Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury

Table 1 Transplantation-based astrocyte replacement in amyotrophic lateral sclerosis animal models

Animal	Type of cells	Delivery	Effect on disease	Main outcomes	Ref.
SOD1G93A ALS rats (80 d-old)	GRPs from rat E13.5 spinal cord, wild-type and overexpressing GLT1	Injections into C4-C6 cervical spinal cord, 6 sites, bilateral 1.5 × 105 cells/site	Delayed decline in motor function and survival extension	Differentiation 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 GDNF	Injection in cisterna magna and cerebral ventricles	No effect on motor function or animal survival	Differentiation in GFAP+ GLT1-expressing and growth factors-secreting astrocytes. Prevented motor neurons loss	[147]
SOD1G93A ALS rats (90 d-old)	Rat adult MSCs	Intrathecal delivery in lumbar cisterna magna, 1.95 × 106 cells	Preserved motor function and survival extension	Differentiation into astroglial cells. Decreased neuroinflammation	[75]
SOD1G93A ALS mice (24-26 wk-old)	Human umbilical cord blood cells overexpressing VEGF and FGF2	Intravenous delivery, 1 × 106 cells	Not investigated	Differentiation in S100+ astrocytes	[146]
SOD1G93A ALS rats (14-26 wk-old)	NSCs from rat E16 brain cortex	Intravenous delivery, 1 × 107 cells	Not investigated	Preferential 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/site	No effect on histological or functional outcomes	Poor cell survival	[124]

ALS: Amyotrophic lateral sclerosis; BDNF: Brain-derived neurotrophic factor; C: Cervical; E: Embryonic; FGF2: Fibroblast growth factor 2; GDNF: Glial cell-derived neurotrophic factor; GFAP: Glial fibrillary acidic protein; GLT1: Glutamate transporter 1; GRP: Glial-restricted precursor; IGF-1: Insulin-like growth factor 1; MSC: Mesenchymal stem cell; NP: Neural precursor; NSC: Neural stem cell; NT-3: Neutrophin-3; SOD1: Superoxide dismutase 1; VEGF: Vascular endothelial growth factor.

Table 2 Transplantation-based astrocyte replacement in spinal cord injury animal models

Animal andtype of SCI	Type of cells	Delivery	Effects on disease	Main outcomes	Ref.
Rat, aspiration of C3 fasciculus gracilis	E14 rat spinal cord astrocytes	Intraparenchymal graft at lesion site	Worsened hindlimb function compared to controls	Migration of grafted GFAP+ astrocytes toward the nucleus gracilis of the host medulla	[184]
Rat, L3 hemisection	Neonatal rat cortical astrocytes	Intraparenchymal injection at lesion site, 2.5 × 105 cells, in suspension or in gelfoam	Not investigated	Migration more than 4 mm away from the injection site, reduced glial scarring	[185]
Rat, photochemically-induced infarction of dorsal funiculus	Neonatal rat mixed glial cells (close to type-1 astrocytes)	Intraparenchymal injection at lesion site	Not investigated	Produced 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 contusion	GRPs from rat E13.5 spinal cord	Intraparenchymal injection at lesion site, 5 × 105 cells	Not investigated	Differentiated 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 hemisection	P3 rat neonatal cortical astrocytes (mainly type I astrocytes)	Intraparenchymal injection at lesion site, 2.5 × 105 astrocytes in a collagen I scaffold	Modest temporary improvements of locomotor function	No migration of astroglial cells out of the implant. Significant increase in the number of ingrowing axonal fibres	[152]
Rat, T8/9 contusion	Mixed NRPs and GRPs (ratio 1:3) from rat E13.5 spinal cord	Intraparenchymal injections at and around lesion site, 3 sites, 1 × 106 cells	Improvement of bladder, sensory and motor functions	Differentiation into neurons and glia. Volume of spinal cord spared was increased and local lumbosacral circuitry was modified	[187]
Rat, T8 complete transection	Adult rat cortical astrocytes	Intraparenchymal injection below lesion site (T11), 1.5 × 105 cells	Not investigated	Massive rostral migration (8 mm)	[188]
Rat, C1/2 or C3/4 dorsal hemisection	GDAsBMP4 from rat E13.5 spinal cord	Intraparenchymal injections at and around lesion site, 6 sites, 2-3 × 104 cells/site	Functional locomotor recovery	Significant axonal regrowth, decreased synthesis of inhibitory proteoglycans, suppression of axotomized neurons atrophy	[156]
Rat, C1/2 or C3/4 dorsal hemisection	GDAsBMP4 from rat E13.5 spinal cord GDAsCNTF from rat E13.5 spinal cord GRPs	Intraparenchymal injections at and around lesion site, 6 sites, 3 × 104 cells/site	Same for GDAsBMP4 as in[156], GRPs and GDAsCNTF caused mechanical allodynia and thermal hyperalgesia	Same results for GDAsBMP4 as in[156], GRPs and GDAsCNTF failed to support axonal regrowth	[115]
Rat, C3/4 dorsal hemisection	GDAsBMP4 and GDAsCNTF from human embryonic spinal cord tissue (week 9 of gestation)	Intraparenchymal injections at and around lesion site, 6 sites, 3 × 104 cells/site	GDAsBMP4 promoted locomotor recovery	GDAsBMP4 supported axonal regrowth, neuronal survival more efficiently than GDAsCNTF	[116]
Mouse, T9/10 contusion	Mouse iPS-derived astrocytes	Intraparenchymal injection at lesion site, 1 site, 1 × 105 cells	No improvement of locomotor or sensory functions	No tumor formation. Long GFAP+ processes from transplanted cells. No interaction with host cells.	[189]
Athymic rats, T10 contusion	hGRPs from fetal cadaver brain tissue (week 18-24 of gestational) GDAsBMP4 derived from hGRPs	Intraparenchymal injections at and around lesion site, 3 sites, 1 × 106 cells	No significant improvements in motor function recovery. hGRP grafts attenuated hyperactive bladder reflexes	Differentiation for 80% of grafted cells into GFAP+ astrocytes	[159]
Athymic rat, C4/5 dorsal hemisection	GRPs, GDAsBMP4 and GDAsCNTF from human and rat embryonic tissue	Intraparenchymal injection at lesion site, 1 site, 6 × 105 cells	Not investigated	In all 3 groups differentiation into astrocytes generating a permissive environment for axonal regrowth, but not out of the lesion	[157]
Rat, T9 contusion	GDAsBMP4 from rat E14 spinal cord and overexpressing D15A	Intraparenchymal injections around lesion site, 4 sites, 4 × 105 cells	Improved locomotor function. No changes in neuropathic pain	Differentiation 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 hemisection	GRPs, GDAsBMP4 and GDAsCNTF from fetal cadaver brain tissue (week 20-21 of gestation)	Intraparenchymal injection at lesion site, 1 site, 6 × 105 cells	Not investigated	Differentiated astrocytes from all 3 groups generated a permissive environment for axonal regrowth	[160]
Rat, T8 contusion	GDAsBMP4 from rat E13.5 spinal cord	Intraparenchymal injection at and around lesion site, 12 sites, 1.5 × 104 cells/site	Improved hindlimb motor function	Promoted axonal regrowth, reduced glial scarring, inhibited neuroinflammation	[190]

BMP4: Bone morphogenic protein 4; CNTF: Ciliary neurotrophic factor; E: Embryonic; CSPG: Chondroitin sulfate proteoglycans; GDA: GRP-derived astrocyte; GFAP: Glial fibrillary acidic protein; GRP: Glial-restricted precursor; h: Human; iPS: Induced-pluripotent stem cells; L: Lumbar; NRP: Neural-restricted precursor; P: Post-natal; SCI: Spinal cord injury; T: Thoracic.