Stem Cell Therapy For Alzheimer’s Disease: An Overview Of Experimental Models And Reality Part 2

2.1.3  |  hUCB-MSCS

The beneficial characteristics of hUCB-MSCs include noninvasive collection, hypo-immunogenicity, superior tropism, high differentiation potentials, and paracrine activity.37,38 Therefore, hUCB-MSCs have been emerging as an alternative source for allogeneic MSC mediated therapy. 

Low immunogenicity refers to a substance that causes little or no immune response in the human body. Substances with low immunogenicity are often used in the manufacture of products such as medical devices and pharmaceuticals. In the human immune system, memory cells are a special type of cells that can preserve a fast and effective immune response to an external substance so that it can respond to it more quickly and effectively when the substance is encountered again in the future. Many people believe that low immunogenicity substances may have adverse effects on the body's memory cells, but in fact, there is no direct relationship between low immunogenicity and memory.

Although low-immunogenic substances themselves do not directly affect memory, they can affect the immune response to certain drugs. For example, medical devices or drugs manufactured using low-immunogenic substances can reduce patients' discomfort and immune responses during treatment, thereby improving the patient's treatment experience and effectiveness.

Low immunogenic substances are widely used in medical science. Most biodegradable plastics, implantable devices, and many commonly used pharmaceuticals are made from low-immunogenic substances. These products can not only better adapt to the human body and reduce stimulation of the immune system, but can also effectively treat diseases and improve the quality of human life. Therefore, low-immunogenic substances are one of the important achievements of modern medicine and life sciences. They are widely used in the medical and health fields and have made great contributions to human health.

In summary, there is no direct relationship between low immunogenicity and memory. In the fields of medicine and life sciences, low-immunogenic substances have been widely used, which can effectively treat diseases and improve patients' treatment experience and efficacy. They are one of the important achievements of modern medicine and life sciences. This shows that we need to improve memory. Cistanche deserticola can significantly improve memory, because Cistanche deserticola has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche deserticola can also It can promote the growth and repair of nerve cells, thereby enhancing the connectivity and function of neural networks. These effects can help improve memory, learning, and thinking speed, and may also prevent the development of cognitive dysfunction and neurodegenerative diseases. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche deserticola can also promote the growth and repair of nerve cells, thereby enhancing the connectivity and function of neural networks. These effects can help improve memory, learning, and thinking speed, and may also prevent the development of cognitive dysfunction and neurodegenerative diseases.

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The therapeutic effects of hUCB-MSCs have been verified in 5 × FAD mice and nontransgenic Sprague-Dawley rats.37,39,40 Moreover, their safety and efficacy have also been evaluated through phase-I/IIa clinical trials (NCT02054208) in patients with Alzheimer's disease.37 

The secretome of hUCB-MSCs includes multifunctional molecules, such as the inhibitory effect of galectin-3 on aberrant tau phosphorylation, the role of ICAM-1 in the removal of Aβ plaques, and the effect of growth/differentiation factor 15 (GDF15) on neurogenesis in AD models.39,41,42 hUCB-MSCs may significantly reduce Aβ-dependent AD pathology, as demonstrated by the co-culture system of hUCB-MSCs and mouse primary hippocampal neurons. 

The paracrine thrombospondin-1 (TSP-1) of hUCB-MSCs can rescue neurons from the Aβ peptide-induced loss of synaptic density, thereby improving cognitive function in the AD-like mouse model.37

2.1.4  |  ESCS

Transplanted mouse ESC-derived neuronal precursor cells can transdifferentiate into cholinergic cell phenotype, improving spatial memory performance in ibotenic acid-induced AD-like rats.43 When human ESCs are transplanted into mouse hippocampal slice, the stable generation of cholinergic neurons promotes synapse formation and functional circuit reconstruction.44 

Another study reports that human ESCs can transform into GABAergic and cholinergic neuronal subtypes, leading to improvements in spatial memory and learning ability in mouse models.45 The cranial transplantation of human ESCs can rescue cognitive impairment in radiation-treated athymic nude rats.46 

Although ESC transplantation has shown the ability to improve cognitive function in rodent models, its clinical significance is limited due to the pluripotent uncontrolled cell growth and tumorigenesis.47 Despite much preclinical research, there are inherent ethical and immunogenic limitations in the use of allogeneic ESC-based therapies.48

2.1.5  |  iPSCS

iPSCs are a product of autologous sources using up-to-date cell technology. Human iPSCs have been generated from primary fibroblasts that are isolated from patients with familial AD or from healthy individuals.49 In iPSCs from sporadic AD, APOE4 can be converted to APOE3 to attenuate multiple AD-related pathologies, such as Aβ aggregates and hyperphosphorylated tau.50,51 

The transplantation of iPSCs has shown long-term survival and efficacy in preclinical studies, including the ischemic stroke rodent model and APP transgenic mice.52,53 The therapeutic effect of iPSC-derived somatic cells on patients with familial AD is being evaluated through clinical trial NCT00874783. 

Human iPSC-derived precursors can differentiate into mature cholinergic neurons and form synaptic networks, improving neurological function and ameliorating memory impairment.52,54 iPSC-NSCs can reduce pro-inflammatory factors through a neurotrophin-associated bystander effect after their implantation in the ipsilesional hippocampus.53 

However, the benefits of autologous iPSCs are limited by the phenotypic neuropathology of neurons generated from AD patients, including abnormal Aβ levels, increased p-tau, decreased neurite length, and susceptibility to inflammatory challenge.55–57

2.2  |  Delivery methods of stem cells

2.2.1  |  Intravenous

Intravenous administration is a relatively convenient method for stem cell delivery, which can be implemented multiple times through the peripheral vein. However, the transfused stem cells travel in the systemic circulation, and they may infiltrate into different organs, with especially large accumulation in the lungs. 

Stem cells injected through the tail vein take time to cross the blood-brain barrier and enter the hippocampus for functional activities. Hence, the therapeutic efficiency of the intravenous method needs to be improved.

2.2.2  |  Intrahippocampal

Intrahippocampal delivery avoids the blood-brain barrier but requires a 3-dimensional positioning device and imaging system. Moreover, stereotactic injection is a traumatic operation that reaches the functional area of the hippocampus. 

Therefore, it is inappropriate to perform multiple injections, which limits its clinical application. In addition, the local pressure can be increased after the stem cells are injected into the hippocampus. 

This pressure change may generate a physical impact, but its potential influence remains to be determined. In contrast, peripheral vein delivery does not have this type of problem.

2.2.3  |  Intracerebroventricular

The intracerebroventricular method is similar to intrahippocampal administration and also requires a 3-dimensional positioning device and imaging system. The physical pressure in the cerebral ventricle is elevated after the injection of stem cells. 

Accordingly, the physical pressure of cerebral tissue is proportional to the volume of transplanted stem cells and depends on the delivery method. Sometimes, even if the same cell type (i.e., BM-MSCs) is used, the volume of stem cells has to be adjusted due to different delivery procedures.11

2.2.4  |  Intranasal

The intranasal route is a noninvasive and convenient way that can easily and repeatedly deliver drugs, exosomes, and stem cells to the brain.58,59 This injury-free method shows clinical feasibility and has important advantages over conventional injection or intracranial transplantation.60 The intranasal delivery of stem cells has been performed in APP/PS1 transgenic mice, and the functional improvement has been verified.59 

Currently, nanotechnology has been combined with the intranasal administration of stem cells, which has exhibited a synergistic effect on the treatment of neurological diseases.60,61 The therapeutic efficiency of intranasal administration has not yet been proven.

2.3  |  The functional mechanism of stem cells

Preclinical studies have shown that there is a complex signal network involved in the improvement of cognitive function following stem cell therapy. Representative signal pathways and potential mechanisms are summarized as follows.

2.3.1  |  Neurogenesis/Synaptogenesis

The transplanted stem cells contribute to hippocampal neurogenesis and synaptic plasticity (Figure 2). hUCB-MSCs can be stereotactically injected into the hippocampus of APP/PS1 transgenic mice, which stimulates neurogenesis and synaptic plasticity through paracrine GDF-15.39 

AD-MSCs improve endogenous neurogenesis in both the subgranular and subventricular zones and reduce cognitive decline in APP/PS1 mice.62 BM-MSCs are transfused into APP/PS1 mice via the tail vein to promote hippocampal neurogenesis.11,63 

The transplanted stem cells can up-regulate the expression of galectin-3, activate the Wnt signaling pathway, and facilitate the secretion of autocrine and paracrine cytokines such as BDNF and NGF, which are associated with the improvement of cognitive ability.39,64–66

2.3.2  |  Amyloid-β and tau pathologies

The deposition of Aβ aggregates and the formation of neurofibrillary tangles are related to neuronal death and synaptic loss. The administration of hUCB-MSCs mitigates the hyperphosphorylation of tau and ameliorates memory impairment in mice. 

Furthermore, the secretion of essential galectin-3 takes part in the removal of aberrant tau tangles by modulating protein-protein interactions.42 The intrahippocampal transplantation of hAM-MSCs remarkably decreases Aβ deposits and improves memory function in APP/PS1 mice.67 

BMMSCs not only reduce the production of Aβ peptides in the cortex and hippocampus but also promote the degradation and transport of Aβ proteins. Moreover, BM-MSCs can attenuate the phosphorylation level of tau protein in APP/PS1 mice.11

2.3.3  |  Inflammation and immunoregulation

The therapeutic effect of BM-MSCs on APP/PS1 transgenic mice involves immunoregulatory mechanisms, including peripheral monocyte recruitment, microglial M1/M2 polarization, pro-/antiinflammatory cytokines, neurotrophin-mediated synaptic plasticity, and so on.68 

BM-MSCs can regulate the microenvironmental immune activity by inhibiting the excessive activation of microglia. The expression of pro-inflammatory TNF-α and IL-1β is downregulated, whereas the level of anti-inflammatory IL-10 is upregulated. 

Moreover, BM-MSCs dramatically reduce the number of astrocytes and microglia.69,70 Human menstrual blood-derived MSCs can reduce the level of several pro-inflammatory cytokines such as IL-1β and TNF-α, which are associated with an altered microglial phenotype in APP/PS1 transgenic mice.71 Inflammation/immunoregulation is a key axis associated with the improvement of synaptic function and cognitive performance.

2.3.4  |  Paracrine and autocrine cytokines

Injected hUCB-MSCs can secrete paracrine GDF-15 in the hippocampus of APP/PS1 transgenic mice, which promotes neurogenesis and synapse formation.39 Also, hUCB-MSCs produce galectin-3 to reduce the hyperphosphorylation of tau, thereby lessening aberrant tau tangles.42 BM-MSCs can stimulate hippocampal angiogenesis through vascular endothelial growth factor (VEGF) expression.70 

Moreover, BM-MSCs regulate the expression of Nrf2, reduce oxidative stress, and decrease neuronal apoptosis.72,73 The upregulation of neurotrophic factors such as BDNF and NGF raises the number of NeuN-positive neurons and boosts neuronal repair.63,74,75

2.3.5  |  Enhancement of synapse formation

The transplanted BM-MSCs have effects on synapse formation and endogenous neurogenesis. Potential mechanisms involve (i) the generation of neurotrophic factors, with stem cell transplantation improving cognitive performance, which may contribute to the recovery of synaptic connectivity through the release of neurotrophins (i.e., growth-associated protein-43 [GAP-43], BDNF)73,76; and (ii) the proliferation of regulatory T cells. 

The immunoregulation of the central nervous system depends on the interaction between microglia and T cells. The microglia-mediated proliferation of Aβ-reactive Th2 cells is linked with the expression of cytokines IL-4 and IL-10, which may counterbalance the toxic level of nitric oxide (NO) induced by the Aβ protein.77,78 

MSCs can stimulate the proliferation of regulatory T cells.79,80 T cells mediate synaptic plasticity by shaping the crosstalk of distinct immune cells or specialized immune networks.

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