Additional Table 2.
Mesenchymal stromal cell-based strategies in Parkinson’s disease
| Reference | Source of MSCs | PD model | MSC survival | DA differentiation | MSC migration | Outcomes |
|---|---|---|---|---|---|---|
| Delcroix et al., 2011 | Human BM-MSCs pre- differentiated to DA cells (1.5 × 105
Intrastriatal 2 wk post-lesion |
6-OHDA (ST) Rat (female) |
Poor survival(1) | No (1) | - | ▪ Strong reduction of amphetamine-induced rotations ▪ Neuroprotection of the nigrostriatal pathway ▪ (1)Increased survival and differentiation of MSCs after adhesion to pharmacologically active microcarriers (PAMs) |
| Park et al., 2012a | Human placental-derived MSCs undifferentiated and differentiated to NPCs (2 × 105 cells/μl) | 6-OHDA (MFB) Rat (male) Intrastriatal 30 days post-lesion |
Yes | Yes | - | ▪ Sprouting of striatal DA fibers |
| Shetty et al., 2013 | Undifferentiated human UC- MSCs or differentiated to DA cells and BM-MSCs and (1 × 106) Intranigral 6w post-lesion |
6-OHDA (SN) Rat (male) |
Yes | Yes | - | ▪ Improvement in rotometer test |
| Wang et al., 2013 | Undifferentiated rat BM-MSCs or differentiated to NPCs under hypoxia or human fetal BM-MSCs (5 × 105) Intrastriatal 4 wk post-lesion |
6-OHDA (MFB) Rat (female) |
Yes | Yes (under hypoxic conditions) | - | ▪ Improvement in rotometer test ▪ Increased striatal DA levels induced by grafting of pre-differentiated MSCs |
| Chen et al., 2017 | Rat BM-MSCs (6 × 104) Intranigral 3 wk post-lesion |
6-OHDA (SN) Rat (male) |
Yes | No (Differentiation to GFAP-and NSE- positive cells) |
Yes | ▪ Improvement in rotometer test ▪ Increased number of DA neurons and striatal fiber density |
| Blandini et al., 2010 | Human MSCs (commercial) (1.8 × 105) Intrastriatal 5 days post-lesion |
6-OHDA (ST) Rat (male) |
Yes | No (GFAP expression) | No | ▪ Improvement in rotometer test ▪ Increased survival of DA neurons and striatal fibers ▪ Increased GDNF levels in the SN |
| Cova et al., 2010 | Human MSCs (commercial) (3.2 × 104 or 1.8 × 105 cells) Intrastriatal 5 days post-lesion |
6-OHDA (ST) Rat (male) |
Yes | No (GFAP expression) | - | ▪ Enhanced neurogenesis in the SVZ ▪ Migration of neuroblasts from the SVZ to the ST ▪ Reduced loss of DA neurons and striatal terminals ▪ Secretion of BDNF after grafting |
| Xiong et al., 2013 | Human BM-MSCs (1 × 106) Intrastriatal 2 wk post-lesion |
Rotenone (SN) Rat (female) |
Yes | Yes (after bFGF exposure) | - | ▪ Improvement in rotometer test ▪ Preservation of DA neurons and striatal fibers ▪ Pre-treatment of MSCs with bFGF promoted neural differentiation and enhanced neuroprotective effects |
| Schwerk et al., 2015 | Human AD-MSCs (3 × 105) Intranigral 6 days post-lesion |
6-OHDA (MFB) Rat (male) |
Yes | No | Yes | ▪ Improvement of cognitive but not motor performance ▪ Reduction of DA degeneration ▪ Increased neurogenesis in the SVZ and DG |
| Bagheri-Mohammadi et al., 2019 | Human endometrial-derived MSCs (1 × 104, 5 × 104 or 1 × 105) Intranasal 4 wk post-lesion |
6-OHDA (ST) Mouse (male) |
Yes | - | Yes (SN) | ▪ Improvement in rotometer test ▪ Increase in the number of DA neurons and striatal terminals |
| Wang et al., 2020 | Human UC-MSCs (1 × 107 cells/kg; repeated infusions) Intravenous (tail vein) 5 wk post-lesion |
MPTP Mouse (female) |
Yes | - | Yes (ST) | ▪ Motor improvements (open field and rotarod) ▪ Increased expression of TH in the ST and SN ▪ Reduced expression of apoptotic factors |
| Lian et al., 2021 | Human AD-MSCs (1 × 105) Intrastriatal 4 wk post-lesion |
6-OHDA (SN) Mouse (male) |
- | - | - | ▪ Behavioral improvement (rotarod and open field) ▪ Neuroprotection of DA neurons ▪ Reduction of apoptotic markers |
| Moloney et al., 2010 | Rat BM-MSCs or MSCs modified to produce GDNF (2 × 105) Intrastriatal 4 days pre-grafting |
6-OHDA (ST) Rat (male) |
Poor survival | - | No | ▪ No neuroprotection ▪ No functional recovery ▪ Sprouting of DA fibers around grafted GDNF- transduced MSCs |
| Sun et al., 2020 | Human AD-MSCs or AD-MSCs modified to produce GDNF (5 × 105) Intrastriatal 9 days post-lesion |
6-OHDA (ST) Mouse (male) |
Yes (GDNF- producing cells) | No (GFAP and Tuj1 expression) | - | ▪ Improved performance on behavioral tests ▪ Increased graft survival when GDNF-secreting cells were transplanted ▪ Neuroprotective effects on DA cells |
| Chao et al., 2009 | Mouse BM-MSCs (1 × 105) Intravenous (tail vein) 1-day post-lesion |
MPTP Mouse (male) |
Yes | No | Yes (SN) | ▪ BBB recovery ▪ Reduction of microglial activation ▪ Prevention of DA cell death |
| Park et al., 2012b | Human BM-MSCs (1 × 106) Intravenous (tail vein) 3 days post-lesion |
MPTP Mouse (male) |
Yes | No | Yes | ▪ Increased neurogenesis in tde SVZ and SN ▪ Increased proliferation in the SN ▪ Reduced loss of DA neurons |
| Inden et al., 2013 | Human BM-MSCs (5 × 105) Intravenous (tail vein) Immediately after lesion |
Rotenone Mouse |
Yes (few cells) | Yes (TH expression) | Yes (ST) | ▪ Significant improvement in behavioral dysfunction (rotarod) ▪ Increased number of DA and NeuN cells in the SN |
| Cerri et al., 2015 | Rat BM-MSCs (1 × 106) Intracarotid 14 days post-lesion |
6-OHDA (ST) + BBB disruption Rat (male) |
Yes | - | Yes (only after BBB disruption) | ▪ Forelimb akinesia is not modified by cell infusion ▪ Reduction in net rotations ▪ No neuroprotective effects |
| Suzuki et al., 2015 | Human BM-MSCs (commercial) (1 × 107) Intravenous (femoral vein) 16 days post-lesion |
6-OHDA (ST) Rat (male) |
No | - | No | ▪ Amelioration in drug-induced rotational behavior ▪ Preservation of DA cells ▪ Inhibition of microglial activation |
| Park and Chang, 2020 | Human MSCs (commercial) (1 × 106; repeated infusions) Intravenous (tail vein) |
MPTP Mouse (male) |
Very low | - | Yes (ST) | ▪ Motor function improved (rotarod) ▪ Neuroprotection of DA cells ▪ Increased levels of GDNF and BDNF in the ST |
| Danielyan et al., 2011 | Rat BM-MSCs (3 or 5 × 105) Intranasal 3-, 7-or 9-days post-lesion |
6-OHDA (MFB) Rat (male) |
Yes | Yes (TH expression) | Yes (ST, SN and others) | ▪ Improvement of motor function ▪ Increased levels of TH in the ST and SN ▪ Reduction in apoptosis markers and pro- inflammatory cytokines |
| Salama et al., 2017 | Mouse BM-MSCs (5 × 105) Intranasal 8 wk post-lesion |
Rotenone Mouse |
Yes | - | Yes | ▪ Improved locomotor performance (parallel rod test, open field, akinesia, tremor) ▪ DA degeneration counteracted |
| Chartoff et al., 2011 | Mouse BM-MSCs (5 × 104) Intranasal 3 wk post-lesion |
6-OHDA (ST) Mouse (male) |
No | - | No | ▪ MSCs did not survive or migrate into the brain after intranasal delivery |
| Bossolasco et al., 2012 | Human BM-MSCs (2 × 106 (intranasal) or 1.8 × 105 (intrastriatal)) 5 days post-lesion |
6-OHDA (ST) Rat (male) |
Variable (1),(2) | - | - | ▪ (1)No signal was detected 60 min after intranasal infusion ▪ (2)Detection 14 days after grafting |
| Camp et al., 2009 | Rat MSCs (commercial) (4 × 105) Intrastriatal Immediately after lesion |
6-OHDA (SN) Rat (female) |
Yes | - | Yes | ▪ MSC administration did not prevent behavioral deficits or DA depletion ▪ Robust cellular immune responses in the ST |
| Forouzandeh et al., 2021 | Neural induced and non-induced human eye conjunctiva-MSCs (encapsulated and non- encapsulated) (3 × 104) Intrastriatal 2 wk post-lesion |
6-OHDA (MFB) Rat (male) |
Yes | Yes | - | ▪ Significant reduction in drug-induced rotations ▪ Increased striatal TH expression |
| Sun et al., 2022 | Human UC-MSCs (1 × 106; repeated infusions) Intranasal 5 days post-lesion |
MPTP Mouse (male) |
- | - | - | ▪ Reduction of motor impairment (pole test and traction test) ▪ Rescue of DA neurons ▪ Inhibition of inflammation ▪ Changes in gut microbiota |
| Venkataramana et al., 2010(1), 2012(2) | Human BM-MSCs (autologous(1)/allogenic(2)) (1 × 106(1) or 2 × 106 cells/kg(2) body weight) Lateral to the SVZ (bilateral grafts) |
PD patients Human |
- | - | - | ▪ No serious adverse events were observed 36 m after transplantation |
6-OHDA: 6-Hydroxydopamine; AD-MSCs; adipose-derived mesenchymal stromal cells; BBB: blood-brain barrier; BDNF: brain derived neurotrophic factor; bFGF: basic fibroblast growth factor; BM-MSCs: bone marrow-derived mesenchymal stromal cells; DA: dopamine; DG: dentate gyrus; GDNF; glial cell line-derived neurotrophic factor; GFAP: glial fibrillary acidic protein; MFB; medial forebrain bundle; MPTP: 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine; NeuN: neuronal nuclear antigen; NPCs: neural precursor cells; NSE: neuron-specific enolase; PD: Parkinson’s disease; SN: substantia nigra; ST: striatum; SVZ; subventricular zone; TH: tyrosine hydroxylase; Tuj1: β-tubulin III, clone Tuj1; UC-MSCs: umbilical cord-derived mesenchymal stromal cells; wk: weeks.