. 2023 Jan 5;13:1098634. doi: 10.3389/fphar.2022.1098634

TABLE 2.

Pre-clinical studies of using EVs derived from BMMSC in IHD.

Year	Animal model	Cell resource	EVs isolation separation	MSC-EVs size (nm)	EVs markers	Doses	Administration method	Effects	Ref
Promote angiogenesis
2015	Myocardial infarction	Rat BMMSC	Exo-Quick-Tc Kit	50–100	CD63⁺	80 µg	Intramyocardial injection 60 min after ligation	Preserve cardiac function, reduced infarct size, enhancing the density of new capillary	Teng et al. (2015)
2018	Myocardial infarction	Mouse BMMSC	Exosome isolation Reagent	NA	CD63⁺, CD9⁺	600 µg	Intramyocardial injection after ligation	miR-132 overexpressed EVs promote angiogenesis and rescue cardiac function	Ma et al. (2018)
2019	STZ induced diabetic cardiomyopathy	Rat BMMSC	Exosome isolation kit	NA	CD63⁺	100 µg Once a week for 12 weeks	Intravenously injection	Downregulate TGF-β1 and Smad2, improve diabetes-induced cardiac fibrosis	Lin et al. (2019)
2020	Myocardial infarction	HIF-1α OE -Rat BMMSC	Ultracentrifugation 12 × 10⁴ g, 70 min	50–200	CD63⁺, TSG101⁺	2 × 10¹⁰ particles of EVs derived from MSC	Intramyocardial injection after ligation	Promoting neovessel formation, inhibiting fibrosis	Sun et al. (2020)
2020	Myocardial infarction	Mouse BMMSC	Exo-Quick-Tc Kit	Around 130	CD63⁺, CD9⁺,CD81⁺,TSG101⁺, Alix⁺, Hsp70⁺	.25 µmol of each	Intramyocardial injection after ligation	miR-19a/19b overexpressed EVs improve cardiac function and reduce cardiac fibrosis	Wang S et al. (2020)
2021	Ischemia 45 min-reperfusion 72 h	Hypoxia-Rat BMMSC	Ultracentrifugation 10 × 10⁴ g, 90 min	50–100	Alix⁺, TSG101⁺	3×10¹¹ particles/100 µL	Caudal vein injection prior to reperfusion	Improved cardiac microvascular functions by reducing PDGFR-β levels at late stage of I/R	Wang et al. (2021)
Reduce apoptosis
2017	Ischemia 30 min-reperfusion 2 h	Hypoxia-Rat BMMSC	Exosome isolation reagent	50–150	NS	5 µg	Intramyocardial injection 5 min prior to reperfusion	Improved cardiac function and reduced apoptosis	Liu et al. (2017)
2018	Myocardial infarction	Hypoxia-Mouse BMMSC	Ultracentrifugation 14 × 10⁴ g, 90 min	40–150	Alix⁺, TSG101⁺	10 μg/g, body weight	Intramyocardial injection after ligation	Inhibit cell apoptosis by delivering miR-125b-5p	Zhu et al. (2018)
2020	Ischemia 60 min-reperfusion 12 h	Mouse BMMSC	Exosome isolation reagent	Around 100	HSP70⁺, CD63⁺, CD9⁺	5 µg	Intramyocardial injection at ischemia 30 min s	Inhibit cell apoptosis and inflammation by delivering miR-25-3p and targeting pro-apoptotic proteins FASL/PTEN	Peng et al. (2020)
2020	Myocardial infarction	MIF overexpressed Human BMMSC	Exosome isolation Reagent	30–100	CD63⁺, CD81⁺	30 µg	Intramyocardial injection after ligation	Reduce infarct size, inhibit mitochondrial fragmentation and apoptosis	Liu et al. (2020)
2020	Myocardial infarction	Hypoxia-Rat BMMSC	Ultracentrifugation 11 × 10⁴ g, 75 min	30–150	CD63⁺, TSG101⁺	The EVs acquired from 1 × 10⁶ MSC	Intramyocardial injection after ligation	Protect cardiomyocyte apoptosis, miR-210/AIFM-3/AKT/P53	Cheng et al. (2020)
Reduce inflammation
2015	Sepsis induced cardiac dysfunctin	Mouse- BMMSC	Ultracentrifuge 3.6 × 10⁴ g, 3 h	34–35	CD63⁺, CD81⁺	2 µg/per g, body weight	Caudal vein injection 1 h after CLP operation	Alleviated inflammation by delivery miR-223	Wang et al. (2015)
2018	Dox induced dilated cardiomyopathy	Mouse BMMSC	Ultracentrifugation 10 × 10⁴ g, 3 h	35	Alix⁺, TSG101⁺, CD9⁺, CD63⁺	300 µg	Caudal vein injection	Suppress cardiac inflammation	Sun et al. (2018)
2019	Ischemia 45min-reperfusion 3, 6, 12 days	Mouse BMMSC	Gradient centrifugation	50–150	CD9⁺, CD63⁺, TSG101⁺, Alix⁺	50 µg	Intramyocardial injection at reperfusion	Reduced infarct size, alleviated inflammation levels, containing miR-182/macrophage polarization	Zhao et al. (2019)
2021	Sepsis induced myocardial injury	Mouse BMMSC	Ultracentrifuge 10 × 10⁴ g, 4 h	Around 100	CD63⁺,CD9⁺	2 µg/per g, body weight	Caudal vein injection 1 h after CLP operation	Alleviated inflammation by miR-141/PTEN/β-catenin	Pei et al. (2021)
2022	Myocardial infarction	Mouse BMMSC	Ultracentrifugation 10 × 10⁴ g, 70 min	50–150	CD81⁺, TSG101⁺	15 µg once a week for 3 weeks	Caudal vein injection	Exosomal miR-129-5p protect hearts by targeting TRAT3/NF-κB	Yan et al. (2022)

AIFM, apoptosis inducing factor, mitochondria associated 3; CLP, cecalligation puncture; FASL, fas ligand; NF-κB, nuclear factor kappa-B; PTEN, phosphatase and tensin homolog deleted on chromosome ten; TRAT3, tumor necrosis factor receptor-associated factor 3.