|Year : 2017 | Volume
| Issue : 3 | Page : 163-166
Endogenous repair mechanisms enhanced in Parkinson's disease following stem cell therapy
Department of Molecular Biosciences, University of California Davis, Davis, California, 95616, USA
|Date of Submission||05-Aug-2017|
|Date of Decision||01-Sep-2017|
|Date of Acceptance||05-Sep-2017|
|Date of Web Publication||12-Oct-2017|
Department of Molecular Biosciences, University of California Davis, Davis, California
Source of Support: None, Conflict of Interest: None
This mini-review highlights the innovative observation that transplanted human neural stem cells can bring about endogenous brain repair through the stimulation of multiple regenerative processes in the neurogenic area (i.e., subventricular zone [SVZ]) in an animal model of Parkinson's disease (PD). In addition, we convey that identifying anti-inflammatory cytokines, therapeutic proteomes, and neurotrophic factors within the SVZ may be essential to induce brain repair and behavioral recovery. This work opens up a new area of research for further understanding the pathology and treatment of PD. This paper is a review article. Referred literature in this paper has been listed in the references section. The datasets supporting the conclusions of this article are available online by searching various databases, including PubMed. Some original points in this article come from the laboratory practice in our research center and the authors' experiences.
Keywords: Central nervous system disorders, endogenous neurogenesis, Parkinson's disease, regenerative medicine, stem cell therapy
|How to cite this article:|
Napoli E. Endogenous repair mechanisms enhanced in Parkinson's disease following stem cell therapy. Brain Circ 2017;3:163-6
| Introduction|| |
Over the past 30 years, clinical trials of cell therapy for treatment of Parkinson's disease (PD) have created interest in the scientific community and in public., Indeed, cell transplantation has emerged as a promising new technology within science largely due to its direct clinical application.,, PD was a logical choice to test the safety and efficacy of cell therapy due to its well-defined pathology and most importantly the possibility of employing a straightforward therapeutic approach through dopaminergic cell replacement.,,,, A promising study in the 1980s including fetal dopaminergic cells transplanted into PD patients,,, resulted in the successful survival of the cells as well as reintegration with the host cells. However, despite these initial results minimal improvements, that lessened over time following transplantation, were recorded in the transplanted PD patients,,, and a few even displayed significant (though debated) side effects, such as worsening dyskinesias. Even with the lackluster outcomes of the treatment in PD, the promise of cell therapy has been researched in other brain diseases,,, including stroke,, traumatic brain injury, and Huntington's disease., Undoubtedly, for cell therapy treatments for central nervous system disorders to reach the clinic, treatments should be optimized to ensure safety and efficacy.
| Testing Stem Cells in Animal Models of Parkinson's Disease|| |
Using an animal model of PD, a study investigated the therapeutic benefits of human neural stem cells (hNSCs), an alternative tissue source which may prove critical in bypassing the ethical issues surrounding fetal cells. Due to the cardinal pathologic feature of the disease, laboratory and clinical studies of PD have thus far been focused on the recovery of nigrostriatal dopaminergic pathways following cell transplantation. This forward thinking group decided to parallel the study of the specific brain dopamine system with the assessment of the subventricular zone (SVZ), a major neurogenic area (the hippocampal subgranular zone [SGZ] being the other stem cell-enriched brain area). This study may have unearthed a possible regenerative pathway in PD with the discovery that the SVZ mounts an endogenous repair mechanism following injury. The key role of the SVZ in the functional recovery of dopamine-depleted animals that received hNSC transplants was evaluated using a suite of effective readouts including behavioral tests, imaging, immunohistochemical assays, and proteomics. Compared to a lesion controlled adult mouse, the group that received 6-hydroxydopamine (6-OHDA)-induced dopamine lesions followed, 7 days later, by transplantation of undifferentiated hNSCs performed better in motor and cognitive tasks. The improvement in behavior was coupled by changes in the proteome profile, neurotrophic factor secretion, and cytokine levels in the SVZ, even in the absence of significant proliferation of the transplanted hNSCs. These findings suggest that the hNSCs did not contribute directly to the functional improvement observed in transplanted parkinsonian animals, which was instead conceivably achieved by stimulation of the endogenous stem cells residing in the neurogenic SVZ.
This scenario advances the idea that transplanted hNSCs, or stem cells, could interact with the SVZ through a bystander mechanism that promotes therapeutic effects. Going against the tide of PD research, this concept challenges the conventional dopaminergic cell replacement strategy. Naturally, due to the recognition of the nigrostriatal dopaminergic pathway as the one affected in PD,,,,, most studies examining the effects of stem cell therapy have been focusing on this system,, as a therapeutic target. Functional outcomes for PD cell therapy have thus far relied on the assessment of dopamine-sensitive tasks and shifted the focus to the reconstruction of dopaminergic circuitry as the goal for cell therapy in PD. Thus, dopamine-induced circling behavior has been the main behavioral testing in cell therapy studies of PD animals.,,,,, The over-reliance on the dopamine depletion pathology and its accompanying symptoms have consequently limited the research area on experimental treatments for PD. When contemplating experimental models of PD, the well-established unilateral 6-OHDA nigrostriatal dopaminergic lesion model has focused the field to a specific and direct cell replacement concept.
| Therapeutic Modalities of Stem Cells|| |
Deviating from this long-held dogma of reconstructing the nigrostriatal dopaminergic system, transplanted stem cells have been shown propel the long-neglected neurogenic niche, notably the SVZ, to assist in the brain repair process, and its high responsivity to cell therapy. Compelling evidence shows that transplantation of the stem cells led to the restoration of the SVZ proteome profile and induced the SVZ to carry out multi-pronged regenerative processes, including the secretion of anti-inflammatory cytokines and a specific set of putative reparative growth factors.
Based on these paradigm-shifting findings, many new observations may serve as the basis for future mechanism and optimization studies. An important insight is that undifferentiated hNSCs were comparably effective in lessening PD symptoms as the fetal dopaminergic cells classically used for transplantation in PD. This is of importance, as a major hurdle encountered in the clinical trials of fetal dopaminergic cells is the need to harvest 3–6 fetuses at about 6–9 weeks gestation,,, requirement that cripples the feasibility of large clinical trials. Similarly, challenging is the possibility to generate a substantial supply of neural stem cells with dopaminergic phenotype from embryonic and induced pluripotent stem cells. The observation that naive, unmanipulated, nondopaminergic hNSCs could create robust functional recovery in PD dodges the requirement of differentiating stem cells into dopaminergic cells.
Another remarkable observation entails the improvement of cognitive performance linked to the hippocampus, the area of the brain responsible for learning and memory,,, broadening the field of research beyond the SVZ. In this regard, a disrupted communication between the hippocampus and the dopaminergic system has been associated with the cognitive impairment related to PD., The hypothesis is that dopamine segregation in the striatum, and possibly in the substantia nigra, likely does not fully encompass the synaptic plasticity dysfunctions in PD. Thus, the extension of neurodegeneration to areas beyond the nigrostriatal dopamine pathway, such as the hippocampus, presents a possible new avenue for PD treatment. Due to its hippocampal location, a study that aims at the evaluation of endogenous stem cell fate, proteome, neurotrophic factor, and cytokine profiling in the SGZ has the potential to unveil the mechanism underlying the contribution of the host neurogenic niches to the bystander effects of cell therapy in PD, as previously tried in rat and primate models of PD. Altogether, these studies not only highlight the role of the SVZ in the brain repair process in PD but also showed that the reconstruction of the damaged dopaminergic neuronal circuitry is likely crucial for long-term recovery. In this regard, the concept of a cellular biobridge has been advanced as an extracellular matrix formed by the transplanted cells that can transfer the endogenous stem cells from the SVZ to injured areas separated from the neurogenic region. Along with the discussed SVZ repair, there is the possibility that the transplanted hNSCs may also utilize a biobridge, which could allow the endogenous SVZ-derived stem cells to be shepherded to the neighboring dopamine-denervated striatum, resulting in the re-establishment of the dopamine-depleted nigrostriatal pathway. In-depth proteomic examination of stem cells and their exosomes, and the following manipulation of identified lead proteomes, growth factors, and anti-inflammatory cytokines through silencing RNAs or viral vector overexpression may show their fully therapeutic potential in functional recovery of PD.
| Conclusion|| |
Transplantation of exogenous stem cells can trigger endogenous brain repair through a myriad of regenerative processes in the host neurogenic niches, including the secretion of anti-inflammatory cytokines, proteomes, and neurotrophic factors., The mechanism underlying the role of these therapeutic molecules and the extent to which they reach the striatum and substantia nigra after the hNSC-mediated SVZ stem cell propagation is paramount in optimizing stem cell-based therapy for targeting the neurogenic niche in treating PD.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Zuo F, Xiong F, Wang X, Li X, Wang R, Ge W, et al.
Intrastriatal transplantation of human neural stem cells restores the impaired subventricular zone in parkinsonian mice. Stem Cells 2017;35:1519-31.
Lindvall O, Brundin P, Widner H, Rehncrona S, Gustavii B, Frackowiak R, et al.
Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease. Science 1990;247:574-7.
Björklund A, Dunnett SB, Brundin P, Stoessl AJ, Freed CR, Breeze RE, et al.
Neural transplantation for the treatment of Parkinson's disease. Lancet Neurol 2003;2:437-45.
Borlongan CV, Sanberg PR, Freeman TB. Neural transplantation for neurodegenerative disorders. Lancet 1999;353 Suppl 1:SI29-30.
Alexi T, Borlongan CV, Faull RL, Williams CE, Clark RG, Gluckman PD, et al.
Neuroprotective strategies for basal ganglia degeneration: Parkinson's and huntington's diseases. Prog Neurobiol 2000;60:409-70.
Borlongan CV. Transplantation therapy for parkinson's disease. Expert Opin Investig Drugs 2000;9:2319-30.
Perlow MJ, Freed WJ, Hoffer BJ, Seiger A, Olson L, Wyatt RJ, et al.
Brain grafts reduce motor abnormalities produced by destruction of nigrostriatal dopamine system. Science 1979;204:643-7.
Ungerstedt U, Ljungberg T, Steg G. Behavioral, physiological, and neurochemical changes after 6-hydroxydopamine-induced degeneration of the nigro-striatal dopamine neurons. Adv Neurol 1974;5:421-6.
Ungerstedt U, Arbuthnott GW. Quantitative recording of rotational behavior in rats after 6-hydroxy-dopamine lesions of the nigrostriatal dopamine system. Brain Res 1970;24:485-93.
Herrera-Marschitz M, Arbuthnott G, Ungerstedt U. The rotational model and microdialysis: Significance for dopamine signalling, clinical studies, and beyond. Prog Neurobiol 2010;90:176-89.
Brundin P, Björklund A. Survival of expanded dopaminergic precursors is critical for clinical trials. Nat Neurosci 1998;1:537.
Lindvall O, Rehncrona S, Brundin P, Gustavii B, Astedt B, Widner H, et al.
Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson's disease. A detailed account of methodology and a 6-month follow-up. Arch Neurol 1989;46:615-31.
Kordower JH, Freeman TB, Snow BJ, Vingerhoets FJ, Mufson EJ, Sanberg PR, et al.
Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson's disease. N Engl J Med 1995;332:1118-24.
Freed CR, Breeze RE, Rosenberg NL, Schneck SA, Kriek E, Qi JX, et al.
Survival of implanted fetal dopamine cells and neurologic improvement 12 to 46 months after transplantation for Parkinson's disease. N Engl J Med 1992;327:1549-55.
Wenning GK, Odin P, Morrish P, Rehncrona S, Widner H, Brundin P, et al.
Short- and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson's disease. Ann Neurol 1997;42:95-107.
Freeman TB, Olanow CW, Hauser RA, Nauert GM, Smith DA, Borlongan CV, et al.
Bilateral fetal nigral transplantation into the postcommissural putamen in Parkinson's disease. Ann Neurol 1995;38:379-88.
Li W, Englund E, Widner H, Mattsson B, van Westen D, Lätt J, et al.
Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain. Proc Natl Acad Sci U S A 2016;113:6544-9.
Hagell P, Piccini P, Björklund A, Brundin P, Rehncrona S, Widner H, et al.
Dyskinesias following neural transplantation in Parkinson's disease. Nat Neurosci 2002;5:627-8.
Dunnett SB, Björklund A, Lindvall O. Cell therapy in Parkinson's disease – Stop or go? Nat Rev Neurosci 2001;2:365-9.
Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, et al.
Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med 2001;344:710-9.
Napoli E, Borlongan CV. Stem cell recipes of bone marrow and fish: Just what the stroke doctors ordered. Stem Cell Rev 2017;13:192-7.
Napoli E, Borlongan CV. Recent advances in stem cell-based therapeutics for stroke. Transl Stroke Res 2016;7:452-7.
Borlongan CV. Preliminary reports of stereotaxic stem cell transplants in chronic stroke patients. Mol Ther 2016;24:1710-1.
Borlongan CV. Age of PISCES: Stem-cell clinical trials in stroke. Lancet 2016;388:736-8.
Kondziolka D, Wechsler L, Goldstein S, Meltzer C, Thulborn KR, Gebel J, et al.
Transplantation of cultured human neuronal cells for patients with stroke. Neurology 2000;55:565-9.
Kalladka D, Sinden J, Pollock K, Haig C, McLean J, Smith W, et al.
Human neural stem cells in patients with chronic ischaemic stroke (PISCES): A phase 1, first-in-man study. Lancet 2016;388:787-96.
Cox CS Jr., Baumgartner JE, Harting MT, Worth LL, Walker PA, Shah SK, et al.
Autologous bone marrow mononuclear cell therapy for severe traumatic brain injury in children. Neurosurgery 2011;68:588-600.
Freeman TB, Cicchetti F, Hauser RA, Deacon TW, Li XJ, Hersch SM, et al.
Transplanted fetal striatum in huntington's disease: Phenotypic development and lack of pathology. Proc Natl Acad Sci U S A 2000;97:13877-82.
Pollock K, Dahlenburg H, Nelson H, Fink KD, Cary W, Hendrix K, et al.
Human mesenchymal stem cells genetically engineered to overexpress brain-derived neurotrophic factor improve outcomes in Huntington's disease mouse models. Mol Ther 2016;24:965-77.
Sanberg PR, Borlongan CV, Othberg AI, Saporta S, Freeman TB, Cameron DF, et al.
Testis-derived Sertoli cells have a trophic effect on dopamine neurons and alleviate hemiparkinsonism in rats. Nat Med 1997;3:1129-32.
Sanberg PR, Borlongan CV, Saporta S, Cameron DF. Testis-derived sertoli cells survive and provide localized immunoprotection for xenografts in rat brain. Nat Biotechnol 1996;14:1692-5.
Lindvall O, Widner H, Rehncrona S, Brundin P, Odin P, Gustavii B, et al. Transplantation of fetal dopamine neurons in Parkinsonís disease: One-year clinical and neurophysiological observations in two patients with putaminal implants. Ann Neurol 1992;31:155-65.
Kefalopoulou Z, Politis M, Piccini P, Mencacci N, Bhatia K, Jahanshahi M, et al.
Long-term clinical outcome of fetal cell transplantation for Parkinson disease: Two case reports. JAMA Neurol 2014;71:83-7.
Kitamura T, Ogawa SK, Roy DS, Okuyama T, Morrissey MD, Smith LM, et al.
Engrams and circuits crucial for systems consolidation of a memory. Science 2017;356:73-8.
Redondo RL, Kim J, Arons AL, Ramirez S, Liu X, Tonegawa S, et al.
Bidirectional switch of the valence associated with a hippocampal contextual memory engram. Nature 2014;513:426-30.
Costa C, Sgobio C, Siliquini S, Tozzi A, Tantucci M, Ghiglieri V, et al.
Mechanisms underlying the impairment of hippocampal long-term potentiation and memory in experimental Parkinson's disease. Brain 2012;135:1884-99.
Calabresi P, Castrioto A, Di Filippo M, Picconi B. New experimental and clinical links between the hippocampus and the dopaminergic system in parkinson's disease. Lancet Neurol 2013;12:811-21.
Hall H, Reyes S, Landeck N, Bye C, Leanza G, Double K, et al.
Hippocampal lewy pathology and cholinergic dysfunction are associated with dementia in Parkinson's disease. Brain 2014;137:2493-508.
Bagetta V, Picconi B, Marinucci S, Sgobio C, Pendolino V, Ghiglieri V, et al.
Dopamine-dependent long-term depression is expressed in striatal spiny neurons of both direct and indirect pathways: Implications for parkinson's disease. J Neurosci 2011;31:12513-22.
Yasuhara T, Matsukawa N, Hara K, Yu G, Xu L, Maki M, et al.
Transplantation of human neural stem cells exerts neuroprotection in a rat model of Parkinson's disease. J Neurosci 2006;26:12497-511.
Redmond DE Jr., Bjugstad KB, Teng YD, Ourednik V, Ourednik J, Wakeman DR, et al.
Behavioral improvement in a primate parkinson's model is associated with multiple homeostatic effects of human neural stem cells. Proc Natl Acad Sci U S A 2007;104:12175-80.
Tajiri N, Kaneko Y, Shinozuka K, Ishikawa H, Yankee E, McGrogan M, et al.
Stem cell recruitment of newly formed host cells via a successful seduction? Filling the gap between neurogenic niche and injured brain site. PLoS One 2013;8:e74857.
Anderson JD, Johansson HJ, Graham CS, Vesterlund M, Pham MT, Bramlett CS, et al.
Comprehensive proteomic analysis of mesenchymal stem cell exosomes reveals modulation of angiogenesis via nuclear factor-kappaB signaling. Stem Cells 2016;34:601-13.
Tansey MG, Goldberg MS. Neuroinflammation in Parkinson's disease: Its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis 2010;37:510-8.
Henderson MX, Chung CH, Riddle DM, Zhang B, Gathagan RJ, Seeholzer SH, et al.
Unbiased proteomics of early lewy body formation model implicates active microtubule affinity-regulating kinases (MARKs) in synucleinopathies. J Neurosci 2017;37:5870-84.