Therapeutic potential of stem cell extracellular vesicles for ischemic stroke in preclinical rodent models: a meta-analysis

Zhao, Jing; Deng, Huiyin; Xun, Chengfeng; Chen, Chunli; Hu, Zhiping; Ge, Lite; Jiang, Zheng

doi:10.1186/s13287-023-03270-2

Stem Cell Research & Therapy

Table 1 Summary of study characteristics of all included articles

From: Therapeutic potential of stem cell extracellular vesicles for ischemic stroke in preclinical rodent models: a meta-analysis

Number	Title	Author year Country	Species	Strain	Sex	Model	Stem cell type	Stem cell source	Compatibility SC-EVs Dose	SC-EVs dose units	Extraction method	Time of delivery	SC-EVs route	Follow-up
1	Microvesicles from brain-extract-treated mesenchymal stem cells improve neurological functions in a rat model of ischemic stroke	Lee et al. (2015) Republic of Korea [22]	Rats	Sprague–Dawley	Male	MCAO	MSC	Adipose tissues, Xenogenic	0.2 mg/kg	Dosed by weight of animal	DC	48 h after pMCAO	IA	7 days
2	MiR-17–92 cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats	Xin et al. (2018) USA [23]	Rats	Wistar	Male	MCAO	MSC	Bone marrow, Allogeneic	100 μg total exosome protein into 0.5 ml PBS	Protein amount	DC	24 h after MCAO	IV	28 days
3	Adipose-derived mesenchymal stem cells reduce autophagy in stroke mice by extracellular vesicle transfer of miR-25	Kuang et al. (2019) Germany [24]	Mice	C57BL/6	Male	MCAO	MSC	Adipose tissue, Allogeneic	200 μl of PBS corresponding to 10 μg of EVs	Protein amount	PEG	12 h after tMCAO	IV	14 days
4	In vivo Monitoring and Assessment of Exogenous Mesenchymal Stem Cell-Derived Exosomes in Mice with Ischemic Stroke by Molecular Imaging	Xu et al. (2020) China [25]	Mice	C57BL/6	Male	A photothrombotic model of ischemic stroke	MSC	Bone marrow, Allogeneic	100 μg, 200 μL PBS	Protein amount	DC	0 h	IV	14 days
5	miR-132-3p priming enhances the effects of mesenchymal stromal cell-derived exosomes on ameliorating brain ischemic injury	Pan et al. (2020) China [26]	Mice	C57BL/6	Not reported	MCAO	MSC	Bone marrow, Allogeneic	1 × 10^10 particles/100 μL in PBS	Particle number	DC	48 h after tMCAO	IV	2 days
6	Exosomes Derived from CXCR4-Overexpressing BMSC Promoted Activation of Microvascular Endothelial Cells in Cerebral Ischemia/Reperfusion Injury	Li et al. (2020) China [27]	Rats	SD	Male	MCAO	MSC	Bone marrow, Allogeneic	100 μg	Protein amount	DC	24 h after MCAO	ICV	21 days
7	Exosomes treatment mitigates ischemic brain damage but does not improve post-stroke neurological outcome	Nalamolu et al. (2020) USA [28]	Rats	Sprague–Dawley	Male	MCAO	MSC	Human umbilical cord blood, Xenogenic	150 μg/animal in 0.5 mL sterile PBS	Protein amount	DC	0 h	IV	7 days
8	Exosomes derived from human neural stem cells stimulated by interferon gamma improve therapeutic ability in ischemic stroke model	Zhang et al. (2020) China [29]	Rats	Sprague Dawley	Male	MCAO	NSC	Human fetal brain tissue, Xenogenic	4 × 10^9 particles in 10 ul PBS/each rat)	Particle number	DC	24 h after tMCAO	ICV	28 days
9	Small extracellular vesicles secreted by human iPSC-derived MSC enhance angiogenesis through inhibiting STAT3-dependent autophagy in ischemic stroke	Xia et al. (2020) China [30]	Rats	Sprague Dawley (SD)	Male	MCAO	IPS	ips, Xenogenic	1 × 10^11 particles in 500 μL PBS	Particle number	DC	4 h after tMCAO	IV	28 days
10	Lithium modulates miR-1906 levels of mesenchymal stem cell-derived extracellular vesicles contributing to post-stroke neuroprotection by toll-like receptor 4 regulation	Haupt et al. (2020) Germany [31]	Mice	C57BL/6	Male	MCAO	MSC	Bone marrow, Allogeneic	13.5 μg 1\3\5 day	Protein amount	PEG	1\3\5 day after MCAO	IV	84 days
11	Mesenchymal Stromal Cell-Derived Small Extracellular Vesicles Induce Ischemic Neuroprotection by Modulating Leukocytes and Specifically Neutrophils	Wang et al. (2020) Germany [32]	Mice	C57BL6/j	Male	MCAO	MSC	Bone marrow, Xenogenic	200 μL	Protein amount	PEG	0 h	IV	3 days
12	Bone mesenchymal stem cell-derived exosomal microRNA-29b-3p prevents hypoxic–ischemic injury in rat brain by activating the PTEN-mediated Akt signaling pathway	Hou et al. (2020) China [33]	Rats	Sprague Dawley (SD)	Male	MCAO	MSC	Bone marrow, Allogeneic	100 μg/kg/day 3 days	Dosed by weight of animal	DC	2 h MCAO	ICV	3 days
13	Human placental mesenchymal stem cells improve stroke outcomes via extracellular vesicles-mediated preservation of cerebral blood flow	Barzegar et al. (2021) USA [34]	Mice	C57Bl/6	Male	MCAO	MSC	Cholesterol treated placentas, Xenogenic	2 × 10^6 in 100 ml HBSS	Particle number	DC	1 h MCAO	IV	1 day
14	Human umbilical cord mesenchymal stem cell-derived exosomal miR-146a-5p reduces microglial-mediated neuroinflammation via suppression of the IRAK1/TRAF6 signaling pathway after ischemic stroke	Zhang et al. (2021) China [35]	Mice	C57BL/6	Not reported	MCAO	MSC	Umbilical cord mesenchymal stem cell, Xenogenic	250 μL PBS with 50 μg	Protein amount	DC	4 h after tMCAO	IV	3 days
15	Dental pulp stem cell-derived exosomes alleviate cerebral ischemia–reperfusion injury through suppressing inflammatory response	Li et al. (2021) China [36]	Mice	C57BL/6	Male	MCAO	MSC	Dental pulp, Xenogenic	10 μg total protein per 100 μL PBS	Protein amount	DC	2 h MCAO	ICV	7 days
16	Upregulation of extracellular vesicles-encapsulated miR-132 released from mesenchymal stem cells attenuates ischemic neuronal injury by Inhibiting smad2/c-jun pathway via acvr2b suppression	Feng et al. (2021) China [37]	Mice	C57BL/6 J	Male	MCAO	MSC	Bone marrow, Allogeneic	200 mg EVs	Protein amount	DC	24 h after tMCAO	IV	1 day
17	miR-31 from adipose stem cell-derived extracellular vesicles promotes recovery of neurological function after ischemic stroke by inhibiting TRAF6 and IRF5	Lv et al. (2021) China [38]	Mice	C57BL/6 J	Male	MCAO	MSC	Adipose tissue, Allogeneic	150 μg EVs	Protein amount	DC	24 h after tMCAO	IV	14 days
18	MiR-17–92 enriched exosomes derived from multipotent mesenchymal stromal cells enhance axon–myelin remodeling and motor electrophysiological recovery after stroke	Xin et al. (2021) USA [39]	Rats	Wistar	Male	MCAO	MSC	Bone marrow, Allogeneic	3 × 10^11 particles	Particle number	DC	24 h after MCAO	IV	28 days
19	Embryonic stem cell-derived small extracellular vesicles modulate regulatory T cells to protect against ischemic stroke	Xia et al. (2021) China [40]	Mice	C57/BL6	Male	MCAO	ESC	Human embryonic stem cells, Xenogenic	10^9 particles in 200 μL of PBS	Particle number	DC	0 h injected three times daily	IV	28 days
20	Exosomal microRNA-22-3p alleviates cerebral ischemic injury by modulating KDM6B/BMP2/BMF axis	Zhang et al. (2021) China [41]	Rats	Sprague Dawley (SD)	Male	MCAO	MSC	Adipose tissue, Allogeneic	100 μg/kg/day 3 days	Dosed by weight of animal	DC	Before the surgery	ICV	3 days
21	microRNA-26a shuttled by extracellular vesicles secreted from adipose-derived mesenchymal stem cells reduce neuronal damage through KLF9-mediated regulation of TRAF2/KLF2 axis	Hou et al. (2021) China [42]	Mice	C57BL/6	Male	MCAO	MSC	Adipose tissue, Allogeneic	100 mmol/kg/d,3 days	Dosed by weight of animal	DC	Before the surgery	ICV	3 days

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