Table 1 Studies demonstrating the effects of MSC-EVs on macrophage polarization
References | Sources of MSC-EVs | Experimental model | Mediator | Major findings |
|---|---|---|---|---|
Spinosa et al. [76] | Human umbilical cord-derived MSC-EVs | Mouse elastase-induced model of abdominal aortic aneurysm | miR-147 | MSC-EVs with miR-147 overexpression reduced macrophage infiltration in vivo and levels of proinflammatory cytokines in coculture of aortic tissue explants and macrophages treated with elastase. |
Lv et al. [77] | Rat BM-derived MSC-EVs | Rat model of myocardial infarction | Â | MSC-EVs incorporated with hydrogel reduced apoptosis of cardiomyocytes in the border zone and enhanced M2 polarization of macrophages in the infarcted zone. |
Xu et al. [78] | Rat BM-derived MSC-EVs | Mouse model of myocardial infarction | Â | LPS-primed MSC-EVs decreased post-infarction inflammation and injury in vivo and elevated M2 macrophage polarization in vitro via AKT1/AKT2 pathway. |
Sun et al. [79] | Mouse BM-derived MSC-EVs | Mouse model of dilated cardiomyopathy | Â | MSC-EVs improved cardiac function, attenuated cardiac dilation, and elevated cardiac M2-like F4/80+CD206+macrophages via activating JAK2-STAT6 pathway. |
Zhao et al. [80] | Mouse BM-derived MSC-EVs | Mouse model of heart ischemia/reperfusion injury | miR-182 | MSC-EVs alleviated myocardial ischemia/reperfusion injury via transfer of miR-182, which induced M2 macrophages polarization via targeting TLR4. |
Li et al. [81] | Mouse BM-derived MSC-EVs | Mouse model of atherosclerosis | let-7 | MSC-EVs alleviated atherosclerosis and enhanced M2 macrophage state in the plaque via miR-let7/HMGA2/NF-κB pathway. |
Morrison et al. [82] | Human BM-derived MSC-EVs | Mouse model of LPS-induced lung injury | Mitochondrial Transfer | MSCs induced M2 phenotype via EV-mediated transfer of mitochondria. Adoptive transfer of macrophages pretreated with MSC-EVs attenuated LPS-induced acute lung injury. |
Li et al. [83] | Mouse BM-derived MSC-EVs | Mouse model of lung ischemia/reperfusion injury | miR-21-5p | MSC-EVs attenuated ischemia/reperfusion injury and M1 polarization of alveolar macrophages in the lung by transferring miR-21-5p. |
Wang et al. [84] | Human adipose-derived MSC-EVs | Mouse model of LPS-induced lung injury | miR-27a-3p | MSC-EVs mitigated acute lung injury via transfer of miR-27a-3p to alveolar macrophages, inducing M2 macrophage polarization. |
Huang et al. [85] | Human adipose-derived MSC-EVs | Mouse model of LPS-induced lung injury | Â | Aging and young MSC-EVs have differential effects in alleviating acute lung injury and macrophage polarization. |
Deng et al. [86] | Mouse BM-derived MSC-EVs | Mouse LPS-induced acute lung injury | Â | MSC-EVs enhanced M2 macrophage polarization via inhibiting glycolysis and alleviated lung inflammation. |
Monsel et al. [87] | Human BM-derived MSC-EVs | Mouse E. coli pneumonia | Keratinocyte growth factor | MSC-EVs promoted survival, alleviated lung inflammation, reduced bacterial load, and induced M2 phenotype via keratinocyte growth factor. |
Phinney et al. [88] | Human BM-derived MSC-EVs | Mouse model of silicosis | Mitochondrial Transfer | MSC-EVs transferred mitochondria to macrophages, blocked TLR signaling in macrophages, and reduced silica-induced lung injury. |
Willis et al. [26] | Human umbilical cord MSC-EVs. | Mouse bronchopulmonary dysplasia | Â | MSC-EVs improved pulmonary development, decreased lung fibrosis, and ameliorated pulmonary vascular remodeling via modulation of lung macrophage phenotype. |
Chaubey et al. [90] | Human umbilical cord MSC-EVs. | Mouse bronchopulmonary dysplasia | TSG-6 | MSC-EVs attenuated injuries in lung, heart and brain. The therapeutic effects were blocked by knockdown of TSG-6 in MSC-EVs. |
Lee et al. [91] | Human umbilical cord MSC-EVs | Mouse model of hypoxic pulmonary hypertension | Â | MSC-EVs alleviated pulmonary hypertension, blocked the influx of macrophages, and reduced the expression of proinflammatory cytokines. |
Klinger et al. [92] | Human BM-derived MSC-EVs | Rat model of pulmonary hypertension | Â | MSC-EVs reversed pulmonary hypertension, which was accompanied by reduced lung macrophages and elevated ratio of M2/M1 macrophages. |
Liu et al. [93] | Mouse adipose-derived MSC-EVs | Mouse LPS/GalN-induced liver injury | miR-17 | MSC-EVs colocalized with hepatic macrophages, reduced NLRP3 inflammasome activation in macrophages, and ameliorated liver injury via miR-17. |
Ohara et al. [94] | Human amnion-derived MSC-EVs | Rat model of nonalcoholic steatohepatitis | Â | MSC-EVs inhibited the M1 activation of hepatic macrophages and decreased the number of hepatic macrophages and the levels of proinflammatory cytokines. |
Zhang et al. [95] | Human umbilical cord-derived MSC-EVs | Mouse LPS/GalN-induced liver injury | miRNA-299-3p | MSC-EVs attenuated liver injury, activation of the NLRP3 inflammasome, and release of proinflammatory cytokines via transfer of miRNA-299-3p to macrophages. |
Lu et al. [96] | Mouse BM-derived MSC-EVs | Mouse model of autoimmune hepatitis | miR-223-3p | MSC-EVs attenuated liver injury via transfer of miR-223-3p which targeted proinflammatory gene STAT3 in macrophages. |
Cao et al. [97] | Mouse BM-derived MSC-EVs | Mouse model of ulcerative colitis | Â | MSC-EVs alleviated ulcerative colitis and elevated M2 macrophages potentially via downregulating the JAK1/STAT1/ STAT6 signaling pathway. |
An et al. [98] | Dog adipose-derived MSC-EVs | Mouse model of ulcerative colitis | TSG-6 | MSC-EVs mitigated colitis and enhanced the macrophage polarization from M1 to M2 phenotype in the colon via TSG-6. |
Eirin et al. [99] | Pig autologous adipose-derived MSC-EVs | Pig with metabolic syndrome + renal artery stenosis | IL-10 | MSC-EVs attenuated renal stenosis and elevated the number of reparative M2 macrophages via IL-10. |
Song et al. [100] | Pig autologous adipose-derived MSC-EVs | Pig with metabolic syndrome + renal artery stenosis | Â | MSC-EVs from lean pigs alleviated tubular injury and fibrosis, upregulated M2 macrophages, and downregulated M1 macrophages in stenotic kidneys. |
Shen et al. [101] | Mouse BM-derived MSC-EVs | Mouse ischemia/reperfusion-induced renal injury | CCR2 | MSC-EVs ameliorated renal ischemia/reperfusion injury and blocked macrophage NF-κB activation via CCR2. |
Liu et al. [102] | Human BM-derived MSC-EVs | Mouse model of spinal cord injury | miR-216a-5p | Hypoxia-preconditioned MSC-EVs alleviated spinal cord injury and induced microglial M2 polarization via transfer miR-216a-5p which targeted TLR4 signaling cascade. |
Sun et al. [103] | Human umbilical cord-derived MSC-EVs | Mouse model of spinal cord injury | Â | MSC-EVs enhanced the locomotor functional recovery by altering the local macrophage subsets towards M2 polarization. |
Li et al. [104] | Human teeth-derived MSC-EVs | Rat model of traumatic brain injury | Â | MSC-EVs improved motor functional recovery and alleviated cortical lesion via microglia M2 polarization. |
Go et al. [105] | Monkey BM-derived MSC-EVs | Rhesus monkey model of cortical injury | Â | MSC-EVs promoted fine motor function of the hand and induced a switch of microglia from proinflammatory towards anti-inflammatory. |
Lankford et al. [106] | Rat BM-derived MSC-EVs | Rat model of spinal cord injury | Â | MSC-EVs were transferred to the site of spinal cord injury and targeted M2 macrophages at the site. |
Yang et al. [107] | Human umbilical cord-derived MSC-EVs | Rat model of post-stroke cognitive impairment | CCR2 | MSC-EVs with CCR2 overexpression enhanced cognitive function by promoting microglia/macrophage M2 polarization. |
Shi et al. [108] | Rat BM-derived MSC-EVs | Rat model of patellar tendon injury | Â | MSC-EVs enhanced tendon healing and blocked inflammatory responses by inducing polarization of M2 macrophages. |
Shen et al. [109] | Mouse adipose MSC-EVs | Mouse model of Achilles tendon injury |  | IFN-γ-primed MSC-EVs alleviated tendon injury and suppressed NF-κB-induced activation of M1 macrophages. |
Henao et al. [110] | Mouse adipose MSC-EVs | Mouse model of thioglycollate-induced peritonitis | Â | MSC-EVs attenuated peritonitis and induced a M2 phenotype in peritoneal macrophages. |
Song et al. [111] | Human umbilical cord-derived MSC-EVs | Mouse model of sepsis | miR-146 | IL-1β primed-MSCs enhanced M2 macrophage polarization and animal survival through EV-mediated transfer of miR-146a. |
Ti et al. [112] | Human umbilical cord-derived MSC-EVs | Rat model of diabetic cutaneous wound | let-7b | LPS-primed MSC-EVs enhanced wound healing and boosted M2 macrophage polarization via transfer of let-7b, which targeted TLR4/NF-κB/STAT3/AKT pathway. |
Lo Sicco et al. [113] | Human adipose-derived MSC-EVs | Mouse model of cardiotoxin-induced muscle injury | Â | MSC-EVs alleviated cardiotoxin-induced muscle injury, reduced the expression of M1 macrophage markers, and enhanced the levels of M2 macrophage markers. |