Mesenchymal stem cells and conditioned media in the treatment of multiple sclerosis patients: Clinical, ophthalmological and radiological assessments of safety and efficacy

Said Dahbour, Fatima Jamali, Dana Alhattab, Ali Al-Radaideh, Osama Ababneh, Nosaiba Al-Ryalat, Muawyeh Al-Bdour, Bayan Hourani, Mohammed Msallam, Murad Rasheed, Ammar Huneiti, Yacoub Bahou, Emad Tarawneh, Abdalla Awidi, Said Dahbour, Fatima Jamali, Dana Alhattab, Ali Al-Radaideh, Osama Ababneh, Nosaiba Al-Ryalat, Muawyeh Al-Bdour, Bayan Hourani, Mohammed Msallam, Murad Rasheed, Ammar Huneiti, Yacoub Bahou, Emad Tarawneh, Abdalla Awidi

Abstract

Aims: This open-label prospective phase I/IIa clinical study used autologous bone marrow-derived mesenchymal stromal cells (BM-MSCs) followed by mesenchymal stromal cells conditioned media (MSC-CM) for the first time to treat multiple sclerosis (MS) patients. The primary goal was to assess the safety and feasibility and the secondary was efficacy. The correlation between the MSC-CM content and treatment outcome was investigated.

Methods: Ten MS patients who failed conventional therapy were enrolled. Adverse events were recorded to assess safety. The Expanded Disability Status Scale (EDSS) was the primary efficacy measurement, the secondary included clinical (25WFT, 9-PHT), cognitive (MMS), ophthalmology (OCT, VEP), and radiological (MRI lesion and volume) tests. The MSCs-CM concentration of 27 inflammatory biomarkers was investigated.

Results: The treatment protocol was well tolerated by patients. There was an overall trend of improvement in all the tests, except the lesion volume which increased significantly. A decrease of 4 and 3.5 points on the EDSS was achieved in two patients. We report a correlation between a decreased lesion number at baseline and higher IL-6, IL-8, and VEGF MSC-CM content.

Conclusion: The used protocol was safe and feasible with possible efficacy. The addition of MSC-CM could be related to the magnitude of EDSS improvement observed.

Keywords: conditioned media; expanded disability status scale; magnetic resonance imaging; mesenchymal stem cells; multiple sclerosis; optical coherence tomography; visual evoked potential.

© 2017 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Flowchart of the study
Figure 2
Figure 2
Expanded Disability Status Scale (EDSS) and white matter (WM) lesions volume outcomes at 12 mo posttreatment
Figure 3
Figure 3
Visual outcomes at 12 mo posttreatment
Figure 4
Figure 4
Top analytes secreted by MS patients' BM‐MSCs

References

    1. Charcot J‐M. Histologie de la sclérose en plaques (leçon recueillie par Bourneville). Gaz Hop Civ. 1868; 1051: 1868.
    1. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372:1502‐1517.
    1. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343:938‐952.
    1. Giovannoni G, Southam E, Waubant E. Systematic review of disease‐modifying therapies to assess unmet needs in multiple sclerosis: tolerability and adherence. Multi Sclerosis J. 2012;18:932‐946.
    1. Rudick RA, Polman CH. Current approaches to the identification and management of breakthrough disease in patients with multiple sclerosis. Lancet Neurol. 2009;8:545‐559.
    1. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab‐associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366:1870‐1880.
    1. Lindsey JW, Haden‐Pinneri K, Memon NB, Buja LM. Sudden unexpected death on fingolimod. Mult Scler. 2012;18:1507‐1508.
    1. Callera F, de Melo CM. Magnetic resonance tracking of magnetically labeled autologous bone marrow CD34+ cells transplanted into the spinal cord via lumbar puncture technique in patients with chronic spinal cord injury: CD34+ cells' migration into the injured site. Stem Cells Dev. 2007;16:461‐466.
    1. Chotivichit A, Ruangchainikom M, Chiewvit P, Wongkajornsilp A, Sujirattanawimol K. Chronic spinal cord injury treated with transplanted autologous bone marrow‐derived mesenchymal stem cells tracked by magnetic resonance imaging: a case report. J Med Case Rep. 2015;9:79.
    1. Trubiani O, Giacoppo S, Ballerini P, et al. Alternative source of stem cells derived from human periodontal ligament: a new treatment for experimental autoimmune encephalomyelitis. Stem Cell Res Ther. 2016;7:1.
    1. Woodbury D, Schwarz EJ, Prockop DJ, Black IB. Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res. 2000;61:364‐370.
    1. Alexanian AR. An efficient method for generation of neural‐like cells from adult human bone marrow‐derived mesenchymal stem cells. Regen Med. 2010;5:891‐900.
    1. Kyurkchiev D, Bochev I, Ivanova‐Todorova E, et al. Secretion of immunoregulatory cytokines by mesenchymal stem cells. World J Stem Cell. 2014;6:552‐570.
    1. Ivanova‐Todorova E, Bochev I, Dimitrov R, et al. Conditioned medium from adipose tissue‐derived mesenchymal stem cells induces CD4+FOXP3+ cells and increases IL‐10 secretion. J Biomed Biotechnol. 2012;2012:295167.
    1. Zappia E, Casazza S, Pedemonte E, et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T‐cell anergy. Blood. 2005;106:1755‐1761.
    1. Uccelli A, Laroni A, Freedman MS. Mesenchymal stem cells for the treatment of multiple sclerosis and other neurological diseases. Lancet Neurol. 2011;10:649‐656.
    1. Crigler L, Robey RC, Asawachaicharn A, Gaupp D, Phinney DG. Human mesenchymal stem cell subpopulations express a variety of neuro‐regulatory molecules and promote neuronal cell survival and neuritogenesis. Exp Neurol. 2006;198:54‐64.
    1. Wilkins A, Kemp K, Ginty M, Hares K, Mallam E, Scolding N. Human bone marrow‐derived mesenchymal stem cells secrete brain‐derived neurotrophic factor which promotes neuronal survival in vitro. Stem Cell Res. 2009;3:63‐70.
    1. Ballerini P, Diomede F, Petragnani N, et al. Conditioned medium from relapsing‐remitting multiple sclerosis patients reduces the expression and release of inflammatory cytokines induced by LPS‐gingivalis in THP‐1 and MO3.13 cell lines. Cytokine. 2017;96:261‐272.
    1. Bai L, Lennon DP, Caplan AI, et al. Hepatocyte growth factor mediates mesenchymal stem cell‐induced recovery in multiple sclerosis models. Nat Neurosci. 2012;15:862‐870.
    1. Suto N, Mieda T, Iizuka A, Nakamura K, Hirai H. Morphological and functional attenuation of degeneration of peripheral neurons by mesenchymal stem cell‐conditioned medium in spinocerebellar ataxia type 1‐knock‐in mice. CNS Neurosci Ther. 2016;22:670‐676.
    1. Mohyeddin Bonab M, Yazdanbakhsh S, Lotfi J, et al. Does mesenchymal stem cell therapy help multiple sclerosis patients? Report of a pilot study. Iran J Immunol. 2007;4:50‐57.
    1. Yamout B, Hourani R, Salti H, et al. Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: a pilot study. J Neuroimmunol. 2010;227:185‐189.
    1. Karussis D, Karageorgiou C, Vaknin‐Dembinsky A, et al. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol. 2010;67:1187‐1194.
    1. Connick P, Kolappan M, Crawley C, et al. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open‐label phase 2a proof‐of‐concept study. Lancet Neurol. 2012;11:150‐156.
    1. Llufriu S, Sepulveda M, Blanco Y, et al. Randomized placebo‐controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis. PLoS ONE. 2014;9:e113936.
    1. Odinak MM, Bisaga GN, Novitskii AV, et al. Transplantation of mesenchymal stem cells in multiple sclerosis. Zh Nevrol Psikhiatr Im S S Korsakova. 2011;111:72‐76.
    1. Cohen JA, Imrey PB, Planchon SM, et al. Pilot trial of intravenous autologous culture‐expanded mesenchymal stem cell transplantation in multiple sclerosis. Mult Scler. 2017. [Epub ahead of print] 10.1177/1352458517703802
    1. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol. 2005;58:840‐846.
    1. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:292‐302.
    1. Fekete N, Rojewski MT, Furst D, et al. GMP‐compliant isolation and large‐scale expansion of bone marrow‐derived MSC. PLoS ONE. 2012;7:e43255.
    1. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315‐317.
    1. Lee RH, Kim B, Choi I, et al. Characterization and expression analysis of mesenchymal stem cells from human bone marrow and adipose tissue. Cell Physiol Biochem. 2004;14:311‐324.
    1. Udupa JK, Samarasekera S. Fuzzy connectedness and object definition: theory, algorithms, and applications in image segmentation. Graph Model Image Process. 1996;58:246‐261.
    1. Christiansson L, Mustjoki S, Simonsson B, Olsson‐Strömberg U, Loskog ASI, Mangsbo SM. The use of multiplex platforms for absolute and relative protein quantification of clinical material. EuPA Open Proteom. 2014;3:37‐47.
    1. Luk F, de Witte SF, Korevaar SS, et al. Inactivated mesenchymal stem cells maintain immunomodulatory capacity. Stem Cells Dev. 2016;25:1342‐1354.
    1. Drago D, Cossetti C, Iraci N, et al. The stem cell secretome and its role in brain repair. Biochimie. 2013;95:2271‐2285.
    1. Kassis I, Grigoriadis N, Gowda‐Kurkalli B, et al. Neuroprotection and immunomodulation with mesenchymal stem cells in chronic experimental autoimmune encephalomyelitis. Arch Neurol. 2008;65:753‐761.
    1. Rudick R, Polman C, Cohen J, et al. Assessing disability progression with the multiple sclerosis functional composite. Mult Scler. 2009;15:984‐997.
    1. Kragt J, van der Linden FA, Nielsen J, Uitdehaag BM, Polman C. Clinical impact of 20% worsening on Timed 25‐foot Walk and 9‐hole Peg Test in multiple sclerosis. Mult Scler. 2006;12:594‐598.
    1. Chiaravalloti ND, DeLuca J. Cognitive impairment in multiple sclerosis. Lancet Neurol. 2008;7:1139‐1151.
    1. Swirsky‐Sacchetti T, Field HL, Mitchell DR, et al. The sensitivity of the Mini‐Mental State Exam in the white matter dementia of multiple sclerosis. J Clin Psychol. 1992;48:779‐786.
    1. Kappos L, Moeri D, Radue EW, et al. Predictive value of gadolinium‐enhanced magnetic resonance imaging for relapse rate and changes in disability or impairment in multiple sclerosis: a meta‐analysis. Gadolinium MRI Meta‐analysis Group. Lancet. 1999;353:964‐969.
    1. Molyneux P, Barker G, Barkhof F, et al. Clinical–MRI correlations in a European trial of interferon beta‐1b in secondary progressive MS. Neurology. 2001;57:2191‐2197.
    1. Hsiao ST‐F, Asgari A, Lokmic Z, et al. Comparative analysis of paracrine factor expression in human adult mesenchymal stem cells derived from bone marrow, adipose, and dermal tissue. Stem Cells Dev. 2012;21:2189‐2203.
    1. Tilg H, Dinarello CA, Mier JW. IL‐6 and APPs: anti‐inflammatory and immunosuppressive mediators. Immunol Today. 1997;18:428‐432.
    1. Casella G, Garzetti L, Gatta AT, et al. IL4 induces IL6‐producing M2 macrophages associated to inhibition of neuroinflammation in vitro and in vivo. J Neuroinflamm. 2016;13:139.
    1. Erta M, Quintana A, Hidalgo J. Interleukin‐6, a major cytokine in the central nervous system. Int J Biol Sci. 2012;8:1254‐1266.
    1. Zhou L, Lin Q, Wang P, et al. Enhanced neuroprotective efficacy of bone marrow mesenchymal stem cells co‐overexpressing BDNF and VEGF in a rat model of cardiac arrest‐induced global cerebral ischemia. Cell Death Dis. 2017;8:e2774.
    1. Horie N, Pereira MP, Niizuma K, et al. Transplanted stem cell‐secreted vascular endothelial growth factor effects poststroke recovery, inflammation, and vascular repair. Stem Cells. 2011;29:274‐285.
    1. Zhou Y, Tang H, Liu J, Dong J, Xiong H. Chemokine CCL2 modulation of neuronal excitability and synaptic transmission in rat hippocampal slices. J Neurochem. 2011;116:406‐414.

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