Transplantation Of Sertoli Cells Research Articles

Grafted Sertoli cells prevent neuronal cell death and memory loss induced by seizures.

Epilepsy significantly reduces the patient's quality of life, and we still need to develop new therapeutic approaches to control it. Transplantation of cells such as Sertoli cells (SCs), having a potent ability to release a variety of growth and immunoprotective substances, have made them a potential candidate to deal with neurological diseases like epilepsy. Hence, this study aims to evaluate whether SCs transplant effectively protects the hippocampus astrocytes and neurons to oppose seizure damage. For this purpose, the effects of bilateral intrahippocampal transplantation of SCs were investigated on the rats with the pentylenetetrazol (PTZ) induced seizure. After one-month, post-graft analysis was performed regarding behavior, immunohistopathology, and the distribution of the hippocampal cells. Our findings showed SCs transplantation reduced astrogliosis, astrocytes process length, the number of branches, and intersections distal to the soma of the hippocampus in the seizure group. In rats with grafted SCs, there was a drop in the hippocampal caspase-3 expression. Moreover, the SCs showed another protective impact, as shown by an improvement in pyramidal neurons' number and spatial distribution. The findings suggested that SCs transplantation can potently modify astrocytes' reactivation and inflammatory responses.

Updates in Sertoli Cell-Mediated Signaling During Spermatogenesis and Advances in Restoring Sertoli Cell Function.

Since their initial description by Enrico Sertoli in 1865, Sertoli cells have continued to enchant testis biologists. Testis size and germ cell carrying capacity are intimately tied to Sertoli cell number and function. One critical Sertoli cell function is signaling from Sertoli cells to germ cells as part of regulation of the spermatogenic cycle. Sertoli cell signals can be endocrine or paracrine in nature. Here we review recent advances in understanding the interplay of Sertoli cell endocrine and paracrine signals that regulate germ cell state. Although these findings have long-term implications for treating male infertility, recent breakthroughs in Sertoli cell transplantation have more immediate implications. We summarize the surge of advances in Sertoli cell ablation and transplantation, both of which are wedded to a growing understanding of the unique Sertoli cell niche in the transitional zone of the testis.

Sertoli cell transplantation attenuates microglial activation and inhibits TRPC6 expression in neuropathic pain induced by spinal cord injury

BackgroundCell therapy is a promising treatment method for relieving neuropathic pain caused by spinal cord injuries (SCI). Sertoli cells (SCs) are an attractive choice given their demonstrated secretion of growth factors and immunosuppressant effect. This study mechanistically characterizes the analgesic effect of SCs transplantation. MethodsThe clip compression SCI model was carried out on the T12-T13 level in male Wistar rats. One-week post-SCI, SCs were transplanted into the site of injury. Animals underwent Basso, Beattie, and Bresnahan locomotor scoring, mechanical allodynia, and thermal hyperalgesia on a weekly basis for a duration of six weeks. Histological examination of the spinal cord and molecular evaluation of Iba-1, P2Y4, TRPC6, and P-mTOR were performed. SCs survival, measured by anti-Müllerian hormone expression in the spinal cord. ResultsAnimals that received SCs transplantation showed improvement in motor function recovery and pain relief. Furthermore, a cavity was significantly decreased in the transplanted animals (p = 0.0024), the expression level of TRPC6 and caspase3 and the number of activated microglia decreased compared to the SCI animals, and p-mTOR and P2Y4R expression remarkably increased compared to the SCI group. ConclusionSCs transplantation produces an analgesic effect which may represent a promising treatment for SCI-induced chronic pain.

Reduced expression of apoptotic proteins in the ischemic rat brain following Sertoli cell transplantation.

Sertoli cells (SCs) may be a new candidate to decrease ischemic damage due to their ability to secrete factors that actively protect neurons and inhibit uncontrollable immune responses. Pre‑treatment with these cells was considered in the current study. SCs were injected into the right striatum in rats using the stereotaxic technique. Ten days after injection, middle cerebral artery occlusion surgery was performed. Following these procedures, neurological deficit scores, brain edema, blood‑brain barrier integrity, infarct volume, and the expression of apoptotic factors in the cortex, striatum, and piriform cortex‑amygdala were evaluated. Analysis showed that behavioral deficits, infarct volume, blood‑brain barrier permeability, and edema in the striatal area in the allograft group demonstrated a significant decrease compared to the control group. Additionally, analysis of the expression of caspase‑3 and Bcl‑2 proteins in the striatum indicated a remarkable reduction and increase, respectively, in the allograft group compared to the control group. According to the obtained results, one possible mechanism for the neuroprotection induced by SCs in an ischemic brain is the reduction of apoptotic factors.

Effect of Sertoli Cell Transplantation on Reducing Neuroinflammation-Induced Necroptosis and Improving Motor Coordination in the Rat Model of Cerebellar Ataxia Induced by 3-Acetylpyridine.

To date, no certain cure has been found for patients with degenerative cerebellar disease. In this trial, we examined the in vivo and in vitro neuroprotective effects of Sertoli cells (SCs) on alleviating the symptoms of cerebellar ataxia. Testicular cells from an immature male rat were isolated and characterized by immunocytochemical analysis for somatic cell markers (anti-Mullerian hormone, vimentin). The protein assessment had already confirmed the expression of neurotrophic factors of glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial factor (VEGF). In vitro neuroprotective impact of SCs was determined after exposing PC12 cells to Sertoli cell-conditioned media (SC-CM) and H2O2, simultaneously. Afterwards, ataxia rat models were induced by a single dose of 3-AP (3-acetylpyridin), and 3days later, SCs were bilaterally implanted. Motor and neuromuscular activity test were conducted following SC transplantation. Finally, immunohistochemistry against RIPK3 and Iba-1 was done in our generation. The in vivo results revealed substantial improvement in neuromuscular response, while ataxia group exhibited aggravated condition over a 28-day period. Our results suggested enhanced motor function and behavioral characteristics due to the ability of SCs to suppress necroptosis and consequently extend cell survival. Nevertheless, more studies are required to affirm the therapeutic impacts of SC transplantation in human cerebellar ataxia. In vitro data indicated cell viability was increased as a result of SC-CM with a significant reduction in ROS.

Allograft of Sertoli Cell Transplantation in Combination with Memantine Alleviates Ischemia-Induced Tissue Damages in An Animal Model of Rat.

Objective Brain ischemia is the most common disease in the world caused by the disruption of the blood supply of brain tissue. Cell therapy is one of the new and effective strategies used for the prevention of brain damages. Sertoli cells (SCs) can hide from the host immune system and secrete trophic factors. So, these cells have attracted the attention of researchers as a therapeutic option for the treatment of neurodegenerative diseases. Also, memantine, as a reducer of glutamate and intracellular calcium, is a suitable candidate for the treatment of cerebral ischemia. The principal target of this research was to examine the effect of SC transplantation along with memantine on ischemic injuries. Materials and Methods In this experimental research, male rats were classified into five groups: sham, control, SC transplant recipient, memantine-treated, and SCs- and memantine-treated groups. SCs were taken from another rat tissue and injected into the right striatum region. A week after stereotaxic surgery and SCs transplantation, memantine was injected. Administered doses were 1 mg/kg and 20 mg/kg at a 12-hour interval. One hour after the final injection, the surgical procedures for the induction of cerebral ischemia were performed. After 24 hours, some regions of the brain including the cortex, striatum, and Piriform cortex-amygdala (Pir-Amy) were isolated for the evaluation of neurological deficits, infarction volume, blood-brain barrier (BBB) permeability, and cerebral edema. Results This study shows that a combination of SCs and memantine caused a significant decrease in neurological defects, infarction volume, the permeability of the blood-brain barrier, and edema in comparison with the control group. ConclusionProbably, memantine and SCs transplantation reduce the damage of cerebral ischemia, through the secretion of growth factors, anti-inflammatory cytokines, and antioxidant factors.

Neuro-restorative effect of sertoli cell transplants in a rat model of amyloid beta toxicity

Alzheimer’s disease (AD) is a degenerative nerve disease which adversely affects memory and learning skills. Currently, there is no disease-modifying therapeutic approach for AD. However, a growing body of literature suggests cell based therapies as a promising remedy for neurological disorders. Among the potential cell sources, testis- derived Sertoli cells (SCs) appear to be an attractive choice due to their immune-privileged capacities. Herein, we investigated the neuro-restorative/protective effects of SC transplants in a rat model of amyloid beta toxicity. To this end, GATA-4 and vimentin positive SCs were transplanted into rats with amyloid beta induced hippocampal lesions. According to our in vivo results, implanted SCs survived, exhibited reduction in both apoptosis as well as astrocytic migration. Additionally, transplantation of SCs restored hippocampus dependent memory and learning, along with the recovery of long-term synaptic plasticity. Taken together, these data indicate that SCs are a valuable source for cell-based therapies particularly aimed at AD.

Effects of Sertoli Cell Transplantation on Spermatogenesis in Azoospermic Mice.

The aim of this study was to evaluate the potential and significant applications of Sertoli cells (SCs) transplantation, and to explore the effect of transplantation on spermatogenesis process, in azospermic mice. In this study, we utilized 18 adult mice (28‒30 g), divided into four experimental groups: (1) control, (2) vehicle (DMSO 2%) (10 µl) (3) busulfan and (4) busulfan+ SCs (1×104 cells/μL). SCs were isolated from the testis of 4-week-old mouse and after using anesthetics, 10 μl of SCs suspension (1×104 cells/μL) was injected over 3-5 min, into each testis and subsequently, sperm samples were collected from the tail of the epididymis. Afterward, the animals were euthanized and testis samples were taken for histopathology experiments, and RNA extraction, in order to examine the expression of c-kit, STRA8 and PCNA genes. Our data showed that SCs transplantation could notably increase the total sperm count and the number of testicular cells, such as spermatogonia, primary spermatocyte, round spermatid, SCs and Leydig cells, compared to the control, DMSO and busulfan groups. Furthermore, the result showed that the expression of c-kit and STRA8 were significantly decreased in busulfan and busulfan/SCs groups, at 8 weeks after the last injection (p<0.001), but no significant decrease was found for PCNA, compared to the control and DMSO groups (P<0.05). These findings suggest that SCs transplantation may be beneficial as a practical approach for therapeutic strategies in reproductive and regenerative medicine. We further highlighted the essential applications that might provide a mechanism for correcting fertility in males, suffering from cell deformity.

Therapeutic Potential of Pretreatment with Allograft Sertoli Cells Transplantation in Brain Ischemia by Improving Oxidative Defenses.

Brain ischemia is one of the most common causes of death and disability worldwide, which usually happens through diminished blood supply to the tissue. Cell therapy and treatments using trophic factors are some of the new methods to protect brain cells against damage. Specific properties of Sertoli cells (SCs) make them suitable for improving neurological disorders. This study is to evaluate possible neuroprotective effects of SCs transplantation on ischemic damage. Rats were divided into three experimental groups including sham, control, and SCs-treated group. In this study, SCs were isolated from testis of rats and were transplanted into the right striatum by using stereotaxic surgery. After a week, ischemic surgery was performed. Twenty-four hours later, rats were scarified and different regions of the brain including the cortex, the piriform cortex-amygdala (Pir-Amy), and the striatum were collected and preserved in - 80°C for further investigations. This study demonstrates that SCs transplantation can reduce brain ischemia deficits and increase superoxide dismutase (SOD) and catalase (CAT) activities. It also decreases malondialdehyde production, which is the main product of lipid peroxidation. SCs improve ischemic behavioral disorder and reduce brain edema, blood-brain barrier permeability, and infarct volume. It seems that transplantation of SCs can protect neural cells against ischemia by decreasing oxidative stress.

An overview of a Sertoli cell transplantation model to study testis morphogenesis and the role of the Sertoli cells in immune privilege.

Advanced testicular germ cells, expressing novel cell surface and intracellular proteins, appear after the establishment of central tolerance and thus are auto-immunogenic. However, due to testis immune privilege these germ cells normally do not evoke a detrimental immune response. The Sertoli cell (SC) barrier (also known as the blood–testis barrier) creates a unique microenvironment required for the completion of spermatogenesis and sequesters the majority of the advanced germ cells from the immune system. Given that an intact SC barrier is necessary for spermatogenesis and that disruption of the SC barrier results in loss of advanced germ cells independent of an immune response, this dual role of the SC barrier makes it difficult to directly test the importance of the SC barrier in immune privilege. The ability of SCs to survive and protect co-grafted cells when transplanted ectopically (outside the testis) across immunological barriers is well-documented. Here, we will discuss the use of a SC transplantation model to investigate the role of SC and the SC barrier in immune privilege. Additionally, the formation of cord/tubule like structures in this model, containing both SCs and myoid cells, further extends its application to study testis morphogenesis. We will also discuss the potential use of this model to study the effects of drugs/environmental toxins on testis morphogenesis, tight junction formation and SC–myoid cell interactions.

VSELs may obviate cryobanking of gonadal tissue in cancer patients for fertility preservation.

BackgroundInfertility is an undesirable side effect and gonadal tissue banking is advocated in young cancer patients who are unable to preserve embryos or gametes prior to oncotherapy to achieve biological parenthood later on. Banking gonadal tissue is challenging and protocols to mature gametes in vitro are not yet clinically established. Transplanting ovarian cortical tissue at hetero-or orthotopic sites in women and bone marrow transplantation (BMT) in both men and women has resulted in spontaneous recovery of fertility, pregnancy and live births. Various studies in humans and mice suggest that genetic origin of offspring after BMT is similar to transplanted patient and not the donor. Thus the source of oocytes/sperm which result in spontaneous pregnancies still remains contentious.FindingsVery small embryonic-like stem cells (VSELs) have been reported in adult human testis and ovary, in azoospermic testicular biopsies from survivors of childhood cancer and also in women with premature ovarian failure and menopause. VSELs survive chemotherapy because of their quiescent nature and can be detected in chemoablated mice gonads at protein and mRNA level and also by flow cytometry. Surviving VSELs spontaneously differentiate into oocyte-like structures and sperm when inhibitory factors are overcome in vitro. Transplantation of mesenchymal cells (isolated from different sources) has led to regeneration of chemoablated mouse gonads and also live births. Spermatogenesis is also restored from endogenous stem cells on inter-tubular transplantation of Sertoli cells in chemoablated mouse testis.ConclusionsEndogenous VSELs (which survive oncotherapy) can possibly regenerate non-functional gonads in cancer survivors when exposed to a healthy niche in vitro or in vivo (by way of transplanting mesenchymal cells which secrete trophic factors required for endogenous VSELs to differentiate into gametes). Presence of VSELs can also explain spontaneous pregnancies after BMT and cortical tissue transplantation (at heterotopic or orthotopic sites). This understanding once verified and accepted by the scientific community could obviate the need to remove whole ovary or testicular biopsy for cryopreservation prior to oncotherapy.

A novel Amh-Treck transgenic mouse line allows toxin-dependent loss of supporting cells in gonads.

Cell ablation technology is useful for studying specific cell lineages in a developing organ in vivo. Herein, we established a novel anti-Müllerian hormone (AMH)-toxin receptor-mediated cell knockout (Treck) mouse line, in which the diphtheria toxin (DT) receptor was specifically activated in Sertoli and granulosa cells in postnatal testes and ovaries respectively. In the postnatal testes of Amh-Treck transgenic (Tg) male mice, DT injection induced a specific loss of the Sertoli cells in a dose-dependent manner, as well as the specific degeneration of granulosa cells in the primary and secondary follicles caused by DT injection in Tg females. In the testes with depletion of Sertoli cell, germ cells appeared to survive for only several days after DT treatment and rapidly underwent cell degeneration, which led to the accumulation of a large amount of cell debris within the seminiferous tubules by day 10 after DT treatment. Transplantation of exogenous healthy Sertoli cells following DT treatment rescued the germ cell loss in the transplantation sites of the seminiferous epithelia, leading to a partial recovery of the spermatogenesis. These results provide not only in vivo evidence of the crucial role of Sertoli cells in the maintenance of germ cells, but also show that the Amh-Treck Tg line is a useful in vivo model of the function of the supporting cell lineage in developing mammalian gonads.

Nondividing, Postpubertal Rat Sertoli Cells Resumed Proliferation after Transplantation1

Conventionally, it was believed that Sertoli cells (SC) stopped proliferating at puberty and became terminally differentiated quiescent cells. However, recent studies have challenged that dogma. In this study, we transplanted nondividing SC isolated from 23- to 27-day-old postpubertal rats transduced with a recombinant adenoviral vector (containing furin-modified human proinsulin cDNA) into diabetic severe combined immunodeficiency mice. Immunostaining the grafts for cell proliferation markers, proliferating cell nuclear antigen (PCNA) and MKI67, revealed that transplanted SC within the grafts were proliferating. Possible causes for resumption of proliferation of SC could be viral transduction, cell isolation and culture, higher abdominal temperature at the transplant site, and/or transplantation. To test for these possible causes, double- immunofluorescence staining was performed for GATA4 (SC marker) and MKI67. None of the SC were positive for MKI67 in tissue collected during SC isolation and culture or at higher temperature. However, nontransduced SC stained positive for MKI67 after transplantation into rats, suggesting viral transduction was not a key factor for induction of SC proliferation. Interestingly, resumption in proliferative ability of nondividing SC was temporary, as SC stopped proliferating within 14 days of transplantation and did not proliferate thereafter. Quantification of 5-bromo-2'-deoxyuridine-labeled SC demonstrated that 7%-9% of the total transplanted SC were proliferating in the grafts. These data indicate for the first time that nondividing SC resumed proliferation after transplantation and further validate previous findings that SC are not terminally differentiated. Hence, transplantation of SC could provide a useful model with which to study the regulation of SC proliferation in vivo.

Very Small Embryonic-Like Stem Cells Survive and Restore Spermatogenesis after Busulphan Treatment in Mouse Testis

Study Objectives: Adult mammalian testes harbor a novel population of quiescent, pluripotent, very small embryonic-like stem cells (VSELs) along with spermatogonial stem cells (SSCs). Present study was undertaken to (i) characterize testicular VSELs (ii) investigate differential effect of chemotherapy on VSELs and SSCs and (iii) to restore the differentiation ability of surviving VSELs by providing healthy somatic microenvironment. Methods: Effect of busulphan (25 mg/Kg) was studied on mouse testes. Syngenic Sertoli cells(105 cells per testis) and bone marrow derived mesenchymal cells (104 cells per testis) were transplanted separately through intertubular route. Effect of niche reconstruction was studied two months later by histology and immuno-localization of germ cell markers MVH and PCNA. Caudal sperm were evaluated for their ability to fertilize oocytes in vitro. Results: VSELs were 2-6 μm in size, SCA-1+/CD45-/LIN-, had high nucleo-cytoplasmic ratio and comprised 0.03% of testicular cells whereas SSC specific marker GFRa localized on a distinct, larger cell population. Busulphan selectively destroyed SSCs and other germ cells however, nuclear OCT-4A, Nanog, Sox-2 and SCA-1 positive VSELs (0.06%) survived. Persisting VSELs were unable to differentiate possibly because chemotherapy also affected the ‘niche’ comprising Sertoli cells. Complete restoration of spermatogenesis was observed two months post transplantation of Sertoli and mesenchymal cells. Transplanted cells formed neo-tubules in the vicinity of surviving tubules and were possibly a source of growth factors essential for VSELs proliferation and differentiation. Both MVH and PCNA showed increased staining in the transplanted group. qRT-PCR studies revealed existence of a meiotic block in busulphan treated testis which was overcome after transplantation. Resulting sperm progressed to epididymis, showed normal motility and ability to fertilize in vitro. Conclusion: Results show that VSELs survive chemotherapy and can restore spermatogenesis in germ cells depleted mice. Results have direct relevance to address fertility issues of cancer survivors.

Effects of Sertoli cells Implantation on Type 2 Diabetes in Nonhuman Primates

Transplanted allo‐ and xenogeneic Sertoli cells, encapsulated in alginate, have been shown to successfully treat endocrine and neurodegenerative dysfunctions in experimental models with efficacy in the diabetic rodents. In order to determine the translational potential for therapeutic efficacy in humans, we have investigated its application in the spontaneously obese nonhuman primate with naturally‐occurring type 2 diabetes. Isolated Sertoli cells 0.05 to 0.1 × 109 cells/kg from outbred prepubertal piglets were encapsulated in alginate and injected (ip) into insulin‐treated diabetic monkeys. One month following transplantation there was a reduction in fasting plasma glucose, HbA1c decreased by 0.5–1.4% accompanied by a reduction of mean AM nonfasting glucose levels without change in daily insulin therapeutic doses (by design). Results suggest that this novel encapsulated cell transplantation treatment protocol utilizing xenogeneic Sertoli cells may have resulted in a potential positive therapeutic effect on the metabolic status of the diabetic condition which occurred without an apparent inflammatory response. Due to the therapeutic evidence and safety of Sertoli cell transplantation to provide clinical relief in models of diabetes, including the monkey, these data support additional studies in nonhuman primates to further establish potential for successful treatment of diabetes in human.

Transplantation Can Reinitiate Proliferation of Terminally Differentiated Sertoli Cells.

Sertoli cells (SC) are immune privileged cells that survive allo- or xeno-transplantation long term, suggesting they could be used as a vehicle to deliver therapeutic proteins. To test this, “non-dividing” SC isolated from 27 day-old post-pubertal rats were transduced with a recombinant adenoviral vector containing modified human insulin cDNA and transplanted underneath the left kidney capsule of diabetic SCID mice. The adenovirus was chosen because it allows for robust expression of the protein of interest for an extended period of time (more than 2 months) in non-dividing cells including SC. Contrary to what was expected, blood glucose levels were lowered only transiently (less than10 days), and when the grafts were analyzed for insulin expression by immunostaining, a loss is insulin expression was observed. Surprisingly, when the grafts were immunostained with cell proliferation markers, PCNA (proliferating cell nuclear antigen) and KI-67, the SC within the grafts were positive, suggesting that the transient expression of insulin was due to loss of the epichromosomal adenoviral vector from the proliferating SC. This is surprising because, the dogma is that SC stop proliferating by puberty and become terminally differentiated. Some of the possible causes for resumption of proliferation by the SC could be viral transduction, cell isolation and culture, transplantation to kidney, and/or higher abdominal temperature at the transplant site. To test for the possible cause of proliferation, tissue samples were collected for histology (n=3) from cryptorchid testes (testes at abdominal temperature), various stages of SC isolation and culture, and transplants of non-diving, non-transduced SC in rats at various time-points between 1-55 days post-transplantation. The collected tissue sections were double immunostained for SC marker GATA-4, and cell proliferation marker KI-67. None of the GATA-4 positive SC stained positive for KI-67 in cryptorchid testes, tissue collected during SC isolation and culture. However, many of the GATA-4 positive SC stained positive for KI-67, between 1-14 days post-transplantation. Interestingly this resumption in proliferative ability of non-dividing SC was temporary, where SC stop proliferating within 19 days of transplantation and do not proliferate thereafter. These data indicate that transplantation of SC, but not the higher temperature, viral transduction, SC isolation or culture, is a potential cause for reinitiating proliferation of these non-dividing SC. Transplantation of SC could provide a useful model to study the regulation of SC proliferation in vivo.

Genetically engineered immune privileged Sertoli cells

Sertoli cells are immune privileged cells, important for controlling the immune response to male germ cells as well as maintaining the tolerogenic environment in the testis. Additionally, ectopic Sertoli cells have been shown to survive and protect co-grafted cells when transplanted across immunological barriers. The survival of ectopic Sertoli cells has led to the idea that they could be used in cell based gene therapy. In this review, we provide a brief overview of testis immune privilege and Sertoli cell transplantation, factors contributing to Sertoli cell immune privilege, the challenges faced by viral vector gene therapy, the use of immune privileged cells in cell based gene therapy and describe several recent studies on the use of genetically engineered Sertoli cells to provide continuous delivery of therapeutic proteins.

Regeneration Potential of Transplanted Adult Mouse Sertoli Cells

The regeneration potential of differentiated Sertoli cells subjected to thermal treatment was studied by the method of cell transplantation. Cells from mice with artificial cryptorchism (1.5 months after fixation of the testes in the body) and after culturing (10 days, 37°C) were transplanted. Transplantation of Sertoli cells from 2-3-month-old and 2-day-old mice served as controls. The cells were transplanted into the testes of recipient mice, from which sex cells and Sertoli cells were removed by busulfan and cadmium salt treatment. Adult mouse Sertoli cells exposed to thermal treatment exhibited much higher regeneration potential than intact cells. Two months after transplantation, mature Sertoli cells subjected to thermal treatment populated the recipient testicular tubules, formed new tubules, and in some cases supported the development of sex cells similarly as immature cells from newborn mice.

Sertoli cell therapy: A novel possible treatment strategy for treatment-resistant major depressive disorder

By the year 2020, depression will be the 2nd most common health problem in the world. Current medications to treat depression are effective in less than 50% of patients. There is the need for novel treatments for depression to address the high rates of resistance to current treatment and the chronic residual symptoms in many patients treated for depression. The heterogeneity of major depressive disorder suggests that multiple neurocircuits and neurochemicals are involved in its pathogenesis thus, finding an alternative to neurotransmitter agonist- or antagonist-based treatments offers an important new approach. Cellular therapy is an emerging treatment strategy for multiple diseases, including depression. Based upon their in vivo function as “nurse cells” within the testis and the documented viability, efficacy, and safety of Sertoli cells transplanted into multiple tissues, including brain, the potential for these cells to provide a neuroprotective, anti-inflammatory, and trophic environment for neurons should be considered. It is proposed that the combination of self-protective, immunoregulatory and trophic properties of Sertoli cells may confer a unique potential for depression treatment and avoid many of the risks and challenges associated with stem cell therapies. At the very least, studies of the effects of Sertoli cell transplantation will add substantially to our understanding of the cellular and molecular processes that underlie depression.

Xenograft of microencapsulated Sertoli cells as a therapy for experimental Laron syndrome.

Introduction and Aim The only treatment of Laron Syndrome (LS), caused by an inherited defect in the gene encoding the GH receptor resulting in the failure to generate IGF-1, consists of chronic administration of recombinant human IGF−1 (rhIGF-1) that is burdened side effects. Moreover, this approach is limited by the restricted availability of this drug for clinical use (orphan drug) which dramatically lowers number of treatable cases. It is known that IGF-1 represents one of the main growth factors produced by Sertoli cells (SC). Aim of our work was to assess if transplantation of barium alginate microencapsulated SC (BaMCs) would induce normalization of clinical features of growth hormone deficiency in “Laron mice”, the best animal model for human LS. Materials and Methods BaMCs were prepared from pre-pubertal piglets, according to our method and examined as far as: (a) SC morphology by light microscopy; (b) SC viability, by fluorescence microscopy after staining with ethidium bromide and fluorescein diacetate (EB+FDA); (c) SC in vitro function (α-aromatase activity and IGF-I secretion); (d) evaluation of growth parameters in Laron transplanted mice were concerned. Results BaMCs showed excellent features in terms of size, morphology, sphericity and coalescence. SC viability was very high (over 90%). Very good α-aromatase activity and IGF-I secretion were associated with the examined SC preparation. Intraperitoneal graft of BaMCs into Laron mice induced a significant increase in growth parameters in terms of weigth and nose-to-anus length as compared to untreated controls. Conclusions SC may be enveloped in BaMCs with no loss of their functional and morphological properties. Xenograft of BaMCs in Laron mice induced, an unprecedented, significant increase in growth parameters as compared to untreated controls. This result may open new perspectives for therapy of human LS.