Modulating poststroke inflammatory mechanisms: Novel aspects of mesenchymal stem cells, extracellular vesicles and microglia

Table 2 Preclinical stroke studies assessing the effect of mesenchymal stem cells and mesenchymal stem cell-derived extracellular vesicles on the activation of microglia

Ref.	Country	Species	Cell type	Dosage	Route	Cell	Delivery	Microglia	Microglia	Signal	Ischemic
						Source	Timing	Marker	Activation	Pathway	Model
Cunningham et al[109], 2020	United Kingdom	Mice	MSCs	1.4 × 106	Sub	BM	1 h and 24 h	Iba1	No effect	IL-1α	MCAO
Narantuya et al[115], 2010	Japan	Rats	MSCs	NA	IV	BM	NA	ED1/Iba1	Inhibit	NA	BCAO
Ishizaka et al[111], 2013	Japan	Rats	MSCs	1 × 106	IA	NA	1, 4 or 7 d	ED1	Inhibit	NA	MCAO
Yamaguchi et al[120], 2018	Japan	Rats	MSCs	1 × 106	IA	Blood	24 h	Iba1	Inhibit	NA	MCAO
Wang et al[119], 2014	China	Rats	MSCs	2 × 106	IV	BM	3 h	CD45/CD11b	Inhibit	NA	dMCAO
Wei et al[19], 2012	America	Rats	MSCs	1 × 106	IV	BM	24 h	Iba1/OX-42	Inhibit	NA	MCAO
Nakajima et al[114], 2017	Japan	Rats	MSCs	1 × 106	IV	BM	0 or 3 h	Iba1/TNF-α/IL6/IL-1β	Inhibit	IL-10	MCAO
McGuckin et al[113], 2013	France	Rats	MSCs	NA	Stereotaxis	UC	NA	ED1/Iba1	Inhibit	CD200/STAT3	Ouabain injection
Li et al[112], 2018	China	Rats	MSCs	1 × 106	IV	BM	1 h	CD68/Iba1	Inhibit	IGF-1/BDNF	dMCAO
Lv et al[108], 2016	China	Cells	MSCs	NA	NA	BM	NA	TNF-α/IL6/IL-1β	Inhibit	TNF-α/MSCs/GDNF	OGD
Wang et al[102], 2020	Germany	Mice	EVs	2 × 106	IV	BM	Immediately	CD45/CD11b	Inhibit	NA	MCAO
Dabrowska et al[99], 2019	Poland	Rats	EVs	5 × 105	IA	BM	48 h	ED1	Inhibit	NA	Ouabain injection
Geng et al[84], 2019	China	Rats	EVs	NA	NA	Adipose	NA	Iba1, TNF-α, IL-1β	Inhibit	miRNA-126	MCAO
Liu et al[87], 2019	China	Rats	EVs	5 × 105	IV	BM	2 h	Iba1	Inhibit	NA	MCAO
Tian et al[91], 2018	China	Mice	EVs	NA	IV	BM	12 h	Iba1	Inhibit	NA	MCAO
Sheikh et al[117], 2019	Japan	Rats	MSCs	3 × 106	IV	BM	24 h	ED1/Iba1	Inhibit	IL-1β/HIF-1α and VEGF	MCAO
Wang et al[118], 2013	Japan	Rats	MSCs	3 × 106	IV	BM	24 h	ED1/Iba1/IL-1β/TNF-α/iNOS, MCP-1	Inhibit	TLR2/CD40/NF-kB	MCAO
Yoo et al[122], 2013	South Korea	Rats	MSCs	5 × 105	Stereotaxis	BM	3 days	CD68/Iba1/MCP-1; TNF-α/iNOS/IL-1β	Inhibit	TGF-β1/MCP-1	MCAO
Sheikh et al[116], 2011	Japan	Rats	MSCs	3 × 106	IV	BM	24 h	Iba1/iNOS/Cox-2/IL8/MCP-1	Inhibit	IL5 and Fractalkine	MCAO
Feng et al[110], 2020	China	Mice	MSCs	1 × 106/20 g	IV	UC	2 weeks	M1: CD16/32, Iba1; M2: CD206	Polarization	H3 methylation	LPS
Yang et al[121], 2020	China	Rats	MSCs	1 × 106	IV	BM	24 h before	M1: iNOS/Iba1; M2: Arg 1	Polarization	miR-30a*	MCAO
Jiang et al[85], 2018	China	Rats	EVs	NA	IV	Adipose	NA	M1: TNF-α/IL-6/iNOS; M2: IL-4/CD206/IL-10	Polarization	miR-30d-5p	MCAO
Li et al[86], 2020	China	Mice	EVs	NA	IV	UC	NA	M1: iNOS/CD38/ IL-6/TNF-α/CCL-2; M2: Arg 1/CD206	Polarization	miR-26b-5p	MCAO
Zhao et al[20], 2020	China	Rats	EVs	200 μL	IV	BM	1 or 14 d	M1: CD16-32/IL-6/IL-1β; M2: CD206/ IL-10	Polarization	miR-223-3p/ CysLT2R	MCAO
Zhao et al[21], 2020	China	Rats	EVs	200 μL	IV	BM	2 h	M1: CD86 NOS/IL-12/TNF-α; M2: CD206 /TGF-β/BDNF	Polarization	CysLT2R and ERK1/2	MCAO

NA: Not available; IA: Intraarterial; IV: Intravenous; Sub: Subcutaneous; BM: Bone marrow; UC: Umbilical cord; OGD: Oxygen-glucose deprivation; HIF-1α: Hypoxia inducible factor-1α; dMCAO: Distal middle cerebral artery occlusion; MSCs: Mesenchymal stem cell; EVs: Extracellular vehicles; LPS: Lipopolysaccharide; BCAO: Bilateral carotid artery occlusion; c(RGDyK): Cyclo (Arg-Gly-Asp-D-Tyr-Lys); MCP-1: Monocyte chemoattractant protein-1; iNOS: Inducible nitric oxide; IL: Interleukin; NF-κB: Nuclear factor-κB; TLR: Toll-like receptor; VEGF: Vascular endothelial growth factor; TGF: Transforming growth factor; IGF: Insulin-like growth factor; BDNF: Brain-derived neurotrophic factor; TNF: Tumor necrosis factor; GDNF: Glial-derived neurotrophic factor; COX-2: Cyclooxygenase-2; CysLT2R: Cysteinyl leukotrienes receptor; ERK: Extracellular regulated protein kinase.