Immunomodulation: The next target of mesenchymal stem cell-derived exosomes in the context of ischemic stroke

Table 1 Mesenchymal stem cell-derived exosomes target cells to mediate immune responses on ischemic stroke

Origin	Targeted cells	Administration/cultivation routes	Pathways/factors involved	Function	Ref.
Human umbilical cord-derived mesenchymal stem cell exosome miR-26b-5p	Microglia	Tail vein injection and microglia co-culture	TLR signaling pathway	Balance microglia polarization	[75]
Bone marrow-derived mesenchymal stem cell exosome miR-182-5p	Microglia	Inject into the brain	TLR4/NF-κB		[81]
Mesenchymal stem cell exosome miR-223-3p	Microglia	Tail vein injection and BV-2 microglia co-culture	CysLT2R-mediated signaling pathway		[87,89]
Mesenchymal stem cell exosome miR-26a-5p	Microglia	Tail vein injection and BV-2 microglia co-culture	CDK6		[97]
Human umbilical cord-derived mesenchymal stem cell exosome miR-146a-5p	Microglia	Tail vein injection	IRAK1/TRAF6		[85]
Bone marrow-derived mesenchymal stem cell exosomes	Microglia	Tail vein injection	NLRP3 inflammasome		[99]
Bone marrow-derived mesenchymal stem cell exosome lncRNA H19	Microglia	BV-2 microglia co-culture	JAK/STAT		[100]
Adipose stem cell-derived exosome miR-30d-5p	Microglia	Tail vein injection and primary microglia co-culture	Autophagy		[91]
Mesenchymal stem cell exosome miR-542-3p	Neuroglia	Inject into paracele of mice	TLR signaling pathway	Mitigate OGD-induced glial cell damage	[71]
Mesenchymal stem cell exosomes	Astrocyte	Ventricular injection and astrocyte co-culture	Nrf2-NF-κB	Modulate astrocyte activation and ameliorate reactive astrogliosis	[104,105]
Bone marrow-derived mesenchymal stem cell exosome miR-138-5p	Astrocyte	Astrocyte co-culture	LCN2		[111]
Mesenchymal stem cell exosome miR-133b	Astrocyte	Tail vein injection	CTGF/RhoA		[118,119]
Human adipose-derived mesenchymal stem cell exosomes	Neutrophil	Neutrophil co-culture	IL-6	Increase neutrophil lifespan and enhance neutrophil phagocytosis	[122]
Wharton's jelly-derived mesenchymal stem cell exosomes	Neutrophil	Neutrophil co-culture	_		[123]
Adipose-derived mesenchymal stem cell-derived exosomes	Macrophage	Macrophage co-culture	MafB and Stat6	Balance macrophage polarization	[129]
Adipose-derived mesenchymal stem cell-derived exosomes	Macrophage	THP-1 cell co-culture	ROCK1/PTEN		[130]
Human adipose-derived mesenchymal stem cell exosomes	T-lymphocyte	T-lymphocyte co-culture	Markers	Inhibition of lymphocyte activation and proliferation	[135]
Bone marrow-derived mesenchymal stem cell-derived exosomes	B-lymphocyte	T-lymphocyte/B-lymphocyte co-culture	Specific mRNAs		[70]
Adipose-derived mesenchymal stem cell-derived exosomes	Dendritic cell	Dendritic cell co-culture	_		[142]

TLR: Toll-like receptors; NF-κB: Nuclear factor-κB; CysLT2R: Cysteinyl leukotriene receptor 2; LCN2: Lipid chainlipoprotein-2; JAK: Janus kinase; STAT: Signal transducer and activator of transcription; IRAK1: Interleukin-1 receptor-associated kinase 1; TRAF6: TNF receptor-associated factor 6; Nrf2: Nuclear factor erythroid 2-related factor 2; RhoA: Ras homolog gene family member A; CTGF: connective tissue growth factor; IL-6: Interleukin-6; ROCK1: Rho associated coiled-coil containing protein kinase 1; PTEN: Phosphatase and tensin homolog; _: Refers to studies without detail the pathways

Table 2 Important immunological factors and their impact

Inflammatory mediators	Impacts	End of MSC-Exos transplantation/culture	Ref.
TNF-α	Pro-inflammatory	Decline	[71,75,81,85,91,100,104,111,130,140,141,143]
IL-1β	Pro-inflammatory	Decline	[81,85,100,104,111,140,141]
IL-6	Pro-inflammatory	Decline	[71,75,81,85,91,100,111,122,130,140-143]
iNOS	Pro-inflammatory	Decline	[81,91]
IFN-γ	Pro-inflammatory	Decline	[135]
IL-8	Pro-inflammatory	Decline	[130]
NLRP3	Pro-inflammatory	Decline	[99,145]
CysLT2R	Pro-inflammatory	Decline	[87,89]
CCL-2	Pro-inflammatory	Decline	[75]
MCP-1	Pro-inflammatory	Decline	[71,81]
IL-4	Anti-inflammatory	Raise	[91]
IL-10	Anti-inflammatory	Raise	[91,100,130,142,143]
TGF-β	Anti-inflammatory	Raise	[130,142]

TNF-α: Tumor necrosis factor-α; IL-1β: Interleukin-1β; IL-6: Interleukin-6; IL-8: Interleukin-8; iNOS: Influx activates nitric oxide synthase; IFN-γ: Interferon gamma; CysLT2R: Cysteinyl leukotriene receptor 2; CCL-2: C-C motif ligand 2; MCP-1: Monocyte chemotactic protein; IL-4: Interleukin-4; IL-10: Interleukin-10; TGF-β: Transforming growth factor-β; NLRP3: NLRP3 inflammasome; MSC-Exos: Mesenchymal stem cell-derived exosomes.