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1
Breeze, Robert E. "TRANSPLANTATION OF EMBRYONIC DOPAMINERGIC NEURONS." Neurosurgery 49, no. 3 (September 1, 2001): 575–76. http://dx.doi.org/10.1097/00006123-200109000-00006.
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Breeze, Robert E. "TRANSPLANTATION OF EMBRYONIC DOPAMINERGIC NEURONS." Neurosurgery 49, no. 3 (September 2001): 575–76. http://dx.doi.org/10.1227/00006123-200109000-00006.
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Lindvall, Olle. "Treatment of Parkinson's disease using cell transplantation." Philosophical Transactions of the Royal Society B: Biological Sciences 370, no. 1680 (October 19, 2015): 20140370. http://dx.doi.org/10.1098/rstb.2014.0370.
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The clinical trials with intrastriatal transplantation of human fetal mesencephalic tissue, rich in dopaminergic neurons, in Parkinson's disease (PD) patients show that cell replacement can work and in some cases induce major, long-lasting improvement. However, owing to poor tissue availability, this approach can only be applied in very few patients, and standardization is difficult, leading to wide variation in functional outcome. Stem cells and reprogrammed cells could potentially be used to produce dopaminergic neurons for transplantation. Importantly, dopaminergic neurons of the correct substantia nigra phenotype can now be generated from human embryonic stem cells in large numbers and standardized preparations, and will soon be ready for application in patients. Also, human induced pluripotent stem cell-derived dopaminergic neurons are being considered for clinical translation. Available data justify moving forward in a responsible way with these dopaminergic neurons, which should be tested, using optimal patient selection, cell preparation and transplantation procedures, in controlled clinical studies.
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Xiao, Jia-Jia, Ming Yin, Ze-Jian Wang, and Xiao-Ping Wang. "Transplanted Neural Stem Cells: Playing a Neuroprotective Role by Ceruloplasmin in the Substantia Nigra of PD Model Rats?" Oxidative Medicine and Cellular Longevity 2015 (2015): 1–9. http://dx.doi.org/10.1155/2015/618631.
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Although mounting evidence suggests that ceruloplasmin (CP) deficiency and iron deposition are pivotal factors responsible for exacerbating demise of dopaminergic neurons in the substantia nigra (SN) of the Parkinsonism and neural stem cells (NSCs) are believed to be excellent candidates for compensating the lost dopaminergic neurons, there are few researches to explore the change of CP expression and of iron deposition in the pathological microenvironment of SN after NSCs transplantation and the ability of grafted NSCs to differentiate directionally into dopaminergic neurons under the changed homeostasis. With substantia nigral stereotaxic technique and NSCs transplantation, we found that tyrosine hydroxylase and CP expression decreased and iron deposition increased in the lesioned SN after 6-OHDA administration compared with control, while tyrosine hydroxylase and CP expression increased and iron deposition decreased after NSCs transplantation compared to 6-OHDA administration alone. Only a small number of embedding NSCs are able to differentiate into dopaminergic neurons. These results suggest that grafted NSCs have an influence on improving the content of CP expression, which may play a neuroprotective role by decreasing iron deposition and ameliorating damage of dopaminergic neurons and possibly underline the iron-related common mechanism of Parkinson’s disease and Wilson’s disease.
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Li, Wen, Elisabet Englund, Håkan Widner, Bengt Mattsson, Danielle van Westen, Jimmy Lätt, Stig Rehncrona, et al. "Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain." Proceedings of the National Academy of Sciences 113, no. 23 (May 2, 2016): 6544–49. http://dx.doi.org/10.1073/pnas.1605245113.
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Clinical trials using cells derived from embryonic ventral mesencephalon have shown that transplanted dopaminergic neurons can survive and function in the long term, as demonstrated by in vivo brain imaging using 18F-fluorodopa and 11C-raclopride positron emission tomography. Here we report the postmortem analysis of a patient with Parkinson’s disease who 24 y earlier underwent unilateral transplantation of embryonic dopaminergic neurons in the putamen and subsequently exhibited major motor improvement and recovery of striatal dopaminergic function. Histopathological analysis showed that a dense, near-normal graft-derived dopaminergic reinnervation of the putamen can be maintained for a quarter of a century despite severe host brain pathology and with no evidence of immune response. In addition, ubiquitin- and α-synuclein–positive inclusions were seen, some with the appearance of typical Lewy bodies, in 11–12% of the grafted dopaminergic neurons, reflecting the spread of pathology from the host brain to the transplants. Because the clinical benefits induced by transplantation in this patient were gradually lost after 14 y posttransplantation, our findings provide the first reported evidence, to our knowledge, that even a viable dopaminergic graft giving rise to extensive striatal reinnervation may lose its efficacy if widespread degenerative changes develop in the host brain.
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Petersén, Åsa, Oskar Hansson, Mia Emgård, and Patrik Brundin. "Grafting of Nigral Tissue Hibernated with Tirilazad Mesylate and Glial Cell Line-Derived Neurotrophic Factor." Cell Transplantation 9, no. 5 (September 2000): 577–84. http://dx.doi.org/10.1177/096368970000900503.
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Transplantation of embryonic ventral mesencephalon is a potential therapy for patients with Parkinson's disease. As only around 5–10% of embryonic dopaminergic neurons survive grafting into the adult striatum, it is considered necessary to use multiple donor embryos. To increase the survival of the grafted dopaminergic neurons, the clinical transplantation program in Lund currently employs the lipid peroxidation inhibitor, tirilazad mesylate, in all solutions used during tissue storage, preparation, and transplantation. However, the difficulty in obtaining a sufficient number of donor embryos still remains an important limiting factor for the clinical application of neural transplantation. In many clinical transplantation programs, it would be a great advantage if human nigral donor tissue could be stored for at least 1 week. This study was performed in order to investigate whether storage of embryonic tissue at 4°C for 8 days can be applied clinically without creating a need to increase the number of donors. We compared the survival of freshly grafted rat nigral tissue, prepared according to the clinical protocol, with tissue transplanted after hibernation. Thus, in all groups tirilazad mesylate was omnipresent. One group of rats was implanted with fresh tissue and three groups with hibernated tissue with or without addition of glial cell line-derived neurotrophic factor (GDNF) in the hibernation medium and/or the final cell suspension. Earlier studies have suggested that GDNF improves the survival of hibernated nigral transplants. We found no statistically significant difference between the groups regarding graft survival after 3 weeks. However, there was a nonsignificant trend for fewer surviving dopaminergic neurons in grafts from hibernated tissue compared to fresh controls. Furthermore, we show that the addition of GDNF to the hibernation medium and/or to the final cell suspension does not significantly increase the survival of the dopaminergic neurons.
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Sawamoto, K., N. Nakao, K. Kobayashi, N. Matsushita, H. Takahashi, K. Kakishita, A. Yamamoto, et al. "Visualization, direct isolation, and transplantation of midbrain dopaminergic neurons." Proceedings of the National Academy of Sciences 98, no. 11 (May 15, 2001): 6423–28. http://dx.doi.org/10.1073/pnas.111152398.
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Vukicevic, Vladimir, Janine Schmid, Andreas Hermann, Sven Lange, Nan Qin, Linda Gebauer, Kuei-Fang Chung, et al. "Differentiation of Chromaffin Progenitor Cells to Dopaminergic Neurons." Cell Transplantation 21, no. 11 (November 2012): 2471–86. http://dx.doi.org/10.3727/096368912x638874.
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The differentiation of dopamine-producing neurons from chromaffin progenitors might represent a new valuable source for replacement therapies in Parkinson's disease. However, characterization of their differentiation potential is an important prerequisite for efficient engraftment. Based on our previous studies on isolation and characterization of chromaffin progenitors from adult adrenals, this study investigates their potential to produce dopaminergic neurons and means to enhance their dopaminergic differentiation. Chromaffin progenitors grown in sphere culture showed an increased expression of nestin and Mash1, indicating an increase of the progenitor subset. Proneurogenic culture conditions induced the differentiation into neurons positive for neural markers β-III-tubulin, MAP2, and TH accompanied by a decrease of Mash1 and nestin. Furthermore, Notch2 expression decreased concomitantly with a downregulation of downstream effectors Hes1 and Hes5 responsible for self-renewal and proliferation maintenance of progenitor cells. Chromaffin progenitor-derived neurons secreted dopamine upon stimulation by potassium. Strikingly, treatment of differentiating cells with retinoic and ascorbic acid resulted in a twofold increase of dopamine secretion while norepinephrine and epinephrine were decreased. Initiation of dopamine synthesis and neural maturation is controlled by Pitx3 and Nurr1. Both Pitx3 and Nurr1 were identified in differentiating chromaffin progenitors. Along with the gained dopaminergic function, electrophysiology revealed features of mature neurons, such as sodium channels and the capability to fire multiple action potentials. In summary, this study elucidates the capacity of chromaffin progenitor cells to generate functional dopaminergic neurons, indicating their potential use in cell replacement therapies.
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Park, Hyunjun, and Keun-A. Chang. "Therapeutic Potential of Repeated Intravenous Transplantation of Human Adipose-Derived Stem Cells in Subchronic MPTP-Induced Parkinson’s Disease Mouse Model." International Journal of Molecular Sciences 21, no. 21 (October 30, 2020): 8129. http://dx.doi.org/10.3390/ijms21218129.
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Parkinson’s disease (PD) is the second most common neurodegenerative disease, which is clinically and pathologically characterized by motor dysfunction and the loss of dopaminergic neurons in the substantia nigra, respectively. PD treatment with stem cells has long been studied by researchers; however, no adequate treatment strategy has been established. The results of studies so far have suggested that stem cell transplantation can be an effective treatment for PD. However, PD is a progressively deteriorating neurodegenerative disease that requires long-term treatment, and this has been insufficiently studied. Thus, we aimed to investigate the therapeutic potential of human adipose-derived stem cells (hASC) for repeated vein transplantation over long-term in an animal model of PD. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model mice, hASCs were administered on the tail vein six times at two-week intervals. After the last injection of hASCs, motor function significantly improved. The number of dopaminergic neurons present in the nigrostriatal pathway was recovered using hASC transplantation. Moreover, the administration of hASC restored altered dopamine transporter expression and increased neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF), in the striatum. Overall, this study suggests that repeated intravenous transplantation of hASC may exert therapeutic effects on PD by restoring BDNF and GDNF expressions, protecting dopaminergic neurons, and maintaining the nigrostriatal pathway.
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Emgard-Mattson, Mia, Jenny Karlsson, Naoyuki Nakao, and Patrik Brundin. "Addition of Lateral Ganglionic Eminence to Rat Mesencephalic Grafts Affects Fiber Outgrowth but Does not Enhance Function." Cell Transplantation 6, no. 3 (May 1997): 277–86. http://dx.doi.org/10.1177/096368979700600310.
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Addition of embryonic striatal tissue, usually as a combination of the lateral and medial ganglionic eminences, to intrastriatal mesencephalic grafts has previously been reported to enhance recovery of drug-induced rotational behavior in the host and to modify axonal fiber outgrowth from the grafted dopaminergic neurons. This study investigated the effects of adding (cografting) either lateral or medial ganglionic eminence tissue to embryonic mesencephalic grafts implanted intrastriatally, in rats with unilateral 6-hydroxydopamine lesions. The cografts did not exhibit increased survival or cell size of dopaminergic neurons when compared to transplants of mesencephalic tissue alone. Neither did recipients of cografts exhibit any enhancement of graft-induced recovery of function, when tested for drug-induced rotational behavior or forelimb function in the staircase test. However, cografts containing lateral ganglionic eminence displayed patches of dense tyrosine hydroxylase-immunoreactive fibers within the graft tissue. These patches largely coincided with patches in adjacent stained sections, which were rich in immunostaining for the striatal-specific marker dopamine- and cyclic AMP-regulated phosphoprotein-32 (DARPP-32). Such patches were not present in rats receiving cografts containing medial ganglionic eminence or mesencephalic tissue alone. Thus, it seems that the grafted dopaminergic neurons preferentially grow into the areas of the transplants containing lateral ganglionic eminence tissue. In summary, the results suggest that embryonic lateral ganglionic eminence exerts trophic effects on the outgrowth of dopaminergic axons, but does not enhance the behavioral effects of grafted dopaminergic neurons.
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Okano, Hideyuki, Takahito Yoshizaki, Takuya Shimazaki, and Kazunobu Sawamoto. "Isolation and transplantation of dopaminergic neurons and neural stem cells." Parkinsonism & Related Disorders 9, no. 1 (October 2002): 23–28. http://dx.doi.org/10.1016/s1353-8020(02)00041-x.
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Liu, Qiuyue, Oliver Z. Pedersen, Jun Peng, Larry A. Couture, Mahendra S. Rao, and Xianmin Zeng. "Optimizing dopaminergic differentiation of pluripotent stem cells for the manufacture of dopaminergic neurons for transplantation." Cytotherapy 15, no. 8 (August 2013): 999–1010. http://dx.doi.org/10.1016/j.jcyt.2013.03.006.
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Karlsson, Jenny, ÅSa Petersén, Gunilla Gidö, Tadeusz Wieloch, and Patrik Brundin. "Combining Neuroprotective Treatment of Embryonic Nigral Donor Tissue with Mild Hypothermia of the Graft Recipient." Cell Transplantation 14, no. 5 (May 2005): 301–9. http://dx.doi.org/10.3727/000000005783983089.
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Around 80–95% of the immature dopaminergic neurons die when embryonic ventral mesencephalic tissue is transplanted. Cell death occurs both during the preparation of donor tissue and after graft implantation, but the effect of combining successful neuroprotective treatments before and after transplantation has not been extensively investigated. We therefore treated embryonic rat mesencephalic tissue with a combination of the lipid peroxidation inhibitor tirilazad mesylate (3 μM) and the caspase inhibitor Ac.YVAD.cmk (500 μM) and transplanted the tissue into hemiparkinsonian rats kept hypothermic (32–33°C) or normothermic (37°C) during, and 90 min following, graft surgery. Suspension cell number did not differ between untreated or tirilazad/YVAD-treated preparations prior to transplantation. When graft survival was evaluated 6 weeks after implantation, both tirilazad/YVAD pretreatment and mild hypothermia increased the survival of transplanted dopaminergic neurons. Approximately 50–57% of the embryonic dopaminergic neurons survived the dissociation and grafting procedure in rats rendered hypothermic, but there was no significant additive effect on graft survival with a combined treatment. All groups of rats exhibited behavioral recovery in the amphetamine-induced rotation test. There was a significantly enhanced functional capacity of grafts placed in hypothermic as compared to normothermic rats. However, tirilazad/YVAD pretreated implants did not afford greater behavioral improvement than control-treated grafts. Our results suggest that neuroprotective treatments administered prior to and immediately after neural graft implantation may under certain conditions rescue, at least in part, the same subset of dopaminergic neurons. The study also emphasizes the importance of the immediate time after grafting for transplant survival, with relevance both for primary mesencephalic implants and stem cell grafts.
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Thompson, Cassandra, Paulina Otero, Bhairavi Srinageshwar, Robert B. Petersen, Gary L. Dunbar, and Julien Rossignol. "Possible roles of epigenetics in stem cell therapy for Parkinson’s disease." Epigenomics 12, no. 7 (April 2020): 647–56. http://dx.doi.org/10.2217/epi-2019-0347.
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Parkinson’s disease (PD) is a neurodegenerative disease with loss of dopaminergic neurons. PD has genetic and epigenetic influences that determine specific changes in the brain. Epigenetic changes result in defective methylation of genes leading to differential gene-expression causing PD. This review provides an overview of stem cell transplantations as potential therapies for PD, with a focus on the epigenetic changes, prior or following transplantation. To date, no reports have addressed epigenetic alterations following stem cell transplantation into the PD brain. Given the potential for affecting the efficacy of stem cell therapy, increased attention needs to be given to the epigenetic processes that occur during stem cell culture and transplantation to maximize the therapeutic potential of stem cells to PD.
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Lindvall, Olle, and Peter Hagell. "Role of cell therapy in Parkinson disease." Neurosurgical Focus 13, no. 5 (November 2002): 1–9. http://dx.doi.org/10.3171/foc.2002.13.5.3.
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Clinical studies involving intrastriatal transplantation of embryonic mesencephalic tissue in patients with Parkinson disease (PD) have provided proof-of-principle for the cell replacement strategy in this disorder. The grafted dopaminergic neurons can reinnervate the denervated striatum, restore regulated dopamine release and movement-related frontal cortical activation, and produce significant symptomatic relief. In the most successful cases, patients have been able to withdraw from levodopa treatment after undergoing transplantation and resume an independent life. There are, however, several problems linked to the use of primary embryonic tissue: 1) lack of sufficient amounts of tissue for transplantation in a large number of patients; 2) variability of functional outcome (major improvement in some and modest if any clinical benefit in others); and 3) occurrence of troublesome dyskinesias in a significant proportion of patients after transplantation. Thus, neural transplantation is still at an experimental stage in the treatment of PD. For the development of a clinically useful cell therapy we need to define better criteria for patient selection and how graft placement should be optimized in each individual. Most importantly, we need to generate large numbers of viable dopamine neurons in preparations that are standardized and quality controlled. Stem cells could be useful as an unlimited source of dopamine neurons. Thus far, neurons with at least some dopaminergic characteristics have been generated from stem cells. In most cases, however, their survival after grafting in animals has been poor, and it is also unclear if they function as normal dopamine neurons. Several scientific issues need to be addressed before stem cell-based therapies can be tested in PD patients.
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Yasuhara, Takao, Tetsuro Shingo, Kenichiro Muraoka, Kazuki Kobayashi, Akira Takeuchi, Akimasa Yano, Yuan WenJi, et al. "Early transplantation of an encapsulated glial cell line—derived neurotrophic factor—producing cell demonstrating strong neuroprotective effects in a rat model of Parkinson disease." Journal of Neurosurgery 102, no. 1 (January 2005): 80–89. http://dx.doi.org/10.3171/jns.2005.102.1.0080.
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Object. Glial cell line—derived neurotrophic factor (GDNF) has been shown to confer neuroprotective effects on dopaminergic neurons. The authors investigated the effects of GDNF on 6-hydroxydopamine (6-OHDA)—treated dopaminergic neurons in vitro and in vivo. Methods. First, the authors examined how 1, 10, or 100 ng/ml of GDNF, administered to cells 24 hours before, simultaneously with, or 2 or 4 hours after 6-OHDA was added, affected dopaminergic neurons. In a primary culture of E14 murine ventral mesencephalic neurons, earlier treatment with the higher dosage of GDNF suppressed 6-OHDA—induced loss of dopaminergic neurons better than later treatment. Next, the authors examined whether continuous infusion of GDNF at earlier time points would demonstrate a greater neuroprotective effect in a rat model of Parkinson disease (PD). They established a human GDNF-secreting cell line, called BHK-GDNF, and encapsulated the cells into hollow fibers. The encapsulated cells were unilaterally implanted into the striatum of adult rats 1 week before; simultaneously with; or 1, 2, or 4 weeks after 6-OHDA was given to induce lesions of the same striatum. With the earlier transplantation of a BHK-GDNF capsule, there was a significant reduction in the number of amphetamine-induced rotations displayed by the animals. Rats that had received earlier implantation of BHK-GDNF capsules displayed more tyrosine hydroxylase—positive neurons in the substantia nigra pars compacta and a tendency for glial proliferation in the striatum. Conclusions. These neuroprotective effects may be related to glial proliferation and signaling via the GDNF receptor α1. The results of this study support a role for this grafting technique in the treatment of PD.
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Galpern, Wendy R., David M. Frim, Stephen B. Tatter, C. Anthony Altar, M. Flint Beal, and Ole Isacson. "Cell-Mediated Delivery of Brain-Derived Neurotrophic Factor Enhances Dopamine Levels in an Mpp+ Rat Model of Substantia Nigra Degeneration." Cell Transplantation 5, no. 2 (March 1996): 225–32. http://dx.doi.org/10.1177/096368979600500211.
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Brain-derived neurotrophic factor (BDNF) promotes the survival of fetal mesencephalic dopaminergic cells and protects dopaminergic neurons against the toxicity of MPP+ in vitro. Supranigral implantation of fibroblasts genetically engineered to secrete BDNF attenuates the loss of substantia nigra pars compacta (SNc) dopaminergic neurons associated with striatal infusion of MPP+ in the adult rat. Using this MPP+ rat model of nigral degeneration, we evaluated the neurochemical effects of supranigral, cell-mediated delivery of BDNF on substantia nigra (SN) dopamine (DA) content and turnover. Genetically engineered BDNF-secreting fibroblasts (~12 ng BDNF/24 h) were implanted dorsal to the SN 7 days prior to striatal MPP+ administration. The present results demonstrate that BDNF-secreting fibroblasts, as compared to control fibroblasts, enhance SN DA levels ipsilateral as well as contralateral to the graft without altering DA turnover. This augmentation of DA levels suggests that local neurotrophic factor delivery by genetically engineered cells may provide a therapeutic strategy for preventing neuronal death or enhancing neuronal function in neurodegenerative diseases characterized by dopaminergic neuronal dysfunction, such as Parkinson's disease.
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Hebb, Adam O., Kari Hebb, Arun C. Ramachandran, and Ivar Mendez. "Glial cell line–derived neurotrophic factor–supplemented hibernation of fetal ventral mesencephalic neurons for transplantation in Parkinson disease: long-term storage." Neurosurgical Focus 13, no. 5 (November 2002): 1–6. http://dx.doi.org/10.3171/foc.2002.13.5.5.
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Object Investigation of fetal dopaminergic tissue transplantation is being conducted in animal models and clinical trials as a potential treatment for advanced Parkinson disease (PD). Because the availability of fetal tissue is limited, however, the duration of its storage prior to transplantation is a key practical issue. Longer storage times may enable fetal tissue obtained over several days to be pooled together for transplantation in a recipient. Glial cell line–derived neurotrophic factor (GDNF) has been shown to improve survival of stored human dopaminergic tissue prior to transplantation. The objective of this study was to evaluate GDNF-supplemented hibernation of fetal dopaminergic tissue for extended periods of 6 to 15 days. Methods A total of 27 rat ventral mesencephalons (VMs) were obtained in gestation Day 14 rat fetuses, and three were cultured immediately (fresh-culture control group). The remaining 24 VMs were divided sagittally along the mid-line to form 48 equal pieces of hemimesencephalons. Twenty-four pieces were stored with GDNF-supplemented hibernation medium for 6, 9, 12, or 15 days, and the 24 “partner” hemimesencephalons were stored in control hibernation medium for the same periods of time. Tissue was cultured for 48 hours and processed for tyrosine hydroxylase (TH) immunoreactivity and cresyl violet. Cell counts for all cultures and percentage of TH-immunoreactive cells were obtained. The percentage of TH-positive cells for the fresh control group was 6.3 ± 0.5%; that measured in cultures derived from tissue hibernated in GDNF-supplemented medium was significantly increased at 6 and 9 days posthiber-nation compared with the fresh-culture control group and the partner groups stored in hibernation medium only. No significant increase in percentage of TH-immunoreactive cells was observed in the 12- and 15-day hibernation groups. Conclusions In summary the authors found that fetal dopaminergic tissue can safely be stored up to 9 days in GDNF-supplemented hibernation medium. Furthermore the percentage of TH-immunoreactive cells is significantly increased after 6 and 9 days of storage in this medium, improving the yield of TH-positive cells prior to transplantation. These observations may have important clinical implications for collecting fetal dopaminergic cells and improving their survival after transplantation.
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Khanna, Aparna, Anna Maria Swistowska, Mahendra Rao, and Xianmin Zeng. "Generation and Transplantation of Dopaminergic Neurons Derived from Embryonic Stem Cells." Current Stem Cell Research & Therapy 2, no. 2 (May 1, 2007): 139–47. http://dx.doi.org/10.2174/157488807780599266.
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Ferrazoli, Enéas G., Héllio D. N. De Souza, Isis C. Nascimento, Ágatha Oliveira-Giacomelli, Telma T. Schwindt, Luiz R. Britto, and Henning Ulrich. "Brilliant Blue G, but not Fenofibrate, Treatment Reverts Hemiparkinsonian Behavior and Restores Dopamine Levels in an Animal Model of Parkinson's Disease." Cell Transplantation 26, no. 4 (April 2017): 669–77. http://dx.doi.org/10.3727/096368917x695227.
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Parkinson's disease (PD) is a neurodegenerative disorder, characterized by the loss of dopaminergic neurons in the substantia nigra and their projections to the striatum. Several processes have been described as potential inducers of the dopaminergic neuron death, such as inflammation, oxidative stress, and mitochondrial dysfunction. However, the death of dopaminergic neurons seems to be multifactorial, and its cause remains unclear. ATP-activating purinergic receptors influence various physiological functions in the CNS, including neurotransmission. Purinergic signaling is also involved in pathological scenarios, where ATP is extensively released and promotes sustained purinergic P2X7 receptor (P2X7R) activation and consequent induction of cell death. This effect occurs, among other factors, by oxidative stress and during the inflammatory response. On the other hand, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) is involved in energy metabolism and mitochondrial biogenesis. Expression and activity upregulation of this protein has been related with reduction of oxidative stress and neuroprotection. Therefore, P2X7R and PGC-1α are potential targets in the treatment of PD. Here hemiparkinsonism was induced by unilateral stereotactic injection of 6-OHDA in a rat model. After 7 days, the establishment of PD was confirmed and followed by treatment with the P2X7R antagonist Brilliant Blue G (BBG) or PGC-1α agonist fenofibrate. BBG, but not fenofibrate, reverted hemiparkinsonian behavior accompanied by an increase in tyrosine hydroxylase immunoreactivity in the substantia nigra. Our results suggest that the P2X7R may be a therapeutic target in Parkinson's disease.
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Hebb, Adam O., Kari Hebb, Arun C. Ramachandran, and Ivar Mendez. "Glial cell line—derived neurotrophic factor—supplemented hibernation of fetal ventral mesencephalic neurons for transplantation in Parkinson disease: long-term storage." Journal of Neurosurgery 98, no. 5 (May 2003): 1078–83. http://dx.doi.org/10.3171/jns.2003.98.5.1078.
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Object. Transplantation of fetal dopaminergic tissue is being investigated in animal models and clinical trials for its potential as a treatment for advanced Parkinson disease. At the same time, the availability of fetal tissue is limited, making its storage time prior to transplantation a key practical issue. Although it results in a smaller percentage of surviving cells, a longer storage time enables fetal tissue obtained over several days to be pooled for transplantation in a recipient. Glial cell line—derived neurotrophic factor (GDNF) has been shown to improve survival of human dopaminergic tissue that has been stored prior to transplantation. The objective of this study was to evaluate the effects on fetal dopaminergic tissue of GDNF-supplemented hibernation for extended periods of 6 to 15 days. Methods. The ventral mesencephalon (VM) was harvested in a total of 27 14-day-old rat fetuses, and three VMs were cultured immediately (fresh control group). The remaining 24 VMs were divided sagittally along the midline to yield 48 equal pieces of hemimesencephalon. Twenty-four pieces were stored with GDNF-supplemented hibernation medium for 6, 9, 12, or 15 days, and the 24 “partner” hemimesencephalon pieces were stored in control hibernation medium for the same periods of time. Tissue was cultured for 48 hours and processed for tyrosine hydroxylase (TH) immunoreactivity and double-stained with cresyl violet. Cell counts for all cultures and the percentage of TH-immunoreactive cells were obtained. The percentage of TH-immunoreactive cells for the fresh control group was 6.3 ± 0.5%. The percentage of TH-immunoreactive cells in cultures derived from tissue stored in GDNF-supplemented medium was significantly increased at 6 and 9 days posthibernation compared with the fresh control group and the “partner” groups stored in hibernation medium only. No significant increase in the percentage of TH-immunoreactive cells was observed in the 12- and 15-day groups. Conclusions. In this study the authors have demonstrated that fetal dopaminergic tissue can be safely stored for up to 9 days in GDNF-supplemented hibernation medium. Furthermore, the percentage of TH-immunoreactive cells is significantly increased after 6 and 9 days of storage in this medium, improving the yield of TH-immunoreactive cells prior to transplantation. These observations have practical clinical implications for collecting fetal dopaminergic cells and improving their survival after transplantation.
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Weiss, B., S. Haas, G. Lessner, S. Mikkat, M. Kreutzer, M. O. Glocker, A. Wree, and O. Schmitt. "The Proteome of the Differentiating Mesencephalic Progenitor Cell Line CSM14.1In Vitro." BioMed Research International 2014 (2014): 1–13. http://dx.doi.org/10.1155/2014/351821.
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The treatment of Parkinson's disease by transplantation of dopaminergic (DA) neurons from human embryonic mesencephalic tissue is a promising approach. However, the origin of these cells causes major problems: availability and standardization of the graft. Therefore, the generation of unlimited numbers of DA neurons from various types of stem or progenitor cells has been brought into focus. A source for DA neurons might be conditionally immortalized progenitor cells. The temperature-sensitive immortalized cell line CSM14.1 derived from the mesencephalon of an embryonic rat has been used successfully for transplantation experiments. This cell line was analyzed by unbiased stereology of cell type specific marker proteins and 2D-gel electrophoresis followed by mass spectrometry to characterize the differentially expressed proteome. Undifferentiated CSM14.1 cells only expressed the stem cell marker nestin, whereas differentiated cells expressed GFAP or NeuN and tyrosine hydroxylase. An increase of the latter cells during differentiation could be shown. By using proteomics an explanation on the protein level was found for the observed changes in cell morphology during differentiation, when CSM14.1 cells possessed the morphology of multipolar neurons. The results obtained in this study confirm the suitability of CSM14.1 cells as anin vitromodel for the study of neuronal and dopaminergic differentiation in rats.
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Chi, Heng, Yunqian Guan, Fengyan Li, and Zhiguo Chen. "The Effect of Human Umbilical Cord Mesenchymal Stromal Cells in Protection of Dopaminergic Neurons from Apoptosis by Reducing Oxidative Stress in the Early Stage of a 6-OHDA-Induced Parkinson’s Disease Model." Cell Transplantation 28, no. 1_suppl (November 28, 2019): 87S—99S. http://dx.doi.org/10.1177/0963689719891134.
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Oxidative stress is an important cause of dopaminergic (DA) neuron apoptosis in Parkinson’s disease (PD). Mesenchymal stromal cells (MSCs) possess antioxidative features. In this study, we investigated whether MSCs could reduce oxidative stress and protect DA neurons from apoptosis by intravenous (I.V.) injection in the early stage of a 6-hydroxydopamine (6-OHDA)-induced PD model. MSCs were injected into the tail vein of mice, and behavioral tests, immunofluorescence staining, western blot, and oxidative stress levels were assessed at different time points. After 6-OHDA exposure, DA neuron apoptosis was detected, together with severe oxidative stress in brain and periphery. Compared with the non-transplanted sham controls, motor function in the 6-OHDA-lesioned group after I.V. injection of MSCs was significantly improved, and the levels of DA neuron apoptosis and oxidative stress decreased. The results demonstrate that MSCs can rescue DA neurons from ongoing apoptosis by reducing oxidative stress, and provide insights on developing new therapeutic strategies to offset the degenerative process of PD.
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Vidal, Nina, Lars Björklund, and Ingrid Strömberg. "Morphological and Functional Evidence for Enhanced Growth and Potassium-Evoked Dopamine Release in Striatal Grafts Innervated with a Patchy Growth Pattern. an in Oculo Nigrostriatal Cograft Study." Cell Transplantation 7, no. 2 (March 1998): 97–108. http://dx.doi.org/10.1177/096368979800700205.
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During development of the nigrostriatal dopamine system, a patchy and a diffuse type of striatal innervation pattern can be seen. It has been suggested that when fetal dopaminergic neurons, obtained from the ventral mesencephalon (VM), are grafted adjacent to mature striatal tissue, only the diffuse growth is induced. Intraocular grafting studies have indicated that the dopaminergic growth pattern might be influenced by the age of the target area, the lateral ganglionic eminence (LGE). In this study VM grafts were allowed to innervate LGE grafts of different ages. Fetal VM was implanted next to 2-wk-old or 26-day-old striatal in oculo grafts, and the resulting dopaminergic innervation of the striatal grafts was studied using tyrosine hydroxylase (TH) immunohistochemistry. In striatal grafts receiving innervation at the age of 2 wk in oculo, a patchy TH-immunoreactive growth pattern was found, while in striatal grafts innervated at the age of 26 days mainly the diffuse growth pattern was seen. This implies that grafted striatum reached maturity at approximately 1 mo of age. The age of the dopaminergic neurons at dissection and grafting was also studied concerning the ability to induce patchy growth into mature striatum. Thus, VM dissected from 13- and 18-mm fetuses was implanted to either 4-mo-old LGE (grafted in sequence) or to LGE from the same fetus (grafted simultaneously) as controls. TH-positive innervation of striatal tissue, evaluated 4 wk after implantation of VM, revealed a patchy growth pattern in LGE grafted simultaneously with 13- and 18-mm VM. However, when the striatum was mature at the time of innervation, diffuse growth was observed in striatum innervated by VM dissected from 13-mm fetuses. Interestingly, patchy growth was noted in striatal areas close to VM grafts when the dopaminergic neurons were derived from older fetuses (CRL 18 mm). Furthermore, potassium-induced dopamine release was greater in striatal grafts exhibiting the patchy growth than those showing the diffuse pattern of innervation. In conclusion, patchy dopaminergic growth can be induced in mature striatal tissue by grafting VM from older fetuses. Functionally, potassium-evoked dopamine release is enhanced in dopaminergic patches. These results have implications in terms of finding ways to induce patchy growth when grafting to the mature striatum of patients suffering from Parkinson's disease.
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Di Santo, Stefano, Stefanie Seiler, Angélique D. Ducray, Morten Meyer, and Hans Rudolf Widmer. "A Subpopulation of Dopaminergic Neurons Coexpresses Serotonin in Ventral Mesencephalic Cultures but not after Intrastriatal Transplantation in a Rat Model of Parkinson's Disease." Cell Transplantation 26, no. 4 (April 2017): 679–91. http://dx.doi.org/10.3727/096368916x693707.
Full textAbstract:
Cell replacement therapy is a promising avenue into the investigation and treatment of Parkinson's disease (PD), and in some cases, significant long-term motor improvements have been demonstrated. The main source of donor tissue is the human fetal ventral mesencephalon (FVM), which consists of a mixed neuronal population, and its heterogeneity likely contributes to the inconsistent outcome observed in clinical trials. Therefore, detailed knowledge about the neuronal subpopulations in the VM seems essential for successful cell transplantation. Interestingly, it has been reported that some tyrosine hydroxylase-positive (TH+) neurons in the VM of adult rats and in cultured midbrain-derived neuroblasts coexpress additional neurotransmitters. Thus, the present study investigated, by means of colocalization analyses, the possible expression of GABA or serotonin in TH+ neurons. For that purpose, both fetal rat and human dissociated, organotypic and neurosphere FVM cultures as well as an animal model of PD were investigated. In dissociated rat FVM cultures, approximately 30% of the TH+ neurons coexpressed serotonin, while no colocalization with GABA was observed. Interestingly, coexpression of TH and serotonin was found to be dependent on the time in culture, the plating density, and the exposure to neurotrophic factors, that is, higher cell densities and treatment with brain-derived neurotrophic factor resulted in a significantly reduced coexpression rate. Notably, even though approximately 30% of the dopaminergic neurons in the donor tissue coexpressed serotonin, no colocalization could be detected in grafts 1 month after intrastriatal transplantation into hemiparkinsonian rats. In conclusion, a significant and susceptible subpopulation of dopaminergic neurons in FVM tissues coexpresses serotonin. This might have potential implications for the future selection and handling of cells prior to transplantation in PD.
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Cameron, D. F., A. I. Othberg, C. V. Borlongan, S. Rashed, A. Anton, S. Saporta, and P. R. Sanberg. "Post-Thaw Viability and Functionality of Cryopreserved Rat Fetal Brain Cells Cocultured with Sertoli Cells." Cell Transplantation 6, no. 2 (March 1997): 185–89. http://dx.doi.org/10.1177/096368979700600212.
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Testis-derived Sertoli cells have been used to create an immune “privileged” site outside of the testis to facilitate cell transplantation protocols for diabetes and neurodegenerative diseases. In addition to secreting immunoprotective factors, Sertoli cells also secrete growth and trophic factors that appear to enhance the posttransplantation viability of isolated cells and, likewise, the postthaw viability of isolated, cryopreserved cells (26). It would be beneficial if Sertoli cells could be cryopreserved with the transplantable cell type without deleterious effects on the cells. This report describes a protocol for the cocryopreservation of rat Sertoli cells with rat ventral mesencephalic neurons, neurons from the lateral and medial ganglionic eminences and the hNT neuron cell line, and reports on the effects of Sertoli cells on the the postthaw viability of these neurons. Results of trypan blue exclusion analysis indicated that the presence of Sertoli cells did not deleteriously effect cryopreserved neurons and may improve their postthaw recoverability and viability in general. Specifically, results of the tyrosine hydroxylase immunostaining showed that Sertoli cells significantly enhance the postthaw viability of ventral mesencephalic dopaminergic cells in vitro.
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Yoshizaki, Takahito, Motoki Inaji, Hiroko Kouike, Takuya Shimazaki, Kazunobu Sawamoto, Kiyoshi Ando, Isao Date, et al. "Isolation and transplantation of dopaminergic neurons generated from mouse embryonic stem cells." Neuroscience Letters 363, no. 1 (June 2004): 33–37. http://dx.doi.org/10.1016/j.neulet.2004.03.074.
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Francis, Nicola L., Nanxia Zhao, Hannah R. Calvelli, Astha Saini, Janace J. Gifford, George C. Wagner, Rick I. Cohen, Zhiping P. Pang, and Prabhas V. Moghe. "Peptide-Based Scaffolds for the Culture and Transplantation of Human Dopaminergic Neurons." Tissue Engineering Part A 26, no. 3-4 (February 1, 2020): 193–205. http://dx.doi.org/10.1089/ten.tea.2019.0094.
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Brundin, Patrik, Jenny Karlsson, Mia Emgård, Gabriele S. Kaminski Schierle, Oskar Hansson, Åsa Petersén, and Roger F. Castilho. "Improving the Survival of Grafted Dopaminergic Neurons: A Review over Current Approaches." Cell Transplantation 9, no. 2 (March 2000): 179–95. http://dx.doi.org/10.1177/096368970000900205.
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Neural transplantation is developing into a therapeutic alternative in Parkinson's disease. A major limiting factor is that only 3–20% of grafted dopamine neurons survive the procedure. Recent advances regarding how and when the neurons die indicate that events preceding actual tissue implantation and during the first week thereafter are crucial, and that apoptosis plays a pivotal role. Triggers that may initiate neuronal death in grafts include donor tissue hypoxia and hypoglycemia, mechanical trauma, free radicals, growth factor deprivation, and excessive extracellular concentrations of excitatory amino acids in the host brain. Four distinct phases during grafting that can involve cell death have been identified: retrieval of the embryo; dissection and preparation of the donor tissue; implantation procedure followed by the immediate period after graft injection; and later stages of graft maturation. During these phases, cell death processes involving free radicals and caspase activation (leading to apoptosis) may be triggered, possibly involving an increase in intracellular calcium. We review different approaches that reduce cell death and increase survival of grafted neurons, typically by a factor of 2–4. For example, changes in transplantation procedure such as improved media and implantation technique can be beneficial. Calcium channel antagonists such as nimodipine and flunarizine improve nigral graft survival. Agents that counteract oxidative stress and its consequences, such as superoxide dismutase overexpression, and lazaroids can significantly increase the survival of transplanted dopamine neurons. Also, the inhibition of apoptosis by a caspase inhibitor has marked positive effects. Finally, basic fibroblast growth factor and members of the transforming growth factor-beta superfamily, such as glial cell line-derived neurotrophic factor, significantly improve the outcome of nigral transplants. These recent advances provide hope for improved survival of transplanted neurons in patients with Parkinson's disease, reducing the need for human embryonic donor tissue and increasing the likelihood of a successful outcome.
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Andres, Robert H., Angelique D. Ducray, Alberto Pérez-Bouza, Uwe Schlattner, Alexander W. Huber, Sandra H. Krebs, Rolf W. Seiler, Theo Wallimann, and Hans R. Widmer. "Creatine Supplementation Improves Dopaminergic Cell Survival and Protects against MPP+ Toxicity in an Organotypic Tissue Culture System." Cell Transplantation 14, no. 8 (September 2005): 537–50. http://dx.doi.org/10.3727/000000005783982756.
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Cell replacement therapy using mesencephalic precursor cells is an experimental approach for the treatment of Parkinson's disease (PD). A significant problem associated with this procedure is the poor survival of grafted neurons. Impaired energy metabolism is considered to contribute to neuronal cell death after transplantation. Creatine is a substrate for mitochondrial and cytosolic creatine kinases (CK) and buffers cellular ATP resources. Furthermore, elevated cellular creatine levels facilitate metabolic channeling and show anti-apoptotic properties. Exogenous creatine supplementation therefore might offer a tool for improvement of dopaminergic neuron survival. The present study aimed at investigating the effects of creatine on cell survival of rat embryonic day 14 (E14) ventral mesencephalic neurons grown as organotypic free-floating roller tube (FFRT) cultures. We found that the brain-specific isoform of CK (BB-CK) and the ubiquitous mitochondrial isoform (uMt-CK) are expressed at high levels in FFRT cultures and colocalize with tyrosine hydroxylase immunoreactive (TH-ir) cells. Exposure of these cultures to creatine induced an increase in the content of the BB-CK isotype. Creatine (5 mM) administration starting at day in vitro (DIV) 7 resulted in a significant increase (+35%) in TH-ir cell density at DIV21. In addition, we observed that creatine treatment provided neuroprotection against 1-methyl-4-phenyl pyridinium ion (MPP+)-induced TH-ir cell loss in the FFRT culture system, resulting in a significantly higher density (+19%) of TH-ir neurons in creatine-treated cultures compared to corresponding controls. The decrease of TH-ir neurons in the MPP+-treated group corresponded with an increase in immunoreactivity for active caspase-3, an effect that was not seen in the group receiving creatine supplementation. In conclusion, our data imply that creatine administration is beneficial for the survival of TH-ir neurons encountering harmful conditions.
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Tsai, Chia-Wen, Rong-Tzong Tsai, Shih-Ping Liu, Chang-Shi Chen, Min-Chen Tsai, Shao-Hsuan Chien, Huey-Shan Hung, Shinn-Zong Lin, Woei-Cherng Shyu, and Ru-Huei Fu. "Neuroprotective Effects of Betulin in Pharmacological and Transgenic Caenorhabditis elegans Models of Parkinson’s Disease." Cell Transplantation 26, no. 12 (December 2017): 1903–18. http://dx.doi.org/10.1177/0963689717738785.
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Parkinson’s disease (PD) is the second most common degenerative disorder of the central nervous system in the elderly. It is characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta, as well as by motor dysfunction. Although the causes of PD are not well understood, aggregation of α-synuclein (α-syn) in neurons contributes to this disease. Current therapeutics for PD provides satisfactory symptom relief but not a cure. Treatment strategies include attempts to identify new drugs that will prevent or arrest the progressive course of PD by correcting disease-specific pathogenic process. Betulin is derived from the bark of birch trees and possesses anticancer, antimicrobial, and anti-inflammatory properties. The aim of the present study was to evaluate the potential for betulin to ameliorate PD features in Caenorhabditis elegans ( C. elegans) models. We demonstrated that betulin diminished α-syn accumulation in the transgenic C. elegans model. Betulin also reduced 6-hydroxydopamine-induced dopaminergic neuron degeneration, reduced food-sensing behavioral abnormalities, and reversed life-span decreases in a pharmacological C. elegans model. Moreover, we found that the enhancement of proteasomes activity by promoting rpn1 expression and downregulation of the apoptosis pathway gene, egl-1, may be the molecular mechanism for betulin-mediated protection against PD pathology. Together, these findings support betulin as a possible treatment for PD and encourage further investigations of betulin as an antineurodegenerative agent.
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Collier, Timothy J., D. Eugene Redmond, Robert H. Roth, John D. Elsworth, Jane R. Taylor, and John R. Sladek. "Metabolic Energy Capacity of Dopaminergic Grafts and the Implanted Striatum in Parkinsonian Nonhuman Primates as Visualized with Cytochrome Oxidase Histochemistry." Cell Transplantation 6, no. 2 (March 1997): 135–40. http://dx.doi.org/10.1177/096368979700600207.
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Histochemistry for visualization of the mitochondrial enzyme cytochrome oxidase has been used to detect cellular and regional differences in brain energy metabolism. We have examined the pattern of cytochrome oxidase (CO) staining in grafts of embryonic ventral mesencephalic tissue, and in the implanted striatum, of MPTP-treated monkeys as one index of the functional activity of grafted tissue and its influence on the host brain. Four monkeys were selected for study based on interesting variations in dopamine (DA) neuron content of their bilateral grafts as demonstrated with tyrosine-hydroxylase (TH) immunocytochemistry. The results suggest that grafts rich in DA neurons increase the metabolic activity of the implanted striatum of DA-depleted monkeys, and that this improvement of local energy metabolism is greater in the vicinity of grafts containing greater numbers of DA neurons. In addition, the pattern of CO staining within tissue transplants indicates that DA neurons exhibit the highest rate of metabolic activity among all cell types contained in the ventral mesencephalic grafts, and that the transplants receive metabolically active innervation from outside or within the grafted tissue.
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Stromberg, Ingrid, Lars Björklund, and Petter Forander. "The Age of Striatum Determines the Pattern and Extent of Dopaminergic Innervation: a Nigrostriatal Double Graft Study." Cell Transplantation 6, no. 3 (May 1997): 287–96. http://dx.doi.org/10.1177/096368979700600311.
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In animal models of Parkinson's disease, transplanted fetal mesencephalic dopaminergic neurons can innervate the dopamine-depleted host brain, but it is unclear why large portions of the host striatum are left uninnervated. During normal development, the dopaminergic innervation first occurs in the form of a dense patchy pattern in the striatum, followed by a widespread nerve fiber network. Using intraocular double grafts we have investigated dopaminergic growth patterns initiated when ventral mesencephalic grafts innervate striatal targets. The fetal lateral ganglionic eminence was implanted into the anterior eye chamber. After maturation in oculo, fetal ventral mesencephalon was implanted and placed in contact with the first graft. In other animals the two pieces of tissue were implanted simultaneously. Tyrosine hydroxylase (TH) immunohistochemistry revealed a pattern of dense TH-positive patches throughout the total volume of the striatal grafts in simultaneously transplanted cografts, while a widespread, less dense, pattern was found when mature striatal transplants were innervated by fetal dopaminergic grafts. To investigate which type or types of growth patterns that developed after grafting to striatum in situ of an adult host, fetal ventral mesencephalic tissue was implanted into the lateral ventricle adjacent to the dopamine-lesioned striatum. After maturation of the mesencephalic graft, the fetal lateral ganglionic eminence was implanted into the reinnervated part of the host striatum. TH immunohistochemistry revealed a few nerve fibers within the striatal graft and the growth pattern was of the widespread type. In conclusion, grafted dopaminergic neurons preferably innervate mature striatum with a widespread sparse nerve fiber network, while the innervation of the immature striatum occurs in the form of dense patches. Furthermore, when the patchy pattern is formed, the total volume of the striatal target is innervated while growth of the widespread type terminates prior to reaching distal striatal parts. Thus, the growth pattern seems essential to the final volume that is innervated. Once the widespread growth pattern is initiated, the presence of immature striatum does not change the dopaminergic growth pattern.
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Bartlett, L. E., and I. Mendez. "Dopaminergic Reinnervation of the Globus Pallidus by Fetal Nigral Grafts in the Rodent Model of Parkinson's Disease." Cell Transplantation 14, no. 2-3 (February 2005): 119–27. http://dx.doi.org/10.3727/000000005783983241.
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The current neural transplantation strategy for Parkinson's disease (PD) involves the dopaminergic reinnervation of the striatum (STR). Although up to 85% reinnervation of the STR has been attained by neural transplantation, functional recovery in animal models and transplanted patients is incomplete. This limitation may be due to an incomplete restoration of the dopaminergic input to other basal ganglia structures such as the external segment of the globus pallidus (GPe, homologue of the rodent GP), which normally receives dopaminergic input from the substantia nigra (SN). As part of our investigation into a multiple grafting strategy for PD, we have explored the effects of dopaminergic grafts in the GP of rodents with unilateral 6-hydroxydopamine (6-OHDA) lesions. In this experiment, lesioned rats received either 300,000 fetal ventral mesencephalic (FVM) cells or a sham injection into the GP. Functional assessment consisted of rotational behavior at 3 and 6 weeks posttransplantation. A fluorogold tracer study was conducted to rule out any behavioral improvement due to striatal outgrowth of the GP graft. Sections were stained for glial fibrillary acidic protein (GFAP) to assess the degree of trauma in the GP by the graft in comparison to the sham injection. Immunohistochemistry for tyrosine hydroxylase (TH) was performed after transplantation to assess graft survival. Animals with GP grafts demonstrated a significant improvement in rotational behavior at 3 and 6 weeks posttransplantation (p < 0.05) while sham control animals did not improve. All animals receiving FVM cells showed TH-immunoreactive grafts in the GP posttransplantation. TH-positive neurons in the GP showed no double labeling with an intrastriatal injection of fluorogold, indicating that behavioral improvement was not due to striatal innervation by the GP graft. These observations suggest that functional recovery was the result of dopaminergic reinnervation of the GP and that this nucleus may be a potential target for neural transplantation in clinical PD.
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Saporta, Samuel, Cesario Borlongan, Joann Moore, Elizabeth Mejia-Millan, Stacey L. Jones, Patrice Bonness, Timothy S. Randall, Richard C. Allen, Thomas B. Freeman, and Paul R. Sanberg. "Microcarrier Enhanced Survival of Human and Rat Fetal Ventral Mesencephalon Cells Implanted in the Rat Striatum." Cell Transplantation 6, no. 6 (November 1997): 579–84. http://dx.doi.org/10.1177/096368979700600608.
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The transplantation of tissue containing dopamine-producing cells into the mammalian central nervous system is an emerging treatment for Parkinson's disease, despite relatively poor survival of implanted tissue. Recent evidence has suggested that Cytodex microcarriers enhance the survival of dopaminergic rat chromaffin cells transplanted into the rat striatum in the absence of immunosuppression. The current study was undertaken to evaluate the survival of rat and human fetal ventral mesencephalic neurons (VM) implanted alone or after attachment to microcarriers in the striatum of rats without immunosuppression. Rat fetal VM neurons demonstrated enhanced survival in the rat striatum when transplanted on microcarriers, compared to their transplantation alone during the 3-mo period examined in the present study. Transplants of human fetal VM neurons on microcarriers also survived remarkably well in the rat striatum without systemic immunosuppression. In contrast, human fetal VM cells transplanted alone into the rat striatum did not survive without systemic immunosuppression. There was no evidence of TH fiber sprouting in the vicinity of any transplant site. These data indicated that Cytodex microcarriers provide enhanced survival of both rat allograft and human xenograft fetal mesencephalic cells in the rat striatum without the necessity of systemic immunosuppression, perhaps by inducing a unique neuron–glia environment.
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Deacon, Terrence, Jonathan Dinsmore, Lauren C. Costantini, Judson Ratliff, and Ole Isacson. "Blastula-Stage Stem Cells Can Differentiate into Dopaminergic and Serotonergic Neurons after Transplantation." Experimental Neurology 149, no. 1 (January 1998): 28–41. http://dx.doi.org/10.1006/exnr.1997.6674.
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Jhao, Yun-Ting, Chuang-Hsin Chiu, Chien-Fu F. Chen, Ta-Kai Chou, Yi-Wen Lin, Yu-Ten Ju, Shinn-Chih Wu, et al. "The Effect of Sertoli Cells on Xenotransplantation and Allotransplantation of Ventral Mesencephalic Tissue in a Rat Model of Parkinson’s Disease." Cells 8, no. 11 (November 11, 2019): 1420. http://dx.doi.org/10.3390/cells8111420.
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Intra-striatal transplantation of fetal ventral mesencephalic (VM) tissue has a therapeutic effect on patients with Parkinson’s disease (PD). Sertoli cells (SCs) possess immune-modulatory properties that benefit transplantation. We hypothesized that co-graft of SCs with VM tissue can attenuate rejection. Hemi-parkinsonian rats were generated by injecting 6-hydroxydopamine into the right medial forebrain bundle of Sprague Dawley (SD) rats. The rats were then intrastriatally transplanted with VM tissue from rats or pigs (rVM or pVM), with/without a co-graft of SCs (rVM+SCs or pVM+SCs). Recovery of dopaminergic function and survival of the grafts were evaluated using the apomorphine-induced rotation test and small animal-positron emission tomography (PET) coupled with [18F] DOPA or [18F] FE-PE2I, respectively. Immunohistochemistry (IHC) examination was used to determine the survival of the grafted dopaminergic neurons in the striatum and to investigate immune-modulatory effects of SCs. The results showed that the rVM+SCs and pVM+SCs groups had significantly improved drug-induced rotational behavior compared with the VM alone groups. PET revealed a significant increase in specific uptake ratios (SURs) of [18F] DOPA and [18F] FE-PE2I in the grafted striatum of the rVM+SCs and pVM+SCs groups as compared to that of the rVM and pVM groups. SC and VM tissue co-graft led to better dopaminergic (DA) cell survival. The co-grafted groups exhibited lower populations of T-cells and activated microglia compared to the groups without SCs. Our results suggest that co-graft of SCs benefit both xeno- and allo-transplantation of VM tissue in a PD rat model. Use of SCs enhanced the survival of the grafted dopaminergic neurons and improved functional recovery. The enhancement may in part be attributable to the immune-modulatory properties of SCs. In addition, [18F]DOPA and [18F]FE-PE2I coupled with PET may provide a feasible method for in vivo evaluation of the functional integrity of the grafted DA cell in parkinsonian rats.
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Mousavinejad, M., S. Skidmore, F. G. Barone, P. Tyers, V. Pisupati, H. Poptani, A. Plagge, et al. "Assessing Human Embryonic Stem Cell-Derived Dopaminergic Neuron Progenitor Transplants Using Non-invasive Imaging Techniques." Molecular Imaging and Biology 22, no. 5 (May 6, 2020): 1244–54. http://dx.doi.org/10.1007/s11307-020-01499-4.
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Abstract Purpose Human pluripotent stem cell (hPSC)-derived dopaminergic neuron progenitor cells (DAPCs) are a potential therapy for Parkinson’s disease (PD). However, their intracranial administration raises safety concerns including uncontrolled proliferation, migration and inflammation. Here, we apply a bimodal imaging approach to investigate the fate of DAPC transplants in the rat striatum. Procedures DAPCs co-expressing luciferase and ZsGreen or labelled with micron-sized particles of iron oxide (MPIOs) were transplanted in the striatum of RNU rats (n = 6 per group). DAPCs were tracked in vivo using bioluminescence and magnetic resonance (MR) imaging modalities. Results Transgene silencing in differentiating DAPCs accompanied with signal attenuation due to animal growth rendered the bioluminescence undetectable by week 2 post intrastriatal transplantation. However, MR imaging of MPIO-labelled DAPCs showed that transplanted cells remained at the site of injection for over 120 days. Post-mortem histological analysis of DAPC transplants demonstrated that labelling with either luciferase/ZsGreen or MPIOs did not affect the ability of cells to differentiate into mature dopaminergic neurons. Importantly, labelled cells did not elicit increased glial reactivity compared to non-labelled cells. Conclusions In summary, our findings support the transplantation of hPSC-derived DAPCs as a safe treatment for PD.
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Othberg, Agneta I., Alison E. Willing, Don F. Cameron, Alex Anton, Samuel Saporta, Thomas B. Freeman, and Paul R. Sanberg. "Trophic Effect of Porcine Sertoli Cells on Rat and Human Ventral Mesencephalic Cells and Hnt Neurons in Vitro." Cell Transplantation 7, no. 2 (March 1998): 157–64. http://dx.doi.org/10.1177/096368979800700210.
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The poor survival of embryonic dopaminergic (DA) neurons transplanted into patients with Parkinson's disease (PD) has encouraged researchers to search for new methods to affect the short- as well as long-term survival of these neurons after transplantation. In several previous rodent studies Sertoli cells increased survival of islet cells and chromaffin cells when cotransplanted in vivo. The aims of this study were to investigate whether porcine Sertoli cells had a positive effect on the survival and maturation of rat and human DA neurons, and whether the Sertoli cells had an effect on differentiation of neurons derived from a human teratocarcinoma cell line (hNT neurons). A significant increase of tyrosine hydroxylase (TH)-positive neurons of both rat and human ventral mesencephalic tissue was found when cocultured with Sertoli cells. Furthermore, there was a significantly increased soma size and neurite outgrowth of neurons in the coculture treated group. The Sertoli cell and hNT coculture also revealed an increased number of TH-positive cells. These results demonstrate that the wide variety of proteins and factors secreted by porcine Sertoli cells benefit the survival and maturation of embryonic DA neurons and suggest that cotransplantation of Sertoli cells and embryonic DA neurons may be useful for a cell transplantation therapy in PD.
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Mcgrath, John, Elishia Lintz, Barry J. Hoffer, Greg A. Gerhardt, E. Matthew Quintero, and Ann-Charlotte Granholm. "Adeno-Associated Viral Delivery of GDNF Promotes Recovery of Dopaminergic Phenotype following a Unilateral 6-Hydroxydopamine Lesion." Cell Transplantation 11, no. 3 (April 2002): 215–27. http://dx.doi.org/10.3727/096020198389988.
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Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor for dopamine neurons that has been proposed for use in the treatment of Parkinson's disease (PD). Previous studies using viral vectors to deliver GDNF in rodent models of PD have entailed administering the virus either prior to or immediately after neurotoxin-induced lesions, when the nigrostriatal pathway is largely intact, a paradigm that does not accurately reflect the clinical situation encountered with Parkinson's patients. In this study, recombinant adeno-associated virus carrying the gene encoding GDNF (rAAV-GDNF) was administered to animals bearing a maximal lesion in the nigrostriatal system, more closely resembling fully developed PD. Rats were treated with 6-hydroxydopamine into the medial forebrain bundle and assessed by apomorphine-induced rotational behavior for 5 weeks prior to virus administration. Within 4 weeks of a single intrastriatal injection of rAAV-GDNF, unilaterally lesioned animals exhibited significant behavioral recovery, which correlated with increased expression of dopaminergic markers in the substantia nigra, the medial forebrain bundle, and the striatum. Our findings demonstrate that rAAV-GDNF is capable of rescuing adult dopaminergic neurons from near complete phenotypic loss following a neurotoxic lesion, effectively restoring a functional dopaminergic pathway and diminishing motoric deficits. These data provide further support for the therapeutic potential of rAAV-GDNF-based gene therapy in the treatment of PD.
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Love, R. M., R. L. Branton, J. Karlsson, P. Brundin, and D. J. Clarke. "Effects of Antioxidant Pretreatment on the Survival of Embryonic Dopaminergic Neurons In Vitro and following Grafting in an Animal Model of Parkinson's Disease." Cell Transplantation 11, no. 7 (October 2002): 653–62. http://dx.doi.org/10.3727/000000002783985431.
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The effect of pretreating cell suspensions of embryonic rat ventral mesencephala (VM) with antioxidant combinations on the survival of dopaminergic (DA) neurons was studied in vitro and following transplantation into the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease. The in vitro experiments examined the effects of two thiol antioxidants, N-acetyl-l-cysteine (NAC) and reduced glutathione (GSH), and a member of the lazaroid family of 21-aminosteroids, U-83836E, singly and in combination, on survival of DA neurons derived from dissociated E14 rat VM tissue. For in vivo studies, cell suspensions were pretreated with combinations of NAC, GSH, and U-83836E prior to transplanting into 6-OHDA-lesioned rats to investigate whether DA neuron survival could be further improved. NAC, GSH, and U-83836E individually increased DA neuron survival in vitro and a combination of all three resulted in the greatest survival. In vivo, pretreatment with U-83836E alone resulted in a significantly greater reduction in amphetamine-induced rotation 6 weeks postgrafting compared with a control group receiving nontreated graft tissue. This functional effect correlated with a significant improvement in DA neuron survival 6 weeks postgrafting. The thiol combination pretreatment of NAC and GSH, and the triple combination of NAC, GSH, and U-83836E, however, failed to improve both functional recovery and DA neuron survival when compared with the nontreated control grafts.
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Mehta, Vivek, Murray Hong, Julian Spears, and Ivar Mendez. "Enhancement of graft survival and sensorimotor behavioral recovery in rats undergoing transplantation with dopaminergic cells exposed to glial cell line-derived neurotrophic factor." Neurosurgical Focus 7, no. 3 (September 1999): E6. http://dx.doi.org/10.3171/foc.1999.7.3.7.
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The goal of this study was to investigate the ability of fetal dopaminergic neurons to improve complex sensorimotor behavior. The authors obtained ventral mesencephalic tissue from 14-day-old rat fetuses. The cells were exposed to glial cell line-derived neurotrophic factor (GDNF) prior to transplantation into rats with unilateral 6-hydroxydopamine lesions of the dopaminergic nigrostriatal pathway. Animals that received 400,000 cells exposed to GDNF demonstrated significant improvement in contralateral forelimb function and showed improvement in rotational behavior faster than animals that received cells not exposed to GDNF. Increasing the number of implanted cells to 800,000 exposed to GDNF did not result in any additional improvement in functional recovery. As neural grafting procedures in the nervous system evolve and genetically engineered cells or stem cells replace fetal tissue, crucial questions about cell number and trophic regulation will need to be addressed. This study demonstrates that grafting of 400,000 cells exposed to GDNF before transplantation has a beneficial effect in the restoration of complex sensorimotor behavior.
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Chi, Kang, Ru-Huei Fu, Yu-Chuen Huang, Shih-Yin Chen, Ching-Ju Hsu, Shinn-Zong Lin, Chi-Tang Tu, Li-Hsun Chang, Ping-An Wu, and Shih-Ping Liu. "Adipose-derived Stem Cells Stimulated with n-Butylidenephthalide Exhibit Therapeutic Effects in a Mouse Model of Parkinson’s Disease." Cell Transplantation 27, no. 3 (March 2018): 456–70. http://dx.doi.org/10.1177/0963689718757408.
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Parkinson’s disease (PD) causes motor dysfunction and dopaminergic cell death. Drug treatments can effectively reduce symptoms but often cause unwanted side effects. Stem cell therapies using cell replacement or indirect beneficial secretomes have recently emerged as potential therapeutic strategies. Although various types of stem cells have been proposed as possible candidates, adipose-derived stem cells (ADSCs) are easily obtainable, more abundant, less ethically disputed, and able to differentiate into multiple cell lineages. However, treatment of PD using adult stem cells is known to be less efficacious than neuron or embryonic stem cell transplantation. Therefore, improved therapies are urgently needed. n-Butylidenephthalide (BP), which is extracted from Angelica sinensis, has been shown to have anti-inflammatory and neuroprotective effects. Indeed, we previously demonstrated that BP treatment of ADSCs enhances the expression of neurogenesis and homing factors such as nuclear receptor related 1 protein, stromal-derived factor 1, and brain-derived neurotrophic factor. In the present study, we examined the ability of BP-pretreated ADSC transplantation to improve PD motor symptoms and protect dopamine neurons in a mouse model of PD. We evaluated the results using neuronal behavior tests such as beam walking, rotarod, and locomotor activity tests. ADSCs with or without BP pretreatment were transplanted into the striatum. Our findings demonstrated that ADSC transplantation improved motor abilities with varied efficacies and that BP stimulation improved the therapeutic effects of transplantation. Dopaminergic cell numbers returned to normal in ADSC-transplanted mice after 22 d. In summary, stimulating ADSCs with BP improved PD recovery efficiency. Thus, our results provide important new strategies to improve stem cell therapies for neurodegenerative diseases in future studies.
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Adil, Maroof M., Tandis Vazin, Badriprasad Ananthanarayanan, Gonçalo M. C. Rodrigues, Antara T. Rao, Rishikesh U. Kulkarni, Evan W. Miller, Sanjay Kumar, and David V. Schaffer. "Engineered hydrogels increase the post-transplantation survival of encapsulated hESC-derived midbrain dopaminergic neurons." Biomaterials 136 (August 2017): 1–11. http://dx.doi.org/10.1016/j.biomaterials.2017.05.008.
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Arendash, Gary W., and Peter C. K. Leung. "Alleviation of Estrogen-Induced Hyperprolactinemia through Intracerebral Transplantation of Hypothalamic Tissue Containing Dopaminergic Neurons." Neuroendocrinology 43, no. 3 (1986): 359–67. http://dx.doi.org/10.1159/000124551.
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Hoban, Deirdre B., Shelby Shrigley, Bengt Mattsson, Ludivine S. Breger, Ulla Jarl, Tiago Cardoso, Jenny Nelander Wahlestedt, Kelvin C. Luk, Anders Björklund, and Malin Parmar. "Impact of α-synuclein pathology on transplanted hESC-derived dopaminergic neurons in a humanized α-synuclein rat model of PD." Proceedings of the National Academy of Sciences 117, no. 26 (June 15, 2020): 15209–20. http://dx.doi.org/10.1073/pnas.2001305117.
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Preclinical assessment of the therapeutic potential of dopamine (DA) neuron replacement in Parkinson’s disease (PD) has primarily been performed in the 6-hydroxydopamine toxin model. While this is a good model to assess graft function, it does not reflect the pathological features or progressive nature of the disease. In this study, we establish a humanized transplantation model of PD that better recapitulates the main disease features, obtained by coinjection of preformed human α-synuclein (α-syn) fibrils and adeno-associated virus (AAV) expressing human wild-type α-syn unilaterally into the rat substantia nigra (SN). This model gives rise to DA neuron dysfunction and progressive loss of DA neurons from the SN and terminals in the striatum, accompanied by extensive α-syn pathology and a prominent inflammatory response, making it an interesting and relevant model in which to examine long-term function and integrity of transplanted neurons in a PD-like brain. We transplanted DA neurons derived from human embryonic stem cells (hESCs) into the striatum and assessed their survival, growth, and function over 6 to 18 wk. We show that the transplanted cells, even in the presence of ongoing pathology, are capable of innervating the DA-depleted striatum. However, on closer examination of the grafts, we found evidence of α-syn pathology in the form of inclusions of phosphorylated α-syn in a small fraction of the grafted DA neurons, indicating host-to-graft transfer of α-syn pathology, a phenomenon that has previously been observed in PD patients receiving fetal tissue grafts but has not been possible to demonstrate and study in toxin-based animal models.
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Ballagi, Andrea E., Per Odin, Agneta Othberg-Cederström, Anja Smits, Wei-Ming Duandr, Olle Lindvall, and Keiko Funa. "Platelet-Derived Growth Factor Receptor Expression after Neural Grafting in a Rat Model of Parkinson's Disease." Cell Transplantation 3, no. 6 (November 1994): 453–60. http://dx.doi.org/10.1177/096368979400300602.
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Platelet-derived growth factor (PDGF) has trophic effect on dopaminergic neurons in vitro. We have previously shown dynamic changes in the expression of PDGF in embryonic mesencephalic grafts and surrounding host striatal tissue following intracerebral transplantation in a rat model of Parkinson's disease. In this study the expression of the PDGF receptors was examined in the same model using immunohistochemistry. Most ventral mesencephalic (VM) cells from E13–E15 rat embryos possessed both PDGF α-and β-receptors before implantation. Double immunofluorescence staining revealed that about 10% of the cells also expressed tyrosine hydroxylase (TH). The PDGF α-receptor was detectable in the graft up to 1 wk after transplantation but had disappeared at 3 wk. In the host tissue, scattered glial cells were positive for the α-receptor but the expression was unchanged following transplantation. The β-receptor expression almost completely disappeared from the grafted tissue by 4 h following transplantation, and only a few cells of the host striatum showed immunoreactivity. However, after 3 wk β-receptor positive cells were again detectable in the graft. These cells appeared to be endothelial cells as identified by an antibody against von Willebrand's factor. Our data suggest that PDGF might act locally on embryonic dopaminergic cells in an autocrine or juxtacrine manner before and shortly after transplantation, and on surrounding glial cells in a paracrine manner after transplantation. Furthermore, PDGF-BB might influence neovascularization in the graft.
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Behl, Tapan, Ishnoor Kaur, Arun Kumar, Vineet Mehta, Gokhan Zengin, and Sandeep Arora. "Gene Therapy in the Management of Parkinson’s Disease: Potential of GDNF as a Promising Therapeutic Strategy." Current Gene Therapy 20, no. 3 (October 9, 2020): 207–22. http://dx.doi.org/10.2174/1566523220999200817164051.
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: The limitations of conventional treatment therapies in Parkinson’s disorder, a common neurodegenerative disorder, lead to the development of an alternative gene therapy approach. Multiple treatment options targeting dopaminergic neuronal regeneration, production of enzymes linked with dopamine synthesis, subthalamic nucleus neurons, regulation of astrocytes and microglial cells and potentiating neurotrophic factors, were established. Viral vector-based dopamine delivery, prodrug approaches, fetal ventral mesencephalon tissue transplantation and dopamine synthesizing enzyme encoding gene delivery are significant therapies evidently supported by numerous trials. The review primarily elaborates on the significant role of glial cell-line derived neurotrophic factor in alleviating motor symptoms and the loss of dopaminergic neurons in Parkinson’s disease. Neuroprotective and neuroregenerative effects of GDNF were established via preclinical and clinical study outcomes. The binding of GDNF family ligands with associated receptors leads to the formation of a receptor-ligand complex activating Ret receptor of tyrosine kinase family, which is only expressed in dopaminergic neurons, playing an important role in Parkinson’s disease, via its association with the essential protein encoded genes. Furthermore, the review establishes delivery aspects, like ventricular delivery of recombinant GDNF, intraparenchymal and intraputaminal delivery using infusion catheters. The review highlights problems and challenges of GDNF delivery, and essential measures to overcome them, like gene therapy combinations, optimization of delivery vectors, newer targeting devices, motor symptoms curbing focused ultrasound techniques, modifications in patient selection criteria and development of novel delivery strategies based on liposomes and encapsulated cells, to promote safe and effective delivery of neurotrophic factor and establishment of routine treatment therapy for patients.
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Mehta, Vivek, Murray Hong, Julian Spears, and Ivar Mendez. "Enhancement of graft survival and sensorimotor behavioral recovery in rats undergoing transplantation with dopaminergic cells exposed to glial cell line—derived neurotrophic factor." Journal of Neurosurgery 88, no. 6 (June 1998): 1088–95. http://dx.doi.org/10.3171/jns.1998.88.6.1088.
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Object. The goal of this study was to investigate the ability of fetal dopaminergic neurons to improve complex sensorimotor behavior. Methods. The authors obtained ventral mesencephalic tissue from 14-day-old rat fetuses. The cells were exposed to glial cell line—derived neurotrophic factor (GDNF) prior to transplantation into rats with unilateral 6-hydroxydopamine lesions of the dopaminergic nigrostriatal pathway. Animals that received 400,000 cells exposed to GDNF demonstrated significant improvement in contralateral forelimb function and showed improvement in rotational behavior faster than animals that received cells not exposed to GDNF. Increasing the number of implanted cells to 800,000 exposed to GDNF did not result in any additional improvement in functional recovery. Conclusions. As neural grafting procedures in the nervous system evolve and genetically engineered cells or stem cells replace fetal tissue, crucial questions about cell number and trophic regulation will need to be addressed. This study demonstrates that grafting of 400,000 cells exposed to GDNF before transplantation has a beneficial effect in the restoration of complex sensorimotor behavior.
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Granholm, Ann-Charlotte, Stephanie Henry, Meleik A. Hebert, Servet Eken, Greg A. Gerhardt, and Craig Van Horne. "Kidney Cografts Enhance Fiber Outgrowth from Ventral Mesencephalic Grafts to the 6-Ohda–Lesioned Striatum, and Improve Behavioral Recovery." Cell Transplantation 7, no. 2 (March 1998): 197–212. http://dx.doi.org/10.1177/096368979800700214.
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Recent studies have demonstrated the presence of many different neurotrophic factors in the developing and adult kidney. Due to its production of this mixture of neurotrophic factors, we wanted to investigate whether fetal kidney tissue could be beneficial for neuritic fiber growth and/or cell survival in intracranial transplants of fetal ventral mesencephalic tissue (VM). A retrograde lesion of nigral dopaminergic neurons was performed in adult Fischer 344 male rats by injecting 6-hydroxydopamine into the medial forebain. The animals were monitored for spontaneous locomotor activity in addition to apomorphine-induced rotations once a week. Four weeks following the lesion, animals were anesthetized and embryonic day 14 VM tissue from rat fetuses was implanted stereotaxically into the dorsal striatum. One group of animals received a cograft of kidney tissue from the same embryos in the same needle track. The animals were then monitored behaviorally for an additional 4 months. There was a significant improvement in both spontaneous locomotor activity (distance traveled) and apomorphine-induced rotations with both single VM grafts and VM–kidney cografts, with the VM–kidney double grafts enhancing the motor behaviors to a significantly greater degree. Tyrosine hydroxylase (TH) immunohistochemistry and image analysis revealed a significantly denser innervation of the host striatum from the VM–kidney cografts than from the single VM grafts. TH-positive neurons were also significantly larger in the cografts compared to the single VM grafts. In addition to the dense TH-immunoreactive innervation, the kidney portion of cografts contained a rich cholinergic innervation, as evidenced from antibodies against choline acetyltransferase (ChAT). The striatal cholinergic cell bodies surrounding the VM–kidney cografts were enlarged and had a slightly higher staining density for ChAT. Taken together, these data support the hypothesis that neurotrophic factors secreted from fetal kidney grafts stimulated both TH-positive neurons in the VM cografts and cholinergic neurons in the host striatum. Thus, these factors may be combined for treatment of degenerative diseases involving both dopaminergic and cholinergic neurons.