast cancer	Exosomal PD-L1	MDA-MB-231 (231) human breast cancer cells and 4T1 mouse mammary tumor cells with PD-L1 expression or PD-L1KO	Exosomal PD-L1 bind to PD-1 on T cells to inhibit T cell activation and killing activities	Yang et al[120]
Lung cancer	EV derived miR-103a	Human adenocarcinoma cell lines NCI-H1437, NCI-H1792, and NCI-H2087 and human embryonic kidney HEK293 cells	miRNA inhibitor could inhibit effectively miR-103a mediated M2-type polarization, improving the cytokine prolife of tumor infiltration macrophages	Hsu et al[121]
Pancreatic cancer	Exosomal miR-301a-3p	Pancreatic cancer blood samples, Pancreatic cancer cell lines PANC-1, BxPC-3 and monocytic cell line THP-1	Pancreatic cells generate miR-301a-3p-rich exosomes in a hypoxic microenvironment, which polarize macrophages to promote malignant behaviors of cancer cells	Wang et al[122]
GVHD	MSC-EVs	Kidney samples from acute cellular rejection	iKEA (integrated kidney exosome analysis) shows a high level of CD3-positive EVs in kidney rejection patients and achieved high detection accuracy (91.1%)	Park et al[126]

RA: Rheumatoid arthritis; SLE: Systemic lupus erythematosus; pSS: Primary Sjgren's syndrome; IBD: Inflammatory bowel diseases; GVHD: Graft-versus-host disease; MSC: mesenchymal stem cell; EV: Extracellular vesicle; MSC-EV: Mesenchymal stem cell derived extracellular vesicle; MMP: Matrix metalloproteinase; VEGF: Vascular endothelial growth factor; TGFBR II: Transforming growth factor beta receptor II; SHIP-1: Src homology 2-containing inositol phosphatase-1; PD-1: Programmed death-1; PD-L1: PD-1 ligand; PD-L1KO: PD-L1 knockout; LCN2: Neutrophil gelatinase-associated lipocalin; APMAP: Adipocyte plasma membrane-associated protein; CPNE1: Copine.