3.1. Search results:
In the present study, 98 papers (Scopus = 36, PubMed = 27, Web of Science = 35, of which, 70 duplicate articles and 7 review articles were excluded. Two authors individually screened all-searches papers for exclusion and inclusion criteria according to title and abstract. 21 articles were screened according to abstract and title. In the next step, the reviewers screened the full-text articles, after full-text evaluation, 12 articles were deleted due to non-fulfillment of inclusion criteria. Finally, of these, 9 papers were selected to review. The flowchart of the screening procedure is illustrated in Figure 1.
3.2. Review of the paper selection procedure
98 articles were found after searching electronic databases. After excluding duplicates and review articles, a total of 21 articles were selected. Then, based on unrelated titles or abstracts, 12 papers were eliminated. In the end, nine papers were chosen (Table 1)
Table 1
Transplantation of SCs on models of NDs
Author, Year | Aim | Method of delivery | Study Design | FINDINGS |
Rodriguez, et al (2003) | Investigating the SCs Transplantation in a 3-Nitropropionic Acid sample of Early Huntington's Disease. | After two injections of 3-NP, Sertoli cells were implanted in the striatum of rats. A locomotor activity test was performed. and after the last behavioral test, animals were sacrificed and Nissl staining, TH immune histochemistry performed. | Experimental study | In a 3-NP replica of early HD, Sertoli transplants can improve locomotor abnormalities (18). |
Luca et al. (2016) | looking into the growing immuno-regulatory and anti-inflammatory characteristics of Sertoli cells In R6/2 transgenic mice (HD), | The lifetime, motor function, and striatal inflammatory pattern of the pilot R6/2 mouse model of Huntington's disease were examined after one intraperitoneal shot of microencapsulated prepubertal pig Sertoli cells. | Experimental study | By modulating immunological dysfunction in the brain, one intraperitoneal shot of microencapsulated prepubertal porcine SCs improved performance and expanded the lifespan of R6/2 Huntington's disease mice (19). |
Ahmadi, et al. (2018) | investigating the in vitro and in vivo potency of primitive SCs, as well as their paracrine action against oxidative stress, using a rat model of HD as a paradigm. | SCs were extracted and immunophenotypically identified by GATA4 expression. The ability of SCs to synthesize GDNF/VEGF was then demonstrated. The vitality and neuritogenesis of PC12 cells treated with hydrogen peroxide in the existence of CM (SC-CM) were then determined. In 3-NP-lesioned rat models, bilateral striatal implantation of SC was conducted, and 1 month later, the post-graft study was performed. | Experimental study | The CM-SC significantly increased cell survival and neurite outgrowth while protecting PC12 cells from oxidative stress. 2- transplanted SCs survived, showed a reduction in gliosis also inflammatory cytokine production, and improved motor regulation and muscle function in HD rats, as well as an increase in striatal mass and dendritic diameter (4). |
Aliaghaei, et al. (2019) | SC transplants in a rat replica of amyloid-beta poisoning were studied for their neuro-restorative/protective effects. | SCs were isolated and implanted into rats with hippocampal lesions caused by amyloid-beta. | Experimental study | SCs that had been implanted survived and showed a decrease in both apoptosis and astrocytic migration. Furthermore, SC transplantation improved hippocampus-reliant memory and learning, as well as long-term synaptic plasticity (7). |
Hemedinger, et al.(2005) | The efficacy of Sertoli cells introduced into the spinal cord parenchyma to preserve motor neurons was investigated. | SCs were isolated and transplanted into the (L4-L5) transgenic mice's spinal ventral horn. The graft site was next examined histologically and morphometrically. | Experimental study | In comparison to the contralateral and uninjected spinal cord, there was a considerable rise in the amount of remaining ChAT-positive motor neurons detected ipsilateral to the injection. In the SOD1 transgenic mouse, implantation of a Sertoli-cell-enhanced mixture provided considerable neuroprotection to susceptible motor neurons (20). |
Saeidikhoo, et al.(2020) | Examining the neuroprotective benefits of SCs in vivo and in vitro in the treatment of cerebellar ataxia symptoms. | 1-after exposing PC12 cells to SC-CM and H2O2, the neuroprotective effect of SCs was assessed. 2-ataxia rat models were induced with one dosage of 3-AP and SCs were implanted bilaterally three days later. Following SC transplantation, a motor and neuromuscular function test was performed. Finally, immunohistochemistry was done against RIPK3 and Iba-1. | Experimental study | 1- In vitro research showed that SC-CM enhanced cell viability while lowering ROS levels significantly. 2- Over 28 days, in vivo data, demonstrated a significant increase in neuromuscular response, whereas the ataxia group's condition deteriorated. Due to SCs' ability to decrease necroptosis, their findings revealed improved motor function and behavioral traits And, as a result, cell survival (21). |
Mohammadi, et al (2018) | Purkinje cell distribution in the ataxic rat's cerebellum following SC transplantation. | 3-AP was injected intraperitoneally into rats, causing ataxia. Differences in the spatial organization of PCs in ataxic rats with (3-AP-SC) or without (3-AP-SC) (3-AP). Second-order stereology was used to assess the transplanting of SCs. The anti-calbindin antibodies were used in the IHC approach within the cerebellum. | Experimental study | Latter to ataxia induction in rats, PCs are not typically oriented after 3-AP, and SCs transplanting stored the spatial configurations of the cells. The number of PCs dramatically increased following SC transplantation, according to IHC analysis (22). |
Yun-Ting Jhao, et al (2019) | The effect of co-grafting SCs with VM tissue was studied on hemi-parkinsonian rats. | Hemi-parkinsonian rats were produced. Intrastriatally implanted VM tissue from rats or pigs (rVM or pVM) with or without a co-graft of SCs (rVM + SCs or pVM + SCs). The apomorphine-induced rotation test and small animal-positron emission tomography (PET) coupled with [18F] DOPA or [18F] FE-PE2I, respectively, were used to assess dopaminergic function and graft survival. Immunohistochemistry (IHC) was utilized to assess the survival of transplanted dopaminergic neurons in the striatum as well as the immune-modulatory effects of SCs. | Experimental study | compared to the VM alone groups, the rVM + SCs and pVM + SCs groups displayed considerably better drug-induced rotating behavior. PET demonstrated a significant increase in [18F] DOPA and [18F] FE-PE2I specific uptake ratios (SURs) in transplanted striatum of the rVM + SCs and pVM + SCs groups compared to the rVM and pVM groups. The co-graft of SC and VM tissue improved the survival of dopaminergic (DA) cells. When compared to the groups without SCs, the co-grafted groups had smaller numbers of T-cells and activated microglia (23). |
Shamekh, et al (2005) | The ability of SCs to modulate the immune system and the viability of xenografting these cells by itself or with allografted and xenografted brain tissue is being investigated. | All animals were euthanized one week after the transplant. In this experiment, all grafts were evaluated and calculated. Individual TH-positive cells were counted, and IHC against GFAP was conducted. | Experimental study | even though all transplants demonstrated active microglia in the center of the graft, transplanting rat SC xenografts into the striatum of the mouse either by the rat or mouse ventral mesencephalon inhibited astrocytic infiltration of the graft area. Every circumstance measured, showed surviving tyrosine hydroxylase-positive neurons (24). |
Huntington's disease
Huntington's disease (HD) is an inherited, progressive, destructive, neurodegenerative disease with obvious symptoms including chorea and low tonicity of muscle, lack of coordination, cognitive lesson, psychiatric signs, and motor problems. The start of symptoms occurs in middle age after patients get married and have family and children. This issue is not absolute and disease can emerge at every age between childhood and old age. Huntington’s is a changed structure protein in Huntington's disease which is created from a developed CAG. Extensive protein repetition of CAG leads to a polyglutamine strand. At last, it is attached to N-Terminus. According to Demonstrations, this defective terminus transforms into a toxic substance that has a destructive function. The excessive deposition of insoluble aggregates is generated by proteins with aberrant structures that result from genetic mutations or metabolic damage which is linked not only to HD but to the increasing range of disorders. (25).
In 2003, Rodiguez et al. evaluated the outcome of Sertoli cell transplantation in a 3-NP sample of early HD in rats. After two injections of 3-NP rats developed the HD. Rats were accidentally separated into two groups and got bilateral SCs transplantation in the striatum (2 µl per site). Locomotor activity was assessed at 4 and12 weeks following transplantation to calculate the process of healing.
After the most recent behavioral assessment, animals were sacrificed and Immunofluorescent photomicroscopy of DiI labeled SCs, Nissl staining, and TH immunohistochemistry was taken. 3- NP-induced locomotor hyperactivity in rats after SCs transplantation was dramatically reduced compared with the control group with some behaviors returning to baseline. Sertoli cells persisted without systemic immunosuppression in the striatum, and some of them produced tubule-like structures. The striatum did not seem to be damaged as a result of the 3-NP dose regimen. Nonetheless, ventricular size analyses revealed control rats given 3-NP, had bigger ventricles than rats who were not given 3-NP, demonstrating 3-NP-induced striatal atrophy (18).
In 2016 Luca et al. evaluated the therapeutic effects of microencapsulated prepubertal porcine Sertoli cells in the R6/2 mouse model of Huntington's disease. Pig Sertoli cell was extracted and isolated and then transplanted into mice with a single intraperitoneal injection (1 × 106 SC/gram of body weight). The lifetime, motor function, and inflammatory pattern in the striatum were all assessed.
The outcomes showed that Proinflammatory factors such as NFKB activation and iNOS, and COX2 protein expression decreased. Also, PCR revealed a decreasing level of TNFa, IL-1b, and IL-10. In summary, Apoptosis was reduced in HD mice given Sertoli cells compared to other groups. In addition, when HD mice were given Sertoli cells, their life duration and motor coordination improved in comparison to others. The beneficial effects of Sertoli cells on motor coordination were observed. Their data significantly demonstrated the anti-inflammatory and neuroprotective effects of intraperitoneal injection of Sertoli cells. These effects improved motor performance and expanded HD mice’ lifespan. Collectively, disease progression decreased during the study period (19).
In 2018, Ahmadi et al. decided to assess the therapeutic effects of SCs in a rat model of HD. Firstly, secretion of neurotrophic factors GDNF and VEGF by SCs was confirmed, secondly, PC12 cells were contacted to hydrogen peroxide in the existence of conditioned media that they gathered from SC (SC-CM), and cell activity and neurogenesis were evaluated. After that, cell survival and neuritogenesis were evaluated. In the in vivo phase, they transplanted SC labeled with Hoechst (5 μg/ml) Bilateral in the striatum in 3-nitropropionic acid (3-NP)-damaged rat models. Due to the in vitro results, cell survival and neurite ramifications noticeably improved since the CM of SC preserved PC12 cells against oxidative stress. Also grafted SCs expressed a decline in both inflammatory factor levels and gliosis. Muscle movement and motor collaboration were recuperated. Also, SCs preserved striatum volume against more atrophy and neuron degeneration in HD rats. In the end, their findings demonstrated that SCs with their favorable effects bring a supportive rule in HD and toxic microenvironment (4).
Alzheimer's disease
The most frequent dementia is Alzheimer's disease (AD). Alzheimer's disease is characterized by amyloid plaques and neurofibrillary tangles in the brain, as well as synapses and neuron loss, which leads to cognitive deficits and eventually dementia. In addition to dementia, the major components of patches and tangles are amyloid- (A) peptide and tau protein (26), respectively. Early Aβ deposition in the precuneus and default mode network cortical areas is followed by regional cortical hypo metabolism, tau pathology accumulation, hippocampal mass reduction, and symptomatic mental decline. The development of cognitive impairment is often associated with the synaptic and neuronal decline in the entorhinal cortex (27). The neurofilament light chain (NfL) in CSF and plasma seems to represent the amount of general neurodegeneration in all types of neurodegenerative dementias (28, 29). Inflammation also plays an important role. The continuous stimulation of the brain's local macrophages (microglia), as well as other immune cells, has been shown to aggravate both amyloid and tau pathology, suggesting that it could have an impact on the disorder's advancement (30). Excessive stimulation of M1 microglia and malfunction of M2 microglia accelerate the development of Alzheimer's disease (31). However, the exact causes are unknown.
In 2019, Aliaghaei et al evaluated the effects of SCs transplantation in rats damaged by injection of 2μg/4 μl of newly prepared Aβ1-42 amyloid-beta toxicity which was introduced on each side of both hippocampus. Bilateral SC transplantation in each hippocampus was done 7 days following the injection of toxin. Cells were labeled with Hoechst (5µg/ml) and by using Hamilton micro syringe injection.
Their investigations proved that the transplantation of SCs revitalized the neural network of the hippocampus which led to dependent memory recovery and learning in lesioned rats. Due to restoration of synaptic communications and long-term synaptic plasticity, further SCs transplantation in the lesioned hippocampus reduced cell death, astrocytic emigration, and gliosis, and also prevented further hippocampal damage (7).
Amyotrophic lateral sclerosis:
Amyotrophic lateral sclerosis (ALS) is a complicated illness marked by the continuous deficit of motor neurons, which ultimately results in paralysis and mortality (32). Degeneration of motor neurons in the anterior horns of the spinal cord, the brainstem, and big pyramidal neurons in the primary motor cortex are among the neuropathological features (33). The present ALS medications have just a minor impact on the disease's clinical progression. The mechanism that causes motor neurons to deteriorate is still unknown (32). Several genes have been found as having the potential to produce ALS in an autosomal dominant way when altered, however, whether SOD1 mutations induce motor neuron degeneration is unknown (34). The majority of ALS patients are sporadic (sALS), with only 5%–20% reporting a family history of the disease (fALS) Most neuropathological traits are shared between sALS and fALS, and clinically, they appear to be extremely similar (35). Different cell types controlling neuroinflammatory processes are thought to be significantly engaged in the development of the disease (36). It is widely assumed that the disease begins inside motor neurons. In 2005, Hemedinger et al investigated the effects of transplantation of Sertoli cells into the parenchyma of the spinal cord in ALS-induced rats (encoding the human Cu–Zn superoxide dismutase (SOD1) gene mutation (G93A). Before the development of clinical symptoms, Sertoli-enriched testicular cells (11×105 cells) were injected into the L4–L5 ventral horn of rats in a unilateral spinal injection. The graft site was examined histologically and morphometrically. In comparison to the contralateral and uninjected spinal cord, there was a notable growing amount of persisting Mot or neurons ipsilateral to the insertion that are ChAT positive. The proximity of the injection site influenced the ipsilateral rise in motor neuron density. There was no variation in motor neuron density in regions rostral or caudal to the insertion location. In the SOD1 transgenic paradigm, implantation of a Sertoli-cell-enhanced mixture shows a considerable neuroprotective advantage to susceptible motor neurons (20).
Cerebellar Ataxia:
Disturbance to the various distinct motor or sensory parts of the CNS and peripheral nerve pathology can cause ataxia. Cerebellum impairment, which is frequently caused by stroke, illness, or tumor, is one of the most prevalent causes of ataxia. Cerebellar injury is associated with ataxia of voluntary limb movement or gait, as well as other pathophysiological symptoms such as nystagmus, dysmetria, postural sway, dyssynergia, and dysarthria (37). These symptoms can cause a tremor with a high amplitude that is accompanied by movement. Purkinje cell abnormalities may contribute to the pathophysiology of ataxias and disturbance in action potential production, according to findings from cell and animal experiments (21).
In 2020, Saeidikhoo et al. investigated the in vitro and in vivo neuroprotective role of SCs on the symptoms of cerebellar ataxia in the year 2020. The expression of neurotrophic factors glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial factor (VEGF) had already been established by the protein analysis (VEGF). After introducing PC12 cells to Sertoli cell-conditioned media (SC-CM) and H2O2, the neuroprotective effect of SCs was assessed in vitro. Then after, ataxia-induced rats were generated with one dosage of 3-AP (3acetylpyridin), then SCs 3×105 cells were implanted bilaterally 3 days later. Following SC transplantation, motor and neuromuscular function tests were performed. Finally, their research used immunohistochemistry targeting RIPK3 and Iba-1.
Over 28 days, the in vivo data demonstrated a significant increase in neuromuscular responsiveness, whereas the ataxia group's condition deteriorated. Due to SCs' ability to decrease necroptosis and hence extend cell longevity, their findings predicted improved motor function and behavioral traits. Also In vitro research showed that SC-CM enhanced cell viability while lowering ROS levels significantly (21).
In 2018, Mohammadi et al. looked at the spatial organization of Purkinje cells in the cerebellum of ataxic rats after Sertoli cells were transplanted. In rats, ataxia was caused by injecting 3-AP (65 mg/kg) intraperitoneally. Second-order stereology was used to assess the spatial pattern of PCs for alterations in ataxic rats with (3-AP-SC) or even without (3-AP) Sertoli cells (SCs) transplantation. The IHC approach, which used anti-calbindin antibodies in the cerebellum, revealed that a random organization exists at greater distances within PCs in the 3-AP and 3-Ap-SC groups. As a result, following 3-AP and SCs transplantation, the PCs are not regularly oriented, and the spatial configurations of the cells after ataxia generation in rats are preserved. The number of PCs dramatically increased following SC transplantation, according to IHC analysis. Finally, SCs transplantation improved the spatial organization of PCs in rats with 3-AP-induced cerebellar ataxia (22).
Parkinson’s disease:
Parkinson's disease (PD) is a frequent neurodegenerative condition characterized by selective degradation of dopaminergic (DA) neurons in the substantia nigra part of pars compacta. Bradykinesia, resting tremors, postural instability, and rigidity are all symptoms of Parkinson's disease (38). Deep brain stimulation and other pharmacological and surgical treatments, for example, deep brain stimulation, can help reduce mentioned symptoms to some extent (39). However, do not halt the progression of the disease. Furthermore, the efficacy of drugs might wane with time, and long-term treatment can result in adverse effects such as paresthesia, depression, and dyskinesia (40, 41).
In 2019, Yun-Ting Jhao and colleagues evaluated the influence of Sertoli cells on xenotransplantation and allotransplantation of ventral mesencephalic tissue. 6-hydroxydopamine was injected into the right medial forebrain bundle of Sprague Dawley (SD) rats to produce hemi-parkinsonian rats. The rats were subsequently implanted intrastriatal with VM tissue from rats or pigs (rVM or pVM), with and without a co-graft of SCs (1× 105 cells) (rVM+SCs or pVM+SCs). The apomorphine-induced rotation test and small animal-positron emission tomography (PET) combined with [18F] DOPA or [18F] FE-PE2I, respectively, were used to assess dopaminergic function and graft survival. The viability of the grafted dopaminergic neurons in the striatum was determined using immunohistochemistry (IHC), and the immune-modulatory effects of SCs were investigated using IHC. When compared to the VM alone groups, the rVM+SCs and pVM+SCs groups displayed considerably enhanced drug-induced rotating behavior. PET demonstrated a significant increase in [18F] DOPA and [18F] FE-PE2I specific uptake ratios (SURs) in the transplanted striatum of the rVM+SCs and pVM+SCs groups compared with the rVM and pVM groups. The co-graft of SC and VM tissue improved the survival of dopaminergic (DA) cells. When compared to the control group, the co-grafted groups had smaller numbers of T-cells and enabled microglia. In a PD rat model, their findings imply that SC co-graft benefits both xeno- and allotransplantation of VM tissue. The use of SCs boosted the persistent and functional improvement of transplanted dopaminergic neurons (23).
Shamekh and colleagues examined the immune-modulatory potential of SCs and the possibility of xenografting them alone as well with allografted and xenografted brain tissue in 2005. SCs were extracted from rats aged 15 to 17 days. The capability of SCs was measured by trypan blue dye exclusion after cell culture methods, and cell concentration was modified to 104 cells/l. The rVM was recovered from 13-15-day mouse embryos. Cell viability and concentration were comparable to SCs. Before surgery, the cells for the VM+SCs co-transplant groups were combined and then injected into two striatum sites. Even though all transplants exhibited active microglia in the center of the graft, xenografts of rat SCs into the mouse striatum either with rat or mouse ventral mesencephalon inhibited astrocytic infiltration at the graft environment. In all of the settings, tyrosine hydroxylase-positive neurons survived, although the grafts were tiny at best. At 1 and 2 weeks after the transplant, SCs were discovered. Two months after the transplant, however, just a few SCs were discovered. More research is being conducted to assess SC immunological capacities in a xenogeneic context (24).