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Cell Biology
Stem cells are a versatile source for cell therapy. Their use is particularly significant for the treatment of neurological disorders for which no definitive conventional medical treatment is available. Neurological disorders are of diverse etiology and pathogenesis. Alzheimer’s disease (AD) is caused by abnormal protein deposits, leading to progressive dementia.
- stem cells
- therapy
- neurodegenerative diseases
- Parkinson’s disease
1. Introduction
In the 21st century, stem cells have gained tremendous importance in the fields of medical research and therapy. Stem cells are recognized as body cells that have unique characteristics, including the ability of self-renewal and differentiation into several type of body cells [1]. They can remain undifferentiated (totipotent) and are capable of differentiating into several mature cells [2]. Stem cells can be categorized depending on their sources: embryonic stem cells, fetal stem cells, adult stem cells and induced pluripotent stem cells [1].
In the medical field, stem cells have been authorized for use in bone marrow transplantation for the treatment of hematological malignancies and some inherited metabolic diseases. Recently, successful stem cell transplantation was reported to cure human immunodeficiency virus (HIV) infection [3]. Several experimental studies and/or clinical trials studied the use of different kinds of stem cells for the treatment of neurological disorders particularly the disorders lacking a definitive medical treatment. These include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s Disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), temporal lobe epilepsy (TLE), neuropathic pain (NP), and brain ischemic stroke (BIS) [4,5].
The significance of stem cells is derived from their reported ability to replenish damaged cells and tissues as well as their anti-inflammatory and immune-modulatory properties. Stem cells can differentiate and replenish cells that have been weakened or destroyed, promoting neural tissue growth and development. Most of the neurological disorders are characterized by the widespread neuronal death and the extremely low regenerative potential of the brain. The treatment needs materials or cells that can cross the blood brain barrier (BBB). All these factors contribute to making stem cell therapy a viable option for treating chronic intractable neurologic diseases [6,7]
By combining additional drugs, the results of stem cell therapy may be improved [8]. Stem cell treatment, for example, in combination with erythropoietin, had synergetic effects on rat neurogenesis. To overcome the limitations of stem cell migration and inclusion in functional networks [9,10,11], nanoparticle distribution systems are investigated. Since they cross the BBB and enter the target brain areas without affecting the surroundings, these nanoparticles are beneficial for drug and cell systems. Another choice for delivering and preserving stem cells in the transplant site is hydrophilic polymer encapsulation, thereby providing mechanical assistance in supply processes and increasing the proliferation and differentiation in hydrogels [12]. In recent research, gene therapy and neural development factors have also been used to extend the retention of AD and PD transplanted stem cells [13].
Many recent trials have shown the value of peripheral stem cell treatments for acute stroke survivors, enabling minimally invasive cell therapy to become a practical alternative option. Additionally, there is consideration of the use of mesenchymal stem cells (MSCs) for supplying bioactive factors, such as brain-derived neurotrophic factors (BDNF), in treating neurologic disorders, such as HD [14,15,16].
2. Selection of Transplant Recipients
Cell transplantation requires several sets of issues that must be considered in preclinical and clinical trials [17]. The first is whether the disease causes brain cell death or initiates a transition in cell interactions. The next is the probability of systemic transplantation, which happens only if the blood–brain barrier (BBB) is known to be open. Another aspect is whether pathology causes an inflammatory response in relation to the condition itself. In this case, the transplanted cells can play not only an alternative role, but also an anti-inflammatory role. All critical issues must be considered for nearly all cells used in clinical trials [17].
Given the above, it is not easy to choose the cells to be transplanted. Many various stem cell types play a possible therapeutic role in the treatment of neurological conditions. Cells must play either a substitutional or trophic role. There was a great focus on the substitution feature in earlier years of stem cell transplantation in neurological disorders. Many experimental studies in animal models showed that transplanted cells in the nerve tissue did not produce a physiological response [18,19]. If the neural dysfunction is still significant and the surgical approach takes place, the tissue’s reconstitution and hence the rebuilding of the injured neural pathways are very complex. Spinal cord damage is associated with the loss of motor neurons with long axons covered by the myelin sheath. In such circumstances, the transplanted cells must replenish neurons and glia; however, to exert their therapeutic activity, they must be capable of expanding their processes in the right direction. It is unlikely that this challenge will be completed with the current expertise, but a potential approach for transplant research in sophisticated tissues may be the fusion of transplant therapy and bioengineering (scaffold construction) [12].
No biomarkers or successful medicines were able to slow down disease development, despite the billions in dollars of clinical trials and considerable advances in studying neurodegenerative mechanisms. This makes stem cell therapy for the treatment of neurodegenerative diseases a beneficial approach to be tested [20]. The first aim of stem cell therapy involves determining distinct neuronal subtypes and the recapitulation of a network of neural diseases similar to those lost. The development of environmental reinforcement in support of host neurons by the production of neurotrophic and scavenging toxic factors and the construction of an auxiliary neural network across the affected areas is another approach to the treatment of neurodegenerative disorders [21]. Another strategic approach is the synthesis of neuroprotective growth factors in the sites of diseases (e.g., glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), the insulin-like factor 1 growth factor (IGF-1), and VEGF).
One of the biggest concerns is immune rejection of transplanted fetal tissue or cells, which can trigger serious host responses [22]. Although the brain is considered immuno-privileged, few human leucocyte antigen cells remain matched to the haplotype, requiring immunosuppression in recipients to prevent cell-induced immune refusal. While there are a few exceptions, new technologies are necessary to increase donors’ and recipients’ compatibility and avoid further immune rejections [23,24].
3. Stem Cells in Alzheimer’s Disease (AD)
Alzheimer’s disease is a widespread chronic, pathologically marked neurodegenerative condition with ß-amyloid plaques and neurofibrillary tangles. Current alternatives to medication only relieve the symptoms without treating the illness, which is a significant problem that impacts the quality of life of patients and their care providers. Stem cell therapy may offer new opportunities for AD patients’ care. More and more research has shown that neural stem cells(NSCs) developed from embryonic stem cells (ESCs) were efficient as a treatment approach in AD models, showing changes both in vitro and in vivo [25,26]. Stem cells have the potential to differentiate from the brain extracellular matrix into neural cells, and they may restore neuroplasticity and neurogenesis via neurotrophic factors [27].
The stem cell approach to treating AD was first examined in animal models [28]. Neural stem cells from neonatal rat brains were used to establish new cholinergic neurons and increased learning and memory in rats with AD [29]. Neuron-like embryonic stem cells were used to restore AD-damaged rat brains [30]. Lately, the most used cells in Alzheimer’s disease research were embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), brain-derived neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs) [31].
The basal forebrain cholinergic neurons (BFCNs) are critically implicated in memory and learning disorders, such as AD [32]. The ESCs possess the pluripotency potential, which is double-bladed. Although that pluripotency is a great advantage for ESCs, it is a considerable disadvantage, as it may lead to the differentiation of the ESCs into several directions, which ultimately can lead to the formation of teratomas and tumors. Moreover, there is a tendency for eliciting disturbed immune reactions and rejection on transplanting ESCs [33,34]. Therefore, although the ESCs showed promising results in rat models of AD and improved memory performance, it has limited clinical applications. Two types of ESCs have been used in AD research: mouse ESCs (mESCs) and human ESCs (hESCs). Both produced the differentiation into BFCNs when transplanted in mice models with AD.
The immune rejection that occurs using allogeneic hESCs can be mitigated by transplanting iPSCs. Therefore, stimulating the differentiation of autologous hiPSCs could be promising in diminishing the chances of such immune rejection. Nevertheless, there are many concerns regarding the safety of using the iPSCs including the potential risk of oncogenesis and teratoma formation, the safety of the long-term use, the reprogramming efficiency, and immunogenic liability. The partial reprogramming and the unstable genes might elicit an immunological reaction with iPSCs. There is a need to develop new methods and protocols to avoid the expression of the tumorigenic genes when using iPSCs [34,35]. The iPSCs can differentiate into different cell types, including neurons. In AD research, iPSCs can be used, for example, to investigate the inflammatory reaction, to induce macrophages that can express a protease that degrades beta-amyloid called neprilysin and to reprogram the fibroblast and hence identify the phenotype of the AD [31,36,37].
Despite the ethical issues, the most widely used type of stem cells utilized in AD research is MSCs obtained from umbilical cord blood. This is attributed to the feasibility of obtaining umbilical cord blood after delivery [31,38]. Previous reports have shown that MSCs can improve the deficits in memory and learning in AD murine models. Boutajangout et al. reported that human umbilical cord mesenchymal stem cell (HUC-MSCs) xenografts improved cognitive decline and reduced the Amyloid burden in a mouse model of Alzheimer’s disease [39].
Many mechanisms have been suggested to be involved in this process, including decreased beta-amyloid plaques, a dramatic decrease in β-secretase 1 (BACE-1) levels, reduced hyperphosphorylation of tau, and the reversal of the inflammatory process in the microglia as well as the enhancement of anti-inflammatory cytokines [40]. Additionally, the immunomodulation and anti-inflammatory effects of MSCs have been reported to occur via enhancing the neuroprotection and depressing the proinflammatory cytokines. Moreover, bone marrow MSCs have been found to stimulate the formation of extracellular vesicles and microvesicles. These vesicles, in turn, target the amyloid-beta [41,42]. Additionally, the evolved plasticity and neurotrophic decline, decreased tau phosphorylation, and neuroinflammation, and tau down-regulation are promising targets for stem cells. Results showed the transgenic mice survived without any harmful effects and showed increased memory. This was confirmed in another study, where synaptogenesis increased the mental capacity in mice [43,44]. The successful preliminary animal studies showed positive findings. Researchers grafted human umbilical mesenchymal stem cells obtained from donor cords, into AD mice. An anti-inflammatory and immune-modulatory reaction was simultaneously induced in the mice by this study, and the presence of M2-like microglia enhanced synapsin and raised A β levels in the brain, thereby decreasing amyloid accumulation [45]. This led to a clinical trial in 2015 using human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) on nine patients with mild-to-to-moderate AD. The hUCB-MSCs were stereotactically inserted into the hippocampus. The method of administration of the stem cells was stable and feasible, with no consequences. Better studies with larger sample size and placebo monitoring are needed to advance the hypothesis. The administration of stem cell therapy was safe but needs to be further checked for its therapeutic efficacy on AD pathogenesis. [46]. The outcome of some studies on Alzheimer’s patients is still unknown such as (NTC01547689, NTC02672306, NTC02054208, and NTC02600130 from Clinicaltrials.gov). Nevertheless, they are all experiments constrained by the variation of neurons affected by AD.
The biotechnology company Nature Cell has begun a new phase II clinical trial using a stem cell medicine for AD (AstroStem) consisting of autologous adipose tissue stem cells administered intravenously into 60 AD patients (200 million cells/injection) (NCT03117738).
This entry is adapted from the peer-reviewed paper 10.3390/cells11213476
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