Additional Table 1.
Co-grafting-based strategies in Parkinson’s disease
| Reference | Co-grafted cells | Animal model | Outcomes |
|---|---|---|---|
| Aguayo et al., 1984 | Rat fVM tissue + rat sciatic nerve | 6-OHDA Rat (female) | ▪ Monoaminergic neurons within the graft extended axons along the nerve bridges |
| van Horne et al., 1991 | Rat fVM tissue + rat sciatic nerve | 6-OHDA Rat (male) | ▪ Improvement in rotational behavior after co-grafting |
| Timmer et al., 2004 | Rat fVM cells (2-2.5 × 105) + rat SC (2-2.5 × 105) Intrastriatal 8 wk post-lesion |
6-OHDA (MFB) Rat (female) | ▪ Increased survival of DA cells in co-grafts |
| Collier et al., 1994 | Monkey fVM cells + monkey saphenous nerve 1 post-lesion |
MPTP Monkey (male) |
▪ No neuroprotective effects |
| Agrawal et al., 2004 | Rat fVM cells (2.5 × 105) + rat OECs (2.5 × 105) Intrastriatal 5 wk post-lesion |
6-OHDA Rat |
▪ Improvement in rotational behavior after co-grafting ▪ Increased survival of grafted DA cells ▪ Restored levels of striatal DA and DOPAC |
| Johansson et al., 2005 | Rat fVM cells (1 × 105) + rat OECs (2 × 105) or rat astrocytes (2 × 105) Intrastriatal 4 wk post-lesion |
6-OHDA (MFB) Rat (female) |
▪ Co-grafts with OECs enhanced DA survival and neurite elongation |
| Weng et al., 2017 | Rat fVM cells (2 × 105) + rat OECs (2 × 105) Intrastriatal 3 wk post-lesion |
6-OHDA (MFB) Rat (male) |
▪ Co-grafted rats exhibited better motor recovery (rotometer) and enhanced survival of grafted DA cells |
| Shukla et al., 2009 | Rat fVM-derived NSCs (2.5 × 105)+ rat OECs (2.5 × 105) Intrastriatal 4 wk post-lesion |
6-OHDA (MFB) Rat (female) |
▪ Restitution of motor function and increased survival and reinnervation of grafted NSCs |
| Weng et al., 2020 | Porcine fVM cells (2.5 × 105) + rat OECs (2.5 × 105) Intrastriatal 2 wk post-lesion |
6-OHDA (MFB) Rat (male) |
▪ Better improvement in apomorphine-induced rotational behavior and higher DA survival and less immune response |
| Brundin et al., 1986 | Rat fVM cells (1.2-1.5 × 105) + rat fST cells (1.5-2 × 105) or rat spinal cord cells (1.5-2 × 105) Intrastriatal 3 wk post-lesion |
6-OHDA (MFB) Rat (female) |
▪ Co-grafted animals showed a tendency to improve behavioral effects (rotation test) ▪ Greater area of reinnervation after co-grafts ▪ Similar number of DA cells in co-grafted rats compared to rats grafted with fVM cells alone |
| Yurek et al., 1990 | Rat fVM cells (6-7.5 × 104) + rat fST cells (6-7.5 × 104) (mixed in the same cell suspension or grafted separately) Intrastriatal 1 wk post-lesion |
6-OHDA Rat (male) |
▪ Larger DA cell body, arborization and improved motor behavior (rotometer) after co-grafting |
| Costantini et al., 1994 | Rat fVM cells (1 × 105) + rat fST cells (1 × 105) Intrastriatal 2-4 months post-lesion |
6-OHDA (LV) Rat (3 days old) |
▪ Co-transplants produced stronger behavioral effects and dense TH-positive patches within the grafts, without increasing DA survival |
| Emgard-Mattson et al., 1997 | Rat fVM + rat fST cells (lateral and medial ganglionic eminences) (7.9-12.7 × 104 total cells in the suspension) Intrastriatal |
6-OHDA (MFB) Rat (female) |
▪ Co-grafts containing lateral ganglionic cells showed patches of dense TH-positive fibers ▪ No functional differences were observed after co-grafting (rotometer and staircase tests) |
| Sortwell et al., 1998 | Rat fVM (1.8 × 105) + rat fST cells (1.8 × 105) (mixed or grafted separately) Intrastriatal 4 wk post-lesion |
6-OHDA (MFB) Rat (male) |
▪ Only rats that received co-grafts placed separately showed significant behavioral recovery and increased DA cell survival ▪ Mixed co-grafts showed enhanced neurite branching and TH-positive rich patches |
| Sladek et al., 2008 | Monkey fVM cells (intranigral) + monkey fST cells (at different points rostrally to the fVM graft, following the nigrostriatal pathway) 2-3 months post-lesion |
MPTP Monkey |
▪ Striatal grafts contained dense DA axons derived from the fVM graft (target-directed outgrowth) |
| Lee et al., 2003 | Human fVM + human fST (1 lateral ganglionic eminence) Intraputamen |
PD patient (male) | ▪ Improved motor function and increased L-DOPA uptake |
| Wilby et al., 1999 | Rat fVM cells (3.4 × 106 cells; intranigral) + GDNF-secreting SC line derived from rat sciatic nerve (2.5 × 105 cells; different deposits along the nigrostriatal pathway) 3 wk post-lesion |
6-OHDA (MFB) Rat (female) |
▪ Co-grafts improved DA survival and neurite outgrowth ▪ No additional effects on motor functions |
| Rodriguez-Pallares et al., 2012 | Rat fVM cells (4.5 × 105) + carotid body cells (4.5 × 105) Intrastriatal 6 wk post-lesion |
6-OHDA (MFB) Rat (female) |
▪ Significantly better motor performance (cylinder test) and improved DA survival and graft-derived DA innervation in rats that received co-grafts |
| Ostenfeld et al., 2002 | Rat fVM cells (2.5 × 105) + expanded NPCs obtained from rat fST tissue and modified to produce GDNF (4 × 105) Intrastriatal 3 wk post-lesion |
6-OHDA (MFB) Rat (female) |
▪ Co-grafting increased DA survival ▪ No significant effects on behavioral recovery |
| JingZhong et al., 2005 | Rat embryonic fibroblasts expressing TH + rat embryonic fibroblasts expressing GDNF (total number = 1 × 106) Intrastriatal 2 wk post-lesion |
6-OHDA (MFB) Rat (female) |
▪ Only rats that received co-grafts showed stable and significant behavioral improvements (rotometer) and biochemical recovery (TH expression) |
| Deng et al., 2013 | Rat fVM cells (2.5 × 105) + rat NSCs overexpressing GDNF (2.5 × 105) Intrastriatal 2 wk post-lesion |
6-OHDA (MFB) Rat (male) |
▪ Co-transplantation significantly reduced apomorphine-induced rotations ▪ Survival and differentiation of NSCs increased after co-grafting. |
| Perez-Bouza et al., 2017 | Cultured rat fVM cells (equivalent to ½ VM) + encapsulated mouse C2C12 myoblasts transfected to produce GDNF Intrastriatal 13 wk post-lesion |
6-OHDA (MFB) Rat (female) |
▪ Higher fiber outgrowth in co-grafted animals ▪ Similar DA survival and graft volume |
| Song et al., 2018 | Mouse or rat fVM-derived NSCs + mouse or rat VM-or cortex-derived astrocytes (ratio 2:1; total number = 4.5 × 105) Intrastriatal |
6-OHDA (SN) Rat (female) |
▪ Co-grafting with VM-derived astrocytes promoted DA differentiation of NPCs and increased fiber outgrowth |
| Leveque et al., 2015 | Porcine fVM cells (3 × 105)+ rat BM-MSCs Intrastriatal 1 wk post-lesion |
6-OHDA (MFB) |
▪ MSCs promoted long-term survival of DA neuroblasts and motor recovery |
| Rodríguez-Pallares et al., 2021 | Rat fVM cells (5 × 105) + rat BM-MSCs (2.5 × 104 (low dose) or 2 × 105 (high dose)) Intrastriatal 6 wk post-lesion |
6-OHDA (MFB) Rat (female) |
▪ Increased survival of DA nigral neurons and striatal terminals after co-grafting fVM cells and low dose of MSCs ▪ High dose of MSCs co-grafted with fVM cells decreased DA survival |
| Shintani et al., 2007 | Rat fVM cells (8 × 104) + mouse CM-derived from BM-MSCs Intrastriatal |
6-OHDA (MFB) Rat (male) |
▪ Increased survival of grafted DA cells |
| Clinical trial identifier NCT03684122 |
Human UC-MSC-derived NSCs (8-12 × 106; intrathecal) + human UC-MSCs (8-12 × 106 (intrathecal) or 4-6 × 107 (intravenous)) | PD patients | ▪ Clinical trial ongoing |
6-OHDA: 6-Hydroxydopamine; BM-MSCs: bone marrow-derived mesenchymal stromal cells; CM: conditioned medium; DA: dopamine; DOPAC: 3,4-dihydroxyphenyl acetic acid; fST: fetal striatal; fVM: fetal ventral mesencephalic; GDNF: glial cell line-derived neurotrophic factor; L-DOPA: L-3,4-dihydroxyphenylalanine; LV: lateral ventricle; MFB: medial forebrain bundle; MPTP: 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine; NPCs: neural precursor cells; NSCs: neural stem cells; OECs: olfactory ensheathing cells; PD: Parkinson’s disease; SC: Schwann cells; SN: substantia nigra; TH: tyrosine hydroxylase; UC-MSCs: umbilical cord-derived mesenchymal stromal cells; wk: weeks.