TABLE 1.
Summary of perinatal EVs mechanisms of action and biological effects.
| Cell type | Model | Target cells | Key molecules/Molecular mechanism | Biological effect | References |
| hUC-MSC | Rat hepatic ischemia-reperfusion injury | Hepatocytes, Neutrophils | Mitochondrial manganese superoxide dismutase Mn(SOD), anti-oxidant activity | Decreased expression of inflammatory cytokines in hepatic tissue and serum, decreased hepatocyte necrosis | Yao et al. (2019) |
| hUC-MSC | Mouse model of acute liver failure; RAW 264.7 macrophages in vitro activated with LPS | Macrophages | Inhibition of NLRP3 inflammasome complex expression | Reduced caspase 1 and inflammatory cytokines (IL-1β and IL-6) | Jiang et al. (2019) |
| hUC-MSC | Mouse model of acute burn | Macrophages | miR-181c downregulation of TLR-4 receptor expression with consequent downregulation of NF-κB/p65 pathway | Reduction of M1 macrophage activation | Li et al. (2016) |
| hUC-MSC | Mouse model of aortic aneurysm | T lymphocytes | miR-147 | Decreased expression of inflammatory cytokines, reduction of lymphocytes infiltration, improved aortic diameter, and elasticity | Spinosa et al. (2018) |
| hUC-MSC (LPS primed) | Wound healing model in diabetic rat | Macrophages | miR-let-7b down regulation of TLR4/NF-κB/STAT3/AKT signaling pathway | Promotion of M2 macrophage activation, enhanced diabetic cutaneous wound healing | Ti et al. (2015) |
| hUC-MSC (IL-1β primed) | Mouse model of sepsis | Macrophages | miR-146a | Increased polarization of macrophages toward the M2 anti-inflammatory subset | Song et al. (2017) |
| hUC-MSC | Mouse and rat spinal cord injury model | Macrophages | - | Reduction of inflammatory cytokines and M2 polarization | Romanelli et al. (2019); Sun et al. (2018) |
| hUC-MSC | Mouse model of inflammatory bowel disease | Macrophages | - | Reduced macrophage recruitment and reduced inflammation | Mao et al. (2017) |
| hUC-MSC | Mouse model of retinal laser injury | Macrophages | - | Downregulation of MCP1 and macrophage infiltration | Yu et al. (2016) |
| hUC-MSC | Rat model of experimental autoimmune uveoretinitis | CD4 T lymphocytes, NK cells, neutrophils and macrophages | - | Reduced infiltration of inflammatory immune cells | Bai et al. (2017) |
| hUC-MSC | Synthetic vascular grafts in rat model of hyperlipidemia | Macrophages | - | Reduced macrophage infiltration and enhanced M2 macrophage polarization, associated with reduced thrombosis and vascular intimal hyperplasia | Wei et al. (2019) |
| hUC-MSC | Alzheimer mouse model | Microglia | - | Reduced number of M1 microglial cells, promotion of M2 microglial polarization associated with reduced neuroinflammation and B amyloid deposition | Ding et al. (2018) |
| hUC-MSC | Human in vitro purified T lymphocytes | T lymphocytes | Adenosine signaling through CD73 expression | Reduced T lymphocyte activation | Kerkelä et al. (2016) |
| hUC-MSC | Mouse model of contact hypersensitivity | T lymphocytes | STAT1 signaling pathway inhibition | Reduced cytotoxic and Th1 lymphocyte infiltration and induced Treg with reduced tissue swelling | Guo et al. (2019) |
| hUC-MSC | Human in vitro purified T lymphocytes | T lymphocytes | - | Reduced T lymphocyte proliferation and inflammatory cytokine production | Monguió-Tortajada et al. (2017) |
| hUC-MSC | GVHD mouse model | T lymphocytes | - | Reduced CD8 cytotoxic T lymphocyte and reduced inflammatory cytokines in serum, alleviated GVHD manifestations and reduced mortality of the recipient mice | Wang et al. (2016) |
| hUC-MSC (β2 microglobulin deficient) | Rat model of myocardial infarction | CD8 T lymphocytes | miR-24 | Reduced CD8 T lymphocyte cytotoxicity with improved preservation of cardiac function after myocardial infarction | Shao et al. (2020) |
| hUC-MSC (primed with TGFβ and IFNy) | In vitro study on human PBMC | Treg | IDO1 | Increased Treg polarization | Zhang et al. (2018) |
| hUC-MSC | In vitro study on hUC-MSC and hCB-MSC | miRNA profiling | miR-a25b, miR26a, miR145, miR181c-5p, miR-Let7e, miR-Let7c, miR-Let7f, and miR.106a | miRNAs with immunoregulatory functions | Meng et al. (2017) |
| hUC-MSC | Rat model of renal ischemic reperfusion injury | NK cells | CXC3L1, TLR-2 | Reduced CXC3L1 and TLR-2 expression with consequent reduced NK cell recruitment | Zou et al. (2016) |
| hWJ-MSC | Mouse model of acute kidney injury | Macrophages | - | Decreased CXCL3 ligand 1, reduced macrophage and T lymphocyte infiltration, and reduced renal injury | Zou et al. (2014) |
| hWJ-MSC | Perinatal brain injury rat model | Microglia | TLR4/CD14 signaling pathway inhibition | Reduced expression of inflammatory cytokines by microglial cells | Thomi et al. (2019) |
| hWJ-MSC | Mouse model of hyperoxia-induced bronchopulmonary dysplasia (BPD) | Neutrophils | Tumor necrosis factor alpha-stimulated gene-6 (TSG-6) | Suppression of hyperoxia-induced neutrophil accumulation in bronchoalveolar lavage (BAL) with improvement of BPD pathology | Chaubey et al. (2018) |
| canine WJ-MSC | In vitro study with canine PBMC | CD4 T lymphocytes | TGF-β1/Adenosine signaling | Reduced CD4 T lymphocyte proliferation | Crain et al. (2019) |
| hWJ-MSC | Hyperoxia-induced bronchopulmonary dysplasia | Macrophages | - | Reduced M1 macrophage lung infiltration, enhanced M2 polarization | Willis et al. (2018) |
| hAF-MSC (primed with IFNy) | In vitro co-culture with PBMC; mouse model of allogeneic skin graft transplantation | Treg | IDO1 | Increased number of Treg cells promoting in vivo allograft survival | Romani et al. (2015) |
| hAF-MSC | In vitro THP1 macrophage cell line; mouse model of monoiodoacetate induced osteoarthritis | Macrophages | - | Promoted skewing of THP1 committed M1 macrophages toward M2 subset. In vivo increased pain tolerance and improved histopathological score | Zavatti et al. (2020) |
| hAF-SC | In vitro and in vivo models of skeletal muscle atrophy (HSA-Cre, SmnF7/F7 mice) | B lymphocytes | - | Reduced B lymphocyte maturation and decreased skeletal muscle inflammation associated with enhanced muscle strength and survival | Balbi et al. (2017) |
| hAEC | Mouse model of CCl4 induced liver fibrosis | Macrophages | - | Reduced liver fibrosis through promotion of M2 macrophage polarization | Alhomrani et al. (2017) |
| hAEC | Bleomycin-induced pulmonary fibrosis | Macrophages/T lymphocytes | - | Reduced lung fibrosis through promotion of M2 macrophage polarization and reduction of T cell infiltration | Tan et al. (2018) |
hUC-MSC, human umbilical cord mesenchymal stromal cells; hAF-SC, human amniotic fluid stem cells; hAF-MSC, human amniotic fluid mesenchymal stromal cells; hWJ-MSC, human Wharton’s jelly mesenchymal stromal cells; IDO1, indoleamine-2,3-dioxygenase-1; LPS, lipopolysaccharide; TLR-2/4, Toll like receptor 2 or 4; CXC3L1, chemokine (C-X3-C motif) ligand 1; GVHD, acute graft-vs-host disease; NK, natural killer cells; MCP-1, monocyte chemotactic protein-1, PBMC; human peripheral blood mononuclear cells.