Therapeutic Effects of Noninvasive Electrical Stimulation in Combination Transplantation of Human Adipose-Derived Stem Cells-Derived Dopaminergic Neuron on the Monkey Model of Parkinson's Disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic neurons (DNs). Currently, there is no treatment that can cure PD. Deep brain stimulation has been used to treat PD due to its good effectiveness, but there are safety issues. Therefore, noninvasive electrical stimulation (NES) may be an effective and safe strategy for the treatment of PD. Here, we performed NES treatment and NES combined with human adipose-derived stem cells-induced DN transplantation (NES-DN) on the PD monkey model to explore the therapeutic effect of NES on PD. The results show that NES or NES-DN can increase dopamine levels, improve mitochondrial dysfunction, reduce neuroinflammation, enhance synaptic function, and protect TH neurons, thereby improving the movement disorders of PD. Moreover, NES/NES-DN may exert immunomodulatory effects by regulating serpin family A member 3 in PD monkeys. Our results support the scientific basis and preclinical evidence for NES in the treatment of PD. Not only does NES alone improve PD, but NES combined with stem cell therapy can greatly enhance the therapeutic effect of PD.

Keywords

human adipose-derived stem cells / neuroinflammation / nonhuman primate / noninvasive electrical stimulation / Parkinson's disease / Serpin family A member 3

References

[1] W. Poewe, K. Seppi, C. M. Tanner, et al., “Parkinson Disease,” Nature Reviews Disease Primers 3 (2017): 17013.

[2] Y. Ben-Shlomo, S. Darweesh, J. Llibre-Guerra, et al., “The Epidemiology of Parkinson's Disease,” The Lancet 403, no. 10423 (2024): 283–292.

[3] H. Ye, L. A. Robak, M. Yu, M. Cykowski, and J. M. Shulman, “Genetics and Pathogenesis of Parkinson's Syndrome,” Annual Review of Pathology: Mechanisms of Disease 18, no. 1 (2023): 95–121.

[4] M. J. Armstrong and M. S. Okun, “Diagnosis and Treatment of Parkinson Disease: A Review,” Jama 323, no. 6 (2020): 548–560.

[5] A. M. Lozano, J. Dostrovsky, R. Chen, and P. Ashby, “Deep Brain Stimulation for Parkinson's disease: Disrupting the Disruption,” The Lancet Neurology 1, no. 4 (2002): 225–231.

[6] A. E. Lang and H. Widner, “Deep Brain Stimulation for Parkinson's disease: Patient Selection and Evaluation,” Movement Disorders 17, no. S3 (2002): S94–S101.

[7] A. D. Wu, F. Fregni, D. K. Simon, C. Deblieck, and A. Pascual-Leone, “Noninvasive Brain Stimulation for Parkinson's Disease and Dystonia,” Neurotherapeutics 5, no. 2 (2008): 345–361.

[8] W. Zhang, B. Deng, F. Xie, et al., “Efficacy of Repetitive Transcranial Magnetic Stimulation in Parkinson's disease: A Systematic Review and Meta-analysis of Randomised Controlled Trials,” Eclinicalmedicine 52 (2022): 101589.

[9] L. Dinkelbach, M. Brambilla, R. Manenti, and A.-K. Brem, “Non-invasive Brain Stimulation in Parkinson's Disease: Exploiting Crossroads of Cognition and Mood,” Neuroscience & Biobehavioral Reviews 75 (2017): 407–418.

[10] A. A. Rabinstein and L. M. Shulman, “Acupuncture in Clinical Neurology,” The Neurologist 9, no. 3 (2003): 137–148.

[11] L. M. Shulman, X. Wen, W. J. Weiner, et al., “Acupuncture Therapy for the Symptoms of Parkinson's Disease,” Movement Disorders 17, no. 4 (2002): 799–802.

[12] B.-Y. Zeng, S. Salvage, and P. Jenner, “Current Development of Acupuncture Research in Parkinson's Disease,” Neurobiology of Acupuncture 111 (2013): 141–158.

[13] J.-Q. Fan, W.-J. Lu, W.-Q. Tan, W.-C. Feng, and L.-X. Zhuang, “Acupuncture for Parkinson's Disease: From Theory to Practice,” Biomedicine and Pharmacotherapy 149 (2022): 112907.

[14] B.-Y. Zeng and K. Zhao, “Effect of Acupuncture on the Motor and Nonmotor Symptoms in Parkinson's Disease—A Review of Clinical Studies,” CNS Neuroscience & Therapeutics 22, no. 5 (2016): 333–341.

[15] J. Q. Yin, J. Zhu, and J. A. Ankrum, “Manufacturing of Primed Mesenchymal Stromal Cells for Therapy,” Nature Biomedical Engineering 3, no. 2 (2019): 90–104.

[16] M. Ghasemi, E. Roshandel, M. Mohammadian, et al., “Mesenchymal Stromal Cell-derived Secretome-based Therapy for Neurodegenerative Diseases Overview of Clinical Trials,” Stem Cell Research & Therapy 14, no. 1 (2023): 122.

[17] Y.-S. Zeng, Y. Ding, H.-Y. Xu, et al., “Electro-acupuncture and Its Combination With Adult Stem Cell Transplantation for Spinal Cord Injury Treatment a Summary of Current Laboratory Findings and a Review of Literature,” CNS Neuroscience & Therapeutics 28, no. 5 (2022): 635–647.

[18] T. E. Salazar, M. R. Richardson, and E. Beli, “Electroacupuncture Promotes CNS-dependent Release of Mesenchymal Stem Cells,” Stem Cells 35, no. 5 (2017): 1303–1315.

[19] C. Yang, Y. Qiu, Y. Qing, et al., “Synergistic Effect of Electric Stimulation and Mesenchymal Stem Cells Against Parkinson's disease,” Aging 12, no. 16 (2020): 16062–16071.

[20] M. F. Beal, “Experimental Models of Parkinson's Disease,” Nature Reviews Neuroscience 2, no. 5 (2001): 325–332.

[21] S. Schildknecht, D. A. Di Monte, R. Pape, K. Tieu, and M. Leist, “Tipping Points and Endogenous Determinants of Nigrostriatal Degeneration by MPTP,” Trends in Pharmacological Sciences 38, no. 6 (2017): 541–555.

[22] J. P. Capitanio and M. E. Emborg, “Contributions of Non-human Primates to Neuroscience Research,” Lancet 371, no. 9618 (2008): 1126–1135.

[23] E. Bezard, C. Imbert, X. Deloire, B. Bioulac, and C. E. Gross, “A Chronic MPTP Model Reproducing the Slow Evolution of Parkinson's Disease Evolution of Motor Symptoms in the Monkey,” Brain Research 766, no. 1-2 (1997): 107–112.

[24] F. Yu, N. Witman, D. Yan, et al., “Human Adipose-derived Stem Cells Enriched With VEGF-modified mRNA Promote Angiogenesis and Long-term Graft Survival in a Fat Graft Transplantation Model,” Stem Cell Research & Therapy 11, no. 1 (2020): 490.

[25] M. Wei, S. Li, Z. Yang, et al., “Tetrahedral DNA Nanostructures Functionalized by Multivalent microRNA132 Antisense Oligonucleotides Promote the Differentiation of Mouse Embryonic Stem Cells Into Dopaminergic Neurons,” Nanomedicine 34 (2021): 102375.

[26] Y. Jin, J. Wang, H. Li, et al., “Extracellular Vesicles Secreted by Human Adipose-derived Stem Cells (hASCs) Improve Survival Rate of Rats With Acute Liver Failure by Releasing lncRNA H19,” EBioMedicine 34 (2018): 231–242.

[27] J.-Q. Fan, W.-J. Lu, and W.-Q. Tan, “Effectiveness of Acupuncture for Anxiety among Patients with Parkinson Disease: A Randomized Clinical Trial,” JAMA Network Open 5, no. 9 (2022): e2232133.

[28] H. Noh, S. Kwon, S.-Y. Cho, et al., “Effectiveness and Safety of Acupuncture in the Treatment of Parkinson's Disease a Systematic Review and Meta-analysis of Randomized Controlled Trials,” Complementary Therapies in Medicine 34 (2017): 86–103.

[29] D. Weintraub, D. Aarsland, K. R. Chaudhuri, et al., “The Neuropsychiatry of Parkinson's Disease: Advances and Challenges,” Lancet Neurology 21, no. 1 (2022): 89–102.

[30] K. Li, S. Xu, R. Wang, et al., “Electroacupuncture for Motor Dysfunction and Constipation in Patients With Parkinson's Disease a Randomised Controlled Multi-centre Trial,” Eclinicalmedicine 56 (2023): 101814.

[31] S. P. Markey and N. R. Schmuff, “The Pharmacology of the Parkinsonian Syndrome Producing Neurotoxin MPTP (1–methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and Structurally Related Compounds,” Medicinal Research Reviews 6, no. 4 (1986): 389–429.

[32] Q. Hu and G. Wang, “Mitochondrial Dysfunction in Parkinson's Disease,” Translational Neurodegeneration 5 (2016): 14.

[33] J. W. Langston, P. Ballard, J. W. Tetrud, and I. Irwin, “Chronic Parkinsonism in Humans due to a Product of Meperidine-analog Synthesis,” Science 219, no. 4587 (1983): 979–980.

[34] J.-S. Han, “Acupuncture: Neuropeptide Release Produced by Electrical Stimulation of Different Frequencies,” Neuron 26, no. 1 (2003): 17–22.

[35] H.-C. Lai, Q.-Y. Chang, and C.-L. Hsieh, “Signal Transduction Pathways of Acupuncture for Treating some Nervous System Diseases,” Evidence-Based Complementary and Alternative Medicine 2019 (2019): 1–37.

[36] M. G. Tansey, R. L. Wallings, M. C. Houser, et al., “Inflammation and Immune Dysfunction in Parkinson disease,” Nature Reviews Immunology 22, no. 11 (2022): 657–673.

[37] J.-H. Jang, M.-J. Yeom, S. Ahn, et al., “Acupuncture Inhibits Neuroinflammation and Gut Microbial Dysbiosis in a Mouse Model of Parkinson's Disease,” Brain, Behavior, and Immunity 89 (2020): 641–655.

[38] X. Ma, Q. Wang, W. Yuan, et al., “Electroacupuncture Alleviates Neuroinflammation and Motor Dysfunction by Regulating Intestinal Barrier Function in a Mouse Model of Parkinson Disease,” Journal of Neuropathology & Experimental Neurology 80, no. 9 (2021): 844–855.

[39] Y.-Y. Xin, J.-X. Wang, and A.-J. Xu, “Electroacupuncture Ameliorates Neuroinflammation in Animal Models,” Acupuncture in Medicine 40, no. 5 (2022): 474–483.

[40] K. A. Walker, J. Chen, L. Shi, et al., “Proteomics Analysis of Plasma From Middle-aged Adults Identifies Protein Markers of Dementia Risk in Later Life,” Science Translational Medicine 15, no. 705 (2023): eadf5681.

[41] Z. Fan, Y. Gao, N. Jiang, et al., “Immune-related SERPINA3 as a Biomarker Involved in Diabetic Nephropathy Renal Tubular Injury,” Frontiers in Immunology 13 (2022): 979995.

[42] N. Fissolo, C. Matute-Blanch, M. Osman, et al., “CSF SERPINA3 Levels Are Elevated in Patients with Progressive MS,” Neurology Neuroimmunology & Neuroinflammation 8, no. 2 (2021): e941.

[43] S. Das and H. Potter, “Expression of the Alzheimer Amyloid-promoting Factor Antichymotrypsin Is Induced in human Astrocytes by IL-1,” Neuron 14, no. 2 (1995): 447–456.

[44] T. Kordula, M. Bugno, R. E. Rydel, and J. Travis, “Mechanism of Interleukin-1- and Tumor Necrosis Factor Alpha-dependent Regulation of the Alpha 1-antichymotrypsin Gene in human Astrocytes,” The Journal of Neuroscience 20, no. 20 (2000): 7510–7516.

[45] Z. Liu, R. Liu, R. Wang, et al., “Sinensetin Attenuates IL-1β-induced Cartilage Damage and Ameliorates Osteoarthritis by Regulating SERPINA3,” Food & Function 13, no. 19 (2022): 9973–9987.

[46] C. R. Abraham, D. J. Selkoe, and H. Potter, “Immunochemical Identification of the Serine Protease Inhibitor Alpha 1-antichymotrypsin in the Brain Amyloid Deposits of Alzheimer's Disease,” Cell 52, no. 4 (1988): 487–501.

[47] N. D. Schiff, J. T. Giacino, C. R. Butson, et al., “Thalamic Deep Brain Stimulation in Traumatic Brain Injury: A Phase 1, Randomized Feasibility Study,” Nature Medicine 29, no. 12 (2023): 3162–3174.

[48] K. J. Clancy, J. A. Andrzejewski, Y. You, et al., “Transcranial Stimulation of Alpha Oscillations Up-regulates the Default Mode Network,” Proceedings of the National Academy of Sciences of the United States of America 119, no. 1 (2021): e2110868119.

[49] J. K. Krauss, N. Lipsman, T. Aziz, et al., “Technology of Deep Brain Stimulation: Current Status and Future Directions,” Nature Reviews Neurology 17, no. 2 (2020): 75–87.

[50] T. Milekovic, E. M. Moraud, N. Macellari, et al., “A Spinal Cord Neuroprosthesis for Locomotor Deficits due to Parkinson's Disease,” Nature Medicine 29, no. 11 (2023): 2854–2865.

[51] D. M. Hoang, P. T. Pham, T. Q. Bach, et al., “Stem Cell-based Therapy for human Diseases,” Signal Transduction and Targeted Therapy 7, no. 1 (2022): 272.

[52] Y.-K. Wang, W.-W. Zhu, M.-H. Wu, et al., “Human Clinical-Grade Parthenogenetic ESC-Derived Dopaminergic Neurons Recover Locomotive Defects of Nonhuman Primate Models of Parkinson's Disease,” Stem Cell Reports 11, no. 1 (2018): 171–182.

[53] A. Morizane, T. Kikuchi, T. Hayashi, et al., “MHC Matching Improves Engraftment of iPSC-derived Neurons in Non-human Primates,” Nature Communications 8, no. 1 (2017): 385.

[54] A. Uccelli, L. Moretta, and V. Pistoia, “Mesenchymal Stem Cells in Health and Disease,” Nature Reviews Immunology 8, no. 9 (2008): 726–736.

[55] H. Gao and W. Ding, “Effect and Mechanism of Acupuncture on Endogenous and Exogenous Stem Cells in Disease Treatment: A Therapeutic Review,” Life Sciences 331 (2023): 122031.

[56] Y. Geng, D. Chen, J. Zhou, et al., “Synergistic Effects of Electroacupuncture and Mesenchymal Stem Cells on Intestinal Ischemia/Reperfusion Injury in Rats,” Inflammation 39, no. 4 (2016): 1414–1420.

[57] S. M. Ahn, Y. R. Kim, Y.-I. Shin, et al., “Therapeutic Potential of a Combination of Electroacupuncture and TrkB-Expressing Mesenchymal Stem Cells for Ischemic Stroke,” Molecular Neurobiology 56, no. 1 (2018): 157–173.

[58] Y. Yang, H. Y. Xu, Q. W. Deng, et al., “Electroacupuncture Facilitates the Integration of a Grafted TrkC-modified Mesenchymal Stem Cell-derived Neural Network Into Transected Spinal Cord in Rats via Increasing Neurotrophin-3,” CNS Neuroscience & Therapeutics 27, no. 7 (2021): 776–791.

[59] T.-Y. Park, J. Jeon, N. Lee, et al., “Co-transplantation of Autologous Treg Cells in a Cell Therapy for Parkinson's disease,” Nature 619, no. 7970 (2023): 606–615.

[60] C. E. Sortwell, M. R. Pitzer, and T. J. Collier, “Time Course of Apoptotic Cell Death Within Mesencephalic Cell Suspension Grafts: Implications for Improving Grafted Dopamine Neuron Survival,” Experimental Neurology 165, no. 2 (2000): 268–277.

[61] M. Emgård, J. Karlsson, O. Hansson, and P. Brundin, “Patterns of Cell Death and Dopaminergic Neuron Survival in Intrastriatal Nigral Grafts,” Experimental Neurology 160, no. 1 (1999): 279–288.

[62] C. Winkler, D. Kirik, and A. Björklund, “Cell Transplantation in Parkinson's Disease: How Can We Make It Work?,” Trends in Neurosciences 28, no. 2 (2005): 86–92.

[63] S. Kriks, J.-W. Shim, J. Piao, et al., “Dopamine Neurons Derived From human ES Cells Efficiently Engraft in Animal Models of Parkinson's disease,” Nature 480, no. 7378 (2011): 547–551.

[64] Y. Tao, S. C. Vermilyea, M. Zammit, et al., “Autologous Transplant Therapy Alleviates Motor and Depressive Behaviors in parkinsonian Monkeys,” Nature Medicine 27, no. 4 (2021): 632–639.

[65] T. W. Kim, S. Y. Koo, M. Riessland, et al., “TNF-NF-κB-p53 Axis Restricts in Vivo Survival of hPSC-derived Dopamine Neurons,” Cell 187, no. 14 (2024): 3671–3689.e3623.

[66] M. G. Otero, S. Bell, A. H. Laperle, et al., “Organ-Chips Enhance the Maturation of Human iPSC-Derived Dopamine Neurons,” International Journal of Molecular Sciences 24, no. 18 (2023): 14227.

[67] F. Zhou, S. Gao, L. Wang, et al., “Human Adipose-derived Stem Cells Partially Rescue the Stroke Syndromes by Promoting Spatial Learning and Memory in Mouse Middle Cerebral Artery Occlusion Model,” Stem Cell Research & Therapy 6, no. 1 (2015): 92.

[68] S. Gao, P. Zhao, C. Lin, et al., “Differentiation of human Adipose-derived Stem Cells Into Neuron-Like Cells Which Are Compatible With Photocurable Three-dimensional Scaffolds,” Tissue Engineering Part A 20, no. 7-8 (2014): 1271–1284.

[69] T. Hayashi, S. Wakao, M. Kitada, et al., “Autologous Mesenchymal Stem Cell–derived Dopaminergic Neurons Function in parkinsonian Macaques,” Journal of Clinical Investigation 123, no. 1 (2012): 272–284.

[70] R. D. Smith, Z. Zhang, R. Kurlan, M. McDermott, and D. M. Gash, “Developing a Stable Bilateral Model of Parkinsonism in rhesus Monkeys,” Neuroscience 52, no. 1 (1993): 7–16.

[71] R. Kurlan, M. H. Kim, and D. M. Gash, “Oral Levodopa Dose-response Study in MPTP-induced Hemiparkinsonian Monkeys Assessment With a New Rating Scale for Monkey Parkinsonism,” Movement Disorders 6, no. 2 (1991): 111–118.

[72] Y. Takagi, J. Takahashi, H. Saiki, et al., “Dopaminergic Neurons Generated From Monkey Embryonic Stem Cells Function in a Parkinson Primate Model,” Journal of Clinical Investigation 115, no. 1 (2005): 102–109.

[73] H. Saiki, T. Hayashi, R. Takahashi, and J. Takahashi, “Objective and Quantitative Evaluation of Motor Function in a Monkey Model of Parkinson's disease,” Journal of Neuroscience Methods 190, no. 2 (2010): 198–204.

[74] K. Någren, L. Müller, C. Halldin, C. G. Swahn, and P. Lehikoinen, “Improved Synthesis of some Commonly Used PET Radioligands by the Use of [11C]Methyl Triflate,” Nuclear Medicine and Biology 22, no. 2 (1995): 235–239.

[75] Z. Tu, S. Yan, B. Han, et al., “Tauopathy Promotes Spinal Cord-dependent Production of Toxic Amyloid-beta in Transgenic Monkeys,” Signal Transduction and Targeted Therapy 8, no. 1 (2023): 358.

[76] E. F. Fang, Y. Hou, K. Palikaras, et al., “Mitophagy Inhibits Amyloid-β and Tau Pathology and Reverses Cognitive Deficits in Models of Alzheimer's Disease,” Nature Neuroscience 22, no. 3 (2019): 401–412.

[77] A. Dobin, C. A. Davis, F. Schlesinger, et al., “STAR: Ultrafast Universal RNA-seq Aligner,” Bioinformatics 29, no. 1 (2013): 15–21.

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