Table 3.
Studies focusing on the therapeutic potential of bone marrow-derived mesenchymal stem/stromal cells in animal models of hypoxic-ischemic encephalopathy.
| Cell Type | Animal Model | Delivery Route (Source, Dose/Admin) Time of Treat. |
Functional Outcome | Brain Damage/ Apoptosis |
SC Engraftment | Other Outcomes/Observations | Ref. |
|---|---|---|---|---|---|---|---|
| BM-MSCs | Rat (RV; 3.5 h hypoxia) |
IC (human; 106 cells) 3 dpi |
↑ | = | Yes | MSCs transdifferentiated into astrocytes (astrocytic markers colocalized more with the transplanted MSCs than neuronal or oligodendrocyte markers). | [55] |
| Mouse (RV; 0.75 h hypoxia) |
ICV (murine; 105 cells) 3 or 10 dpi |
↑ | ↓ | - | No difference between treatment at 10 and 3 dpi; increase in cell proliferation; no differentiation of MSCs into mature cell types; increase in the number of mature neurons, astrocytes, and oligodendrocytes; decrease in microglial activation. | [57] | |
| Mouse (RV; 0.75 h hypoxia) |
IN (murine; 5 × 105 cells) 10 dpi |
↑ | ↓ | Yes | No differentiation of MSCs into mature cell types. | [58] | |
| Mouse (RV; 0.75 h hypoxia) |
ICV (murine; 105 cells) 3 and/or 10 dpi |
3 and 10 dpi ↑ | 3 and 10 dpi ↓ | - | Injection at 3 dpi: Increase in mature neurons and oligodendrocytes count. Injection at 10 dpi: Increase in oligodendrocyte maturation, remyelination, and neuronal repair without new cell formation. |
[56] | |
| Mouse (RV; 0.75 h hypoxia) |
ICV (murine; 105 cells) 3 and 10 dpi |
↑ | ↓ | - | Decrease in the HI-induced contralateral axonal rewiring and HI-induced changes in the white matter; increase in the axonal connectivity in the ipsilateral hemisphere. | [59] | |
| Rat (transient MCAO) |
IN (murine; 106 cells) 3 dpi |
↑ | ↓ | - | Increase in cell proliferation. | [61] | |
| Mouse (RV; 0.75 h hypoxia) |
IN (murine; 0.25–1 × 106 cells) 3/10/17 dpi |
0.5 × 106 ↑ 3 or 10 dpi ↑ |
0.5 × 106 ↓ 3 or 10 dpi ↓ 17 dpi = |
Yes | 0.5 × 106 cells: Lowest dose to produce alterations. |
[60] | |
| Sheep Fetuses (0.4 h UCO) |
IV (human; 3.5 × 106 cells) 1 h after UCO |
- | ↓ | Low | Decrease of the cerebral inflammatory response, T-cell invasion, and electrographic seizure activity; increase in persistent tolerance of T-cells and preOLs count. | [82] | |
| Mouse (RV; 0.75 h hypoxia) |
IN (human; 1 or 2 × 106 cells) 10 dpi |
↑ | 1 × 106 = 2 × 106 ↓ |
Low | Decrease in astrogliosis and microglial activation. | [62] | |
| Mouse (RV; 0.75 h hypoxia) |
IN (murine; 0.5 × 106 cells) 10 dpi |
↑ | ↓ | - | No detection of adverse effects during the animal’s lifespan and no induction of tumors or other lesions in the brain or nasal turbinates. | [63] | |
| Rat (RV; 2.5 h hypoxia) |
ICV (murine; 106 cells) 2 dpi |
↑ | ↓ | - | Decrease in TLR2 expression levels. | [64] | |
| Rat (RV; 1.5 h hypoxia) |
SC (murine; 0.75–1 × 106 cells or 0.8–1.2 × 105 cells) 7 dpi |
↑ | - | - | Increase in striatal medium spiny projection neurons—restored to uninjured levels with the higher dosage. | [65] | |
| Rat (RV; 2 h hypoxia) |
ICV (murine; 2 × 105 cells) 1 dpi |
↑ | - | Yes | Improvement in the neuronal pathological changes induced by the HI insult; increase in autophagy levels. | [66] | |
| Rat (RV; 1 h hypoxia) |
IV (murine; 105 cells) 1 dpi |
↑ | ↓ | - | Decrease in microglial activation. | [54] | |
| Rat (RV; 2 h hypoxia) |
IV (murine; 106 cells) 3 dpi |
↑ | ↓ | - | Increase in the number of neurons and synapses. | [67] | |
| Rat (RV; 1 h hypoxia) |
IV (murine; 105 cells) 4 hpi and 1 dpi |
- | ↓ | - | Decrease in microglia activation (M1 phenotype); increase in anti-inflammatory cytokine and growth factor levels. | [73] | |
| Mouse (RV; 1 h hypoxia) |
IN + TH (murine; 106 cells) 3 dpi |
MSCs/TH ↑ MSCs + TH ↑↑ |
MSCs + TH ↑ | - | MSCs or TH: Decrease in growth factor expression levels. MSCs: Decrease in hypomyelination. MSCs + TH (compared to either therapy alone): Increase in the infiltration of endothelial cells and peripheral immune cells; increase in pro-inflammatory cytokines levels; decrease in growth factor expression levels (bellow control levels). |
[68] | |
| Rat (RV; 2.5 h hypoxia) |
IV (6 × 106 cells) ? |
- | - | Yes | Increase in HIF-1α and SDF-1α protein levels in the hippocampus. | [122] | |
| Mouse (RV; 0.75 h hypoxia) |
IN (106 cells) 10 dpi |
- | ↓ | Yes | Increase in DCX+ cells in the SVZ, number of astrocytes at the lesion site, and the number of neurons; decrease in reactive astrocytes and microglial activation (M2 phenotype). | [80] | |
| Rat (bilateral ligation of cephalic arteries, 1.5 h hypoxia) |
IV or ICV (3 × 106 cells) 1 dpi |
IV ↑ ICV ↑↑ |
IV ↓ ICV ↓↓ |
- | Decrease of astrogliosis. | [35] | |
| Rat (RV, 2.5 h hypoxia) |
ICV (murine; 2 × 105 cells) 5 dpi |
↑ | - | - | Enhanced long-term potentiation. | [70] | |
| Rat (RV, 2.5 h hypoxia) |
ICV (murine; 2 × 105 cells) 5 dpi |
↑ | - | - | Decrease in the number of proliferating astrocytes. | [69] |
Abbreviations: ↑ increase or upregulation; ↓ decrease or downregulation; = no significant difference; - not evaluated; BM—bone marrow; DCX—doublecortin; hpi/dpi/wpi—hours post insult/days post insult/weeks post insult; IC—intracardiac; ICV—intraventricular; IN—intranasal; IV—intravenous; HI—hypoxic-ischemic; HIF—hypoxia-inducible factor; MCAO—middle cerebral artery occlusion; MSCs—mesenchymal stem/stromal cells; pre-OLs—oligodendrocyte progenitors; PX—postnatal day X; RV—Rice–Vannucci/Rice–Vannucci adaptation; SDF—stromal cell-derived factor; SVZ—subventricular zone; TH—therapeutic hypothermia; TLR—toll-like receptor; UCO—umbilical cord occlusion.