Review
Copyright ©The Author(s) 2015.
World J Stem Cells. Mar 26, 2015; 7(2): 380-398
Published online Mar 26, 2015. doi: 10.4252/wjsc.v7.i2.380
Table 1 Transplantation-based astrocyte replacement in amyotrophic lateral sclerosis animal models
AnimalType of cellsDeliveryEffect on diseaseMain outcomesRef.
SOD1G93A ALS rats (80 d-old)GRPs from rat E13.5 spinal cord, wild-type and overexpressing GLT1Injections into C4-C6 cervical spinal cord, 6 sites, bilateral 1.5 × 105 cells/siteDelayed decline in motor function and survival extensionDifferentiation into functional astrocytes. Prevented motor neurons loss independently from growth factors secretion, sustained GLT1 levels, alleviated microgliosis[104]
SOD1G93A ALS mice (75 d-old)Human neural precursors (hNPs) overexpressing BDNF, IGF-1, VEGF, NT-3, or GDNFInjection in cisterna magna and cerebral ventriclesNo effect on motor function or animal survivalDifferentiation in GFAP+ GLT1-expressing and growth factors-secreting astrocytes. Prevented motor neurons loss[147]
SOD1G93A ALS rats (90 d-old)Rat adult MSCsIntrathecal delivery in lumbar cisterna magna, 1.95 × 106 cellsPreserved motor function and survival extensionDifferentiation into astroglial cells. Decreased neuroinflammation[75]
SOD1G93A ALS mice (24-26 wk-old)Human umbilical cord blood cells overexpressing VEGF and FGF2Intravenous delivery, 1 × 106 cellsNot investigatedDifferentiation in S100+ astrocytes[146]
SOD1G93A ALS rats (14-26 wk-old)NSCs from rat E16 brain cortexIntravenous delivery, 1 × 107 cellsNot investigatedPreferential homing to late symptomatic ALS brain and spinal cord. Differentiation into neurons and astrocytes[135]
SOD1G93A ALS mice (50-60 d-old)hGRPs from fetal cadaver brain tissue (week 17-24 of gestational)Injections into C4-C5 cervical spinal cord, 4 sites, bilateral 1.2 × 105 cells/siteNo effect on histological or functional outcomesPoor cell survival[124]
Table 2 Transplantation-based astrocyte replacement in spinal cord injury animal models
Animal andtype of SCIType of cellsDeliveryEffects on diseaseMain outcomesRef.
Rat, aspiration of C3 fasciculus gracilisE14 rat spinal cord astrocytesIntraparenchymal graft at lesion siteWorsened hindlimb function compared to controlsMigration of grafted GFAP+ astrocytes toward the nucleus gracilis of the host medulla[184]
Rat, L3 hemisectionNeonatal rat cortical astrocytesIntraparenchymal injection at lesion site, 2.5 × 105 cells, in suspension or in gelfoamNot investigatedMigration more than 4 mm away from the injection site, reduced glial scarring[185]
Rat, photochemically-induced infarction of dorsal funiculusNeonatal rat mixed glial cells (close to type-1 astrocytes)Intraparenchymal injection at lesion siteNot investigatedProduced dense clusters of astrocytes surrounded by meningeal cells within the cyst[186]
Neonatal kitten mixed glial cells (giving rise to type-2 astrocytes)Produced cells that filled the cyst with a loose network devoid of meningeal cell infiltration at the lesion
CG4-mixed glial cells (differentiated into type-2 astrocytes)Filled the cyst with a loose network and increased the density of blood vessels in the lesion core
Rat, T9/10 contusionGRPs from rat E13.5 spinal cordIntraparenchymal injection at lesion site, 5 × 105 cellsNot investigatedDifferentiated into oligodendrocytes and astrocytes. Reducing glial scar and proteoglycans synthesis. Supported axonal regrowth in the lesion but not on long-distance[155]
Rat, T8 dorsal hemisectionP3 rat neonatal cortical astrocytes (mainly type I astrocytes)Intraparenchymal injection at lesion site, 2.5 × 105 astrocytes in a collagen I scaffoldModest temporary improvements of locomotor functionNo migration of astroglial cells out of the implant. Significant increase in the number of ingrowing axonal fibres[152]
Rat, T8/9 contusionMixed NRPs and GRPs (ratio 1:3) from rat E13.5 spinal cordIntraparenchymal injections at and around lesion site, 3 sites, 1 × 106 cellsImprovement of bladder, sensory and motor functionsDifferentiation into neurons and glia. Volume of spinal cord spared was increased and local lumbosacral circuitry was modified[187]
Rat, T8 complete transectionAdult rat cortical astrocytesIntraparenchymal injection below lesion site (T11), 1.5 × 105 cellsNot investigatedMassive rostral migration (8 mm)[188]
Rat, C1/2 or C3/4 dorsal hemisectionGDAsBMP4 from rat E13.5 spinal cordIntraparenchymal injections at and around lesion site, 6 sites, 2-3 × 104 cells/siteFunctional locomotor recoverySignificant axonal regrowth, decreased synthesis of inhibitory proteoglycans, suppression of axotomized neurons atrophy[156]
Rat, C1/2 or C3/4 dorsal hemisectionGDAsBMP4 from rat E13.5 spinal cord GDAsCNTF from rat E13.5 spinal cord GRPsIntraparenchymal injections at and around lesion site, 6 sites, 3 × 104 cells/siteSame for GDAsBMP4 as in[156], GRPs and GDAsCNTF caused mechanical allodynia and thermal hyperalgesiaSame results for GDAsBMP4 as in[156], GRPs and GDAsCNTF failed to support axonal regrowth[115]
Rat, C3/4 dorsal hemisectionGDAsBMP4 and GDAsCNTF from human embryonic spinal cord tissue (week 9 of gestation)Intraparenchymal injections at and around lesion site, 6 sites, 3 × 104 cells/siteGDAsBMP4 promoted locomotor recoveryGDAsBMP4 supported axonal regrowth, neuronal survival more efficiently than GDAsCNTF[116]
Mouse, T9/10 contusionMouse iPS-derived astrocytesIntraparenchymal injection at lesion site, 1 site, 1 × 105 cellsNo improvement of locomotor or sensory functionsNo tumor formation. Long GFAP+ processes from transplanted cells. No interaction with host cells.[189]
Athymic rats, T10 contusionhGRPs from fetal cadaver brain tissue (week 18-24 of gestational) GDAsBMP4 derived from hGRPsIntraparenchymal injections at and around lesion site, 3 sites, 1 × 106 cellsNo significant improvements in motor function recovery. hGRP grafts attenuated hyperactive bladder reflexesDifferentiation for 80% of grafted cells into GFAP+ astrocytes[159]
Athymic rat, C4/5 dorsal hemisectionGRPs, GDAsBMP4 and GDAsCNTF from human and rat embryonic tissueIntraparenchymal injection at lesion site, 1 site, 6 × 105 cellsNot investigatedIn all 3 groups differentiation into astrocytes generating a permissive environment for axonal regrowth, but not out of the lesion[157]
Rat, T9 contusionGDAsBMP4 from rat E14 spinal cord and overexpressing D15AIntraparenchymal injections around lesion site, 4 sites, 4 × 105 cellsImproved locomotor function. No changes in neuropathic painDifferentiation into GFAP+ astrocytes not secreting CSPG and allowing robust axonal regeneration. Increased spared white matter and decreased injury size compared to controls[181]
Athymic rat, C4/5 dorsal hemisectionGRPs, GDAsBMP4 and GDAsCNTF from fetal cadaver brain tissue (week 20-21 of gestation)Intraparenchymal injection at lesion site, 1 site, 6 × 105 cellsNot investigatedDifferentiated astrocytes from all 3 groups generated a permissive environment for axonal regrowth[160]
Rat, T8 contusionGDAsBMP4 from rat E13.5 spinal cordIntraparenchymal injection at and around lesion site, 12 sites, 1.5 × 104 cells/siteImproved hindlimb motor functionPromoted axonal regrowth, reduced glial scarring, inhibited neuroinflammation[190]