Table 3.
Functions and applications of exosomes in NEC
| Exosome type | Exosome origin | Exosome isolation | Exosome concentration | Exosome administration | Model | Modeling methoda | Main findings | Mechanism | Reference |
|---|---|---|---|---|---|---|---|---|---|
| AF-MSC-Ex | Rat | ExoQuick reagent | / | Intraperitoneal injection |
In vitro In vivo Ex vivo |
Mouse pup with formula, exposure to hypoxia for 4 days and oral LPS injection (4 mg/kg for 2 days) |
AF-MSC-Exs increase cellular proliferation, reduce inflammation, and regenerate a normal epithelium. AF-MSC-Exs attenuate NEC intestinal injury via activating the Wnt signaling pathway. |
Wnt/β-catenin (ISCs) | [28] |
| BM-MSC-Ex | Mouse |
Serial centrifugation (in vitro) PureExo Exosome Isolation kit (in vivo) |
~ 2.5 ×109 exosomes/50 μL | Intraperitoneal injection |
In vitro In vivo |
Mouse pup with formula, hypoxia (100% N2, 1.5 min, bid for 4 days) and hypothermia (4 °C, 10 min, bid for 4 days) |
BM-MSC-Exs increase wound healing in vitro. BM-MSC-Exs significantly lower gut permeability and the incidence of NEC in vivo. |
/ | [43] |
| AF-MSC-Ex | Rat | Ultra-centrifugation | 4 × 108 exosomes/50 μL | Intraperitoneal injection | In vivo | Rat pups with formula, hypoxia (100% N2, 1.5 min, tid for 4 days) and hypothermia (4 °C, 10 min, tid for 4 days) |
BM-MSC-Exs, AF-MSC-Exs, amniotic fluid-derived NSC-Exs and enteric NSC-Exs demonstrate equivalent reductions in NEC incidence. Stem cell-derived exosomes are equivalent to stem cells in NEC therapy. |
/ | [44] |
| BM-MSC-Ex | |||||||||
| NSC-Ex (amniotic fluid-derived) | |||||||||
| NSC-Ex (enteric) | |||||||||
| HM-Ex | Human | Ultra-centrifugation | 0–10 μg | / | In vitro | / | HM-Exs reduce oxidative stress-related injury on intestinal epithelial cells. | / | [45] |
| HM-Ex | Human | Serial centrifugation | 0.1 μg/μL | / | Ex vivo | / |
HM-Exs derived from colostrum, transitional or mature human milk prevent inflammatory injury. HM-Exs derived from colostrum are most effective in decreasing inflammatory cytokine. |
/ | [46] |
| HM-Ex | Human | Ultra-centrifugation | 200 μg/mL | Gavage | In vivo | Rat pups with formula and hypoxia (5% O2, 75% N2, 5 min, bid for 4 days) |
HM-Exs promote the proliferation and migration of intestinal epithelial cells both in vitro and in vivo. Peptidomic differences between preterm and term milk exosomes are revealed. |
/ | [47] |
| HM-Ex | Human | Ultra-centrifugation | 0–1 × 108 exosomes/100 μL |
Intraperitoneal injection Gavage |
In vitro In vivo |
Rat pups with formula, hypoxia (< 1.5% O2, 1.5 min, tid for 4 days), hypothermia (4 °C, 10 min, tid for 4 days) and LPS (2 mg/kg, day 1) |
HM-Exs increase the proliferation and decrease the apoptosis of intestinal epithelial cells. HM-Exs administered intraperitoneally or enterally decrease NEC incidence. HM-Ex enteral administration has better effects. |
/ | [48] |
| HM-Ex | Human | Ultra-centrifugation | 1.15–1.19 g/mL | Gavage |
Ex vivo In vivo |
Mouse pups with formula, hypoxia (5% O2, 10 min, tid for 5 days) and LPS (4 mg/kg, qd for 5 days) |
HM-Exs reduce inflammation and improve mucus production in vivo. HM-Exs decrease inflammation in hypoxia and LPS-treated intestinal organoids. Pasteurized HM-Exs are as effective as raw HM-Exs. |
/ | [49] |
| HM-Ex | Human | ExoQuick reagent | 0.5 mg/mL | / | In vitro | / | HM-Exs upregulate Wnt/β-catenin signaling in ISCs and increase cell viability under H2O2 exposure compared to the control group. | Wnt/β-catenin (ISCs) | [50] |
| PM-Ex | Pig | Ultra-centrifugation | 0.037 mg/μL | Gavage |
In vitro In vivo |
Mouse pups with LPS (7.5 mg/kg, qd for 7 days) |
PM-Exs inhibit intestinal epithelial cell apoptosis and decrease TLR4/NF-κB signaling through miRNAs in vitro. PM-Exs prevent LPS-induced intestinal injury and inflammation in vivo. |
miRNAs (miR-4334, -219, -338) | [51] |
| BovM-Ex | Cow | Ultra-centrifugation | 1 μg/μL | Gavage |
In vitro In vivo |
Mouse pups with formula, hypoxia (5% O2, 10 min, tid for 5 days) and LPS (4 mg/kg, day 6 and 7) | BovM-Exs promote goblet cell and endoplasmic reticulum chaperone protein expression both in vitro and in vivo, which increases mucus production and protect the intestine. | TFF3, MUC2 (goblet cell), and GRP94 (endoplasmic reticulum) | [52] |
aModeling methods for in vivo studies