Table 3.
Summary of studies on MSC-EVs in ROP, NEC, and perinatal lung growth.
| Reference | MSC source | MSC product | Isolation | Disease model | Route | Dose/ frequency | Main result/action↑↓ | Pathway/active factor |
|---|---|---|---|---|---|---|---|---|
| ROP | ||||||||
| Mathew B. et al. (2019) | BM- MSCs (human) |
EVs | Sequential centrifugation, ultrafiltration & Exo Quick-TC EV | In vivo: rat model of retinal ischemia in vitro: OGD of R28 retinal cells |
IVit | 1 Dose 4 μL of 1 × 109 particles/mL 24 h post-injury in both the ischemic and non-ischemic eyes |
↓ Cell death & ↑ cell proliferation ↑ functional recovery ↓ neuro-inflammation & apoptosis |
Delivery of pro-survival proteins from the cAMP response element-binding protein (CREB) pathway |
| Moisseiev et al. (2017) | BM-MSCs (human) cultured in 1% O2 for 48hr | Exosomes | Serial centrifugation, TFF, VivaSpin filtration column | In vivo Oxygen-induced Retinopathy (OIR) (75% O2) |
IVit | 1 Dose 1 μl ≈ 20 μg protein on PN12 |
Partially preserved Retinal vascular flow ↓ retinal thinning ↓ retinal neovascularization no immunogenicity or ocular/systemic adverse effects were observed |
|
| NEC | ||||||||
| Rager et al. (2016) | BMSCs (rat) |
Cells and Exosomes | In vivo: P100 PureExo Exosome Isolation kit in vitro: serial centrifugation & UC |
In vivo NEC rodent model in vitro: Intestinal epithelial cell wound healing assay IEC-6 cells |
IP | 1 Dose MSCs: 3 × 105 cells or Exosomes: 2.5 × 109 5h post-delivery |
In vivo: ↓ the incidence and severity of disease preserve gut barrier function in vitro: ↑wound healing of IEC-6 cells |
|
| McCulloh et al. (2018) | AF-MSC, BM-MSC, AF-NSC and E-NSC (rat) |
Exosomes | Differential UC | In vivo: NEC rodent model |
IP | 1 Dose 50 μL of MSC-Exosomes 1 h post-delivery. 1.3 × 105 EVs/50 μL, 6.4 × 105 EVs/50 μL, 3.2 × 106 EVs/50 μL, 1.6 × 107 EVs/50 μL, 8.0 × 107 EVs 50 μL, 4.0 × 108 EVs/50 μL |
↓ NEC incidence and severity Equal efficacy of EVs and parent MSCs Best results at 8 × 107 or 4.0 × 108 EVs/50 μL |
|
| LIet al. (2020) | AFSC (rat) | Cells and EVs | ExoQuick | In vivo: NEC mouse model in vitro: Intestinal epithelial cell wound healing assay IEC-18 cells |
IP | 2 Doses 2 × 106 AFSCsOr AFSC-EVs derived from 200 μL of CM of 2 × 106 AFSCs at PN 6 and 7 Or at PN3 and 4 prior to NEC injury induction |
AFSC and EV attenuate NEC intestinal injury ↑cellular proliferation, ↓inflammation regenerating a normal intestinal epithelium |
Activate the Wnt signaling pathway |
| O’Connell et al. (2021) | AFSC (human) | EVs | Sequential centrifugation, UC | In vivo: NEC mouse model | IP | 2 Doses 100 μL of 3.0 × 107 cell equivalents PN 6 and 7 |
↓ Intestinal injury ↓NEC incidence ↓intestinal inflammation (IL -6, TNF-α) ↑ Intestinal stem cell expressionand ↑cellular proliferation |
|
| Perinatal lung growth | ||||||||
| Abele et al. (2021) | BM-MSCs (human) | EVs | Differential centrifugation, TFF, OptiPrepTM cushion density flotation | In vivo: chorioamnionitis rat model In vitro: Fetal Lung Explants |
IA | 1 Dose 0.25 × 106 cell equivalents ≈ to 4.25 × 108 particles |
↓Placental inflammatory cytokines normalized spiral artery architecture preserved distal lung growth and mechanics In vitro: ↑ distal lung branching ↑ VEGF & SPC gene expression |
|
| Taglauer et al. (2021) | WJMSCs (human) | EVs | Differential centrifugation, TFF, OptiPrepTM cushion density flotation | In vivo: lung injury in experimental preeclampsia, Hmox1-null model in vitro: Fetal lung explants |
IV | 3 Doses (weeks 1, 2, and 3 of pregnancy) ≈ 5 × 106 cell equivalents |
Normalization of lung developmental genes ↑ pup birth weight ↓ alveolar simplification and lung developmental arrest altered the amniotic fluid proteomic profile AF of MEx treated pregnancies: ↑ distal lung branching ↑lung developmental genes |
Normalization of fetal lung development by altering the AF proteomic profile |
Abbreviations: AF, amniotic fluid; AF-MSCs, amniotic fluid-derived mesenchymal stem cells; AF-NSCs, amniotic fluid-derived neural stem cells; E-NSCs, neonatal enteric neuronal stem cells; BM-MSCs, bone marrow mesenchymal stem cells; CM, conditioned media; EVs, extracellular vesicles; hUC MSCs, human umbilical cord blood mesenchymal stem cells; IA, intra-amniotic; IL-6, interleukin 6; IP, intraperitoneally; IT, intratracheally; IV, intravenously; IVit, intravitreally; LPS, lipopolysaccharide; MEx, mesenchymal stem cell derived small extracellular vesicles; miR, microRNA; NEC, necrotizing enterocolitis; OGD, oxygen/glucose deprivation assay; PEG, polyethylene glycol; PN, post-natal day; ROP, retinopathy of prematurity; SPC, surfactant protein-C; TFF, tangential flow filtration; TNF-α, tumor necrosis factor alpha; UC, ultracentrifugation; VEGF, vascular endothelial growth factor; WJ-MSCs, umbilical cord Wharton’s jelly mesenchymal stem cells.