Table 1 AD rodent model stem cell transplantation studies in the last 5 years
Study | [23] | [24] | [26] | [27] | [34] | [35] | [36] | [37] | [38] | [39] | [45] |
|---|---|---|---|---|---|---|---|---|---|---|---|
Cell type | Murine embryonic NSCs | Human fetal NSCs | Human fetal NSCs | Human fetal NSCs | Human UCB-MSCs | Human PD-MSCs | Human U-MSCs Human U-MSC-NCs | Human A-MSCs | Murine BM-MSCs | Human BM-MSCs | Human iPSC-derived neuronal precursors |
Model | B6C3-Tg (APPswe/PSEN1dE9) transgenic mice | NSE-APPswe transgenic mice | Tg2576 (APPswe) transgenic mice | 3×Tg-AD transgenic mice CaM/Tet-DTA mice | APP/PS1 transgenic mice | Aβ1–42 cerebrally infused mice | B6C3-Tg (APPswe/ PSEN1dE9) transgenic mice | Tg2576 (APPswe) transgenic mice 3xTg-AD transgenic mice | APP/PS1 transgenic mice | Aβ1–42 cerebro-ventricular infused mice | PDAPP transgenic mice |
Delivery route | Bilateral intra-hippocampal stereotactic injection 5 × 105 to 1 × 106 cells Sham: PBS vehicle | Bilateral intra-ventricular stereotactic injection 5 × 105 cells Sham: H-H buffer vehicle | Bilateral intra-hippocampal stereotactic injection 2.5 × 105 cells Sham: culture media vehicle | Bilateral intra-hippocampal stereotactic injection 1 × 105 cells Sham: vehicle | Three bilateral intra-hippocampal injections at 2 week intervals 1 × 105 cells per injection Sham: PBS vehicle | Intravenous injection 1 × 105, 5 × 105, or 1 × 106 cells Sham: Saline vehicle | Bilateral intra-hippocampal stereotactic injection 5 × 104 cells Sham: PBS vehicle | Intravenous injection 2 × 106 cells Sham: PBS vehicle | Intravenous injection 1 × 106 cells Sham: NaCl solution vehicle | Intravenous injection 1 × 106 cells Sham: PBS vehicle | Bilateral intra-hippocampal stereotactic injection 2 × 105 cells Sham: PBS vehicle |
Findings | 10 weeks post-operation Extensive donor cell migration 14.6% neuron, 36.2% astrocyte, and 28.5% oligodendroctye phenotypic differentiation Improved spatial memory (Morris water maze) Decreased expression of pro-inflammatory cytokines IL-1β, IL-6, TNF-α and PGE2 Aβ levels unchanged | 7 weeks post- operation Extensive donor cellular migration NSC phenotype remained in >80% of cells Improved spatial memory (Morris water maze) Decreased levels of phosphorylated tau, Aβ plaques, astrogliosis, microgliosis and apoptosis Decreased expression of pro-inflammatory cytokines IL-1β, IL-6, TNF- α and iNOS Increased cerebral neurotrophin levels and increased hippocampal synaptic density | 5 weeks post- operation Donor cells in the dentate gyrus polymorphic layer 70% neuron, 20% astrocyte phenotypic differentiation Improved spatial memory (Morris water maze) Increased endogenous neurogenesis in the dentate gyrus Reduced cerebral Aβ levels | 6 weeks post-operation Donor cells in the CA1 hippocampal subregion 36.6% and 41.1% cell survival in 3 × Tg-AD and CaM/Tet-DTA, respectively Improved spatial memory (Morris water maze, context- and place-dependent NOR task) Majority of donor cells expressed NSC phenotype Increased levels of synaptic proteins in the hippocampus Soluble, insoluble and hyperphosphorylated tau, Aβ40, and Aβ42 levels unchanged | 41 days post-operation (first injection) Improved spatial memory (Morris water maze) Reduced phosphorylated tau, Aβ plaques, vascular Aβ40, and BACE-1 expression in the cortex and hippocampus Increased levels of activated microglia in the cortex and hippocampus Reduced levels of pro-inflammatory cytokines IL-1β and TNF-α, and increased anti-inflammatory cytokine IL-4 | 2 weeks post-operation Limited donor cells in the hippocampus, and no neural differentiation Improved spatial memory (Morris water maze) Reduced levels of cerebral APP and BACE1, and reduced β- and γ-secretase activity Reduced levels of activated astrocytes and microglia Attenuation Aβ1–42 induced hippocampal apoptosis, and impaired endogenous neuronal differentiation Reduced expression of inflammatory proteins iNOS and COX-2, and an array of pro-inflammatory cytokines | 4 weeks post-operation No donor cells present at 4 weeks post-surgery Improved spatial memory (Morris water maze) in the U-MSC-NC group Increased hippocampal levels of synapsin I in the U-MSC-NC group Decreased hippocampal Aβ deposition, decreased soluble Aβ40 and Aβ42 levels, and increased Aβ-degrading enzymes in the U-MSC-NC group Increased number of M2 activated microglia in the U-MSC-NC group Reduced pro-inflammatory cytokines (IL-1β and TNF-α), and increased anti-inflammatory cytokine IL-4 in the U-MSC-NC group | 6 weeks post-operation (Tg2576 mice) Improved spatial memory (Morris water maze) 1 and 12 weeks post-operation (3 × Tg-AD mice) Donor cells in the spleen, lung, liver, but not brain Reduced number and size of Aβ plaques Increased density of activated microglia in the hippocampus by week 1, lower density than in sham animals by week 12 Increased phagocytotic microglia Reduced proinflammatory cytokines IL-1 and TNF-α at week 1 Increased anti-inflammatory cytokines IL-10 and TNF-β at week 12 Increased levels of Aβ-degrading enzymes | 1 and 4 -weeks post-operation Donor cells in the cerebral cortex and hippocampus, bone marrow, lung, and liver No reduction in total Aβ levels Reduced total levels and vascular deposition of pE3-Ab protein at 4 weeks Increased number of <50 μm Aβ plaques, and reduced number of 50–100 μm Aβ plaques Reduced levels of activated astrocytes and ramified microglia Reduced levels of cortical and hippocampal microglia Reduced levels of hippocampal TNF-α, IL-6, and elevated levels of hippocampal PTGER2 | 1, 2, and 4 weeks post-operation Donor cell neuronal differentiation in the entorhinal cortex and hippocampus Improved working memory performance (Radial Arm Maze) Attenuation of impaired neurogenesis and neuronal differentiation in the hippocampus at 2- and 4-week time points Increased hippocampal expression of neural specification proteins β-catenin and Ngn1 | 2 weeks post-operation Improved spatial memory (Morris water maze) 45 days post-operation Improved spatial memory (Morris water maze) Donor cell survival and neuronal differentiation in the hippocampus Donor cells expression of cholinergic and GABAergic neuronal markers |
Therapeutic mechanism | Modulation of inflammation | Modulation of inflammation and microglia immune response, and protection from Aβ neurotoxicity | Neurotrophic support of endogenous neurogenesis and synaptic connectivity | Neurotrophic support of endogenous neurogenesis and synaptic connectivity | Modulation of inflammation and microglia, and anti-amyloidogenic | Neurotrophic support of endogenous neurogenesis, modulation of inflammation and microglia immune response, and anti-amyloidogenic | Modulation of inflammation and microglia immune response | Modulation of inflammation and microglia immune response | Modulation of microglia immune response | Neurotrophic support of endogenous neurogenesis and protection from Aβ neurotoxicity | Regeneration of depleted neural networks |