Top

Published in:

Open Access 01-12-2017 | Review

Advances, challenges and future directions for stem cell therapy in amyotrophic lateral sclerosis

Authors: Yuri Ciervo, Ke Ning, Xu Jun, Pamela J. Shaw, Richard J. Mead

Published in: Molecular Neurodegeneration | Issue 1/2017

Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative condition where loss of motor neurons within the brain and spinal cord leads to muscle atrophy, weakness, paralysis and ultimately death within 3–5 years from onset of symptoms. The specific molecular mechanisms underlying the disease pathology are not fully understood and neuroprotective treatment options are minimally effective.

In recent years, stem cell transplantation as a new therapy for ALS patients has been extensively investigated, becoming an intense and debated field of study. In several preclinical studies using the SOD1^G93A mouse model of ALS, stem cells were demonstrated to be neuroprotective, effectively delayed disease onset and extended survival. Despite substantial improvements in stem cell technology and promising results in preclinical studies, several questions still remain unanswered, such as the identification of the most suitable and beneficial cell source, cell dose, route of delivery and therapeutic mechanisms. This review will cover publications in this field and comprehensively discuss advances, challenges and future direction regarding the therapeutic potential of stem cells in ALS, with a focus on mesenchymal stem cells. In summary, given their high proliferation activity, immunomodulation, multi-differentiation potential, and the capacity to secrete neuroprotective factors, adult mesenchymal stem cells represent a promising candidate for clinical translation. However, technical hurdles such as optimal dose, differentiation state, route of administration, and the underlying potential therapeutic mechanisms still need to be assessed.

Walling AD. Amyotrophic lateral sclerosis: Lou Gehrig's disease. Am Fam Physician. 1999;59(6):1489–96.PubMed

Andersen PM, Al-Chalabi A. Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat Rev Neurol. 2011;7(11):603–15.PubMedCrossRef

Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, et al. Mutations in cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993;362(6415):59–62.PubMedCrossRef

Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, Vande Velde C, et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet. 2008;40(5):572–4.PubMedCrossRef

Rutherford NJ, Zhang YJ, Baker M, Gass JM, Finch NA, YF X, et al. Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genet. 2008;4(9):e1000193.PubMedPubMedCentralCrossRef

Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009;323(5918):1205–8.PubMedCrossRef

Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009;323(5918):1208–11.PubMedPubMedCentralCrossRef

Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature. 2010;465(7295):223–6.PubMedCrossRef

Johnson JO, Mandrioli J, Benatar M, Abramzon Y, Van Deerlin VM, Trojanowski JQ, et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron. 2010;68(5):857–64.PubMedPubMedCentralCrossRef

10.

Shaw CE, Capturing VCP. Another molecular piece in the ALS jigsaw puzzle. Neuron. 2010;68(5):812–4.PubMedCrossRef

11.

Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N, et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature. 2011;477(7363):211–5.PubMedPubMedCentralCrossRef

12.

Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011;72(2):257–68.PubMedPubMedCentralCrossRef

13.

DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72(2):245–56.PubMedPubMedCentralCrossRef

14.

Cirulli ET, Lasseigne BN, Petrovski S, Sapp PC, Dion PA, Leblond CS, et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science. 2015;347(6229):1436–41.PubMedPubMedCentralCrossRef

15.

Freischmidt A, Wieland T, Richter B, Ruf W, Schaeffer V, Muller K, et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat Neurosci. 2015;18(5):631–6.PubMedCrossRef

16.

Poppe L, Rue L, Robberecht W, Van Den Bosch L. Translating biological findings into new treatment strategies for amyotrophic lateral sclerosis (ALS). Exp Neurol. 2014;262 Pt B:138–151.

17.

Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, et al. Motor neuron degeneration in mice that express a human cu,Zn superoxide dismutase mutation. Science. 1994;264(5166):1772–5.PubMedCrossRef

18.

Cleveland DW, Bruijn LI, Wong PC, Marszalek JR, Vechio JD, Lee MK, et al. Mechanisms of selective motor neuron death in transgenic mouse models of motor neuron disease. Neurology. 1996;47(4 Suppl 2):S54–S61; discussion S-2.

19.

Lagier-Tourenne C, Polymenidou M, Hutt KR, AQ V, Baughn M, Huelga SC, et al. Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat Neurosci. 2012;15(11):1488–97.PubMedPubMedCentralCrossRef

20.

Kitamura A, Inada N, Kubota H, Matsumoto G, Kinjo M, Morimoto RI, et al. Dysregulation of the proteasome increases the toxicity of ALS-linked mutant SOD1. Genes Cells. 2014;19(3):209–24.PubMedPubMedCentralCrossRef

21.

Highley JR, Kirby J, Jansweijer JA, Webb PS, Hewamadduma CA, Heath PR, et al. Loss of nuclear TDP-43 in amyotrophic lateral sclerosis (ALS) causes altered expression of splicing machinery and widespread dysregulation of RNA splicing in motor neurones. Neuropathol Appl Neurobiol. 2014;40(6):670–85.PubMedCrossRef

22.

Alexander GM, Deitch JS, Seeburger JL, Del Valle L, Heiman-Patterson TD. Elevated cortical extracellular fluid glutamate in transgenic mice expressing human mutant (G93A) cu/Zn superoxide dismutase. J Neurochem. 2000;74(4):1666–73.PubMedCrossRef

23.

Shi P, Gal J, Kwinter DM, Liu X, Zhu H. Mitochondrial dysfunction in amyotrophic lateral sclerosis. Biochim Biophys Acta. 2010;1802(1):45–51.PubMedCrossRef

24.

Saxena S, Cabuy E, Caroni PA. Role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice. Nat Neurosci. 2009;12(5):627–36.PubMedCrossRef

25.

Zhang B, Tu P, Abtahian F, Trojanowski JQ, Lee VM. Neurofilaments and orthograde transport are reduced in ventral root axons of transgenic mice that express human SOD1 with a G93A mutation. J Cell Biol. 1997;139(5):1307–15.PubMedPubMedCentralCrossRef

26.

Barber SC, Shaw PJ. Oxidative stress in ALS: key role in motor neuron injury and therapeutic target. Free Radic Biol Med. 2010;48(5):629–41.PubMedCrossRef

27.

Clement AM, Nguyen MD, Roberts EA, Garcia ML, Boillee S, Rule M, et al. Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science. 2003;302(5642):113–7.PubMedCrossRef

28.

Pramatarova A, Laganiere J, Roussel J, Brisebois K, Rouleau GA. Neuron-specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment. J Neurosci. 2001;21(10):3369–74.PubMed

29.

Kang SH, Li Y, Fukaya M, Lorenzini I, Cleveland DW, Ostrow LW, et al. Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat Neurosci. 2013;16(5):571–9.PubMedPubMedCentralCrossRef

30.

Alexianu ME, Kozovska M, Appel SH. Immune reactivity in a mouse model of familial ALS correlates with disease progression. Neurology. 2001;57(7):1282–9.PubMedCrossRef

31.

Feeney SJ, McKelvie PA, Austin L, Jean-Francois MJ, Kapsa R, Tombs SM, et al. Presymptomatic motor neuron loss and reactive astrocytosis in the SOD1 mouse model of amyotrophic lateral sclerosis. Muscle Nerve. 2001;24(11):1510–9.PubMedCrossRef

32.

Ferraiuolo L. The non-cell-autonomous component of ALS: new in vitro models and future challenges. Biochem Soc Trans. 2014;42(5):1270–4.PubMedCrossRef

33.

Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145–7.PubMedCrossRef

34.

Shin S, Dalton S, Stice SL. Human motor neuron differentiation from human embryonic stem cells. Stem Cells Dev. 2005;14(3):266–9.PubMedCrossRef

35.

Rossi SL, Nistor G, Wyatt T, Yin HZ, Poole AJ, Weiss JH, et al. Histological and functional benefit following transplantation of motor neuron progenitors to the injured rat spinal cord. PLoS One. 2010;5(7):e11852.PubMedPubMedCentralCrossRef

36.

Wyatt TJ, Rossi SL, Siegenthaler MM, Frame J, Robles R, Nistor G, et al. Human motor neuron progenitor transplantation leads to endogenous neuronal sparing in 3 models of motor neuron loss. Stem Cells Int. 2011;2011:207230.PubMedPubMedCentralCrossRef

37.

Toma JS, Shettar BC, Chipman PH, Pinto DM, Borowska JP, Ichida JK, et al. Motoneurons derived from induced pluripotent stem cells develop mature phenotypes typical of endogenous spinal Motoneurons. J Neurosci. 2015;35(3):1291–306.PubMedPubMedCentralCrossRef

38.

Mothe A, Tator CH. Isolation of neural stem/progenitor cells from the periventricular region of the adult rat and human spinal cord. J Vis Exp. 2015;99:e52732.

39.

Xu L, Ryugo DK, Pongstaporn T, Johe K, Koliatsos VE. Human neural stem cell grafts in the spinal cord of SOD1 transgenic rats: differentiation and structural integration into the segmental motor circuitry. J Comp Neurol. 2009;514(4):297–309.PubMedPubMedCentralCrossRef

40.

Xu L, Shen P, Hazel T, Johe K, Koliatsos VE. Dual transplantation of human neural stem cells into cervical and lumbar cord ameliorates motor neuron disease in SOD1 transgenic rats. Neurosci Lett. 2011;494(3):222–6.PubMedPubMedCentralCrossRef

41.

Yan J, Xu L, Welsh AM, Hatfield G, Hazel T, Johe K, et al. Extensive neuronal differentiation of human neural stem cell grafts in adult rat spinal cord. PLoS Med. 2007;4(2):e39.PubMedPubMedCentralCrossRef

42.

Yan J, Xu L, Welsh AM, Chen D, Hazel T, Johe K, et al. Combined immunosuppressive agents or CD4 antibodies prolong survival of human neural stem cell grafts and improve disease outcomes in amyotrophic lateral sclerosis transgenic mice. Stem Cells. 2006;24(8):1976–85.PubMedCrossRef

43.

Xu L, Yan J, Chen D, Welsh AM, Hazel T, Johe K, et al. Human neural stem cell grafts ameliorate motor neuron disease in SOD-1 transgenic rats. Transplantation. 2006;82(7):865–75.PubMedCrossRef

44.

Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.PubMedCrossRef

45.

Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.PubMedCrossRef

46.

Dimos JT, Rodolfa KT, Niakan KK, Weisenthal LM, Mitsumoto H, Chung W, et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science. 2008;321(5893):1218–21.PubMedCrossRef

47.

Karumbayaram S, Novitch BG, Patterson M, Umbach JA, Richter L, Lindgren A, et al. Directed differentiation of human-induced pluripotent stem cells generates active motor neurons. Stem Cells. 2009;27(4):806–11.PubMedPubMedCentralCrossRef

48.

Popescu IR, Nicaise C, Liu S, Bisch G, Knippenberg S, Daubie V, et al. Neural progenitors derived from human induced pluripotent stem cells survive and differentiate upon transplantation into a rat model of amyotrophic lateral sclerosis. Stem Cells Transl Med. 2013;2(3):167–74.PubMedPubMedCentralCrossRef

49.

Nizzardo M, Simone C, Rizzo F, Ruggieri M, Salani S, Riboldi G, et al. Minimally invasive transplantation of iPSC-derived ALDHhiSSCloVLA4+ neural stem cells effectively improves the phenotype of an amyotrophic lateral sclerosis model. Hum Mol Genet. 2014;23(2):342–54.PubMedCrossRef

50.

Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143–7.PubMedCrossRef

51.

Woodbury D, Schwarz EJ, Prockop DJ, Black IB. Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res. 2000;61(4):364–70.PubMedCrossRef

52.

Hermann A, Gastl R, Liebau S, Popa MO, Fiedler J, Boehm BO, et al. Efficient generation of neural stem cell-like cells from adult human bone marrow stromal cells. J Cell Sci. 2004;117(Pt 19):4411–22.PubMedCrossRef

53.

Rivera FJ, Couillard-Despres S, Pedre X, Ploetz S, Caioni M, Lois C, et al. Mesenchymal stem cells instruct oligodendrogenic fate decision on adult neural stem cells. Stem Cells. 2006;24(10):2209–19.PubMedCrossRef

54.

Boucherie C, Schafer S, Lavand'homme P, Maloteaux JM, Hermans E. Chimerization of astroglial population in the lumbar spinal cord after mesenchymal stem cell transplantation prolongs survival in a rat model of amyotrophic lateral sclerosis. J Neurosci Res. 2009;87(9):2034–46.PubMedCrossRef

55.

Sanchez-Ramos J, Song S, Cardozo-Pelaez F, Hazzi C, Stedeford T, Willing A, et al. Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol. 2000;164(2):247–56.PubMedCrossRef

56.

Wislet-Gendebien S, Hans G, Leprince P, Rigo JM, Moonen G, Rogister B. Plasticity of cultured mesenchymal stem cells: switch from nestin-positive to excitable neuron-like phenotype. Stem Cells. 2005;23(3):392–402.PubMedCrossRef

57.

Joe IS, Jeong S-G, Cho G-W. Resveratrol-induced SIRT1 activation promotes neuronal differentation of human bone marrow mesenchymal stem cells. Neurosci Lett 2014;584:97–102.

58.

Chan-Il C, Young-Don L, Heejaung K, Kim SH, Suh-Kim H, Kim SS. Neural induction with neurogenin 1 enhances the therapeutic potential of mesenchymal stem cells in an amyotrophic lateral sclerosis mouse model. Cell Transplant. 2013;22(5):855–70.PubMedCrossRef

59.

Choi YK, Lee DH, Seo YK, Jung H, Park JK, Cho H. Stimulation of neural differentiation in human bone marrow mesenchymal stem cells by extremely low-frequency electromagnetic fields incorporated with MNPs. Appl Biochem Biotechnol. 2014;174(4):1233–45.PubMedCrossRef

60.

Lewis CM, Suzuki M. Therapeutic applications of mesenchymal stem cells for amyotrophic lateral sclerosis. Stem Cell Res Ther. 2014;5(2):32.PubMedPubMedCentralCrossRef

61.

Zhao CP, Zhang C, Zhou SN, Xie YM, Wang YH, Huang H, et al. Human mesenchymal stromal cells ameliorate the phenotype of SOD1-G93A ALS mice. Cytotherapy. 2007;9(5):414–26.PubMedCrossRef

62.

Uccelli A, Milanese M, Principato MC, Morando S, Bonifacino T, Vergani L, et al. Intravenous mesenchymal stem cells improve survival and motor function in experimental amyotrophic lateral sclerosis. Mol Med. 2012;18:794–804.PubMedPubMedCentralCrossRef

63.

Habisch HJ, Janowski M, Binder D, Kuzma-Kozakiewicz M, Widmann A, Habich A, et al. Intrathecal application of neuroectodermally converted stem cells into a mouse model of ALS: limited intraparenchymal migration and survival narrows therapeutic effects. J Neural Transm (Vienna). 2007;114(11):1395–406.CrossRef

64.

Kim H, Kim HY, Choi MR, Hwang S, Nam KH, Kim HC, et al. Dose-dependent efficacy of ALS-human mesenchymal stem cells transplantation into cisterna magna in SOD1-G93A ALS mice. Neurosci Lett. 2010;468(3):190–4.PubMedCrossRef

65.

Zhang C, Zhou C, Teng JJ, Zhao RL, Song YQ. Multiple administrations of human marrow stromal cells through cerebrospinal fluid prolong survival in a transgenic mouse model of amyotrophic lateral sclerosis. Cytotherapy. 2009;11(3):299–306.PubMedCrossRef

66.

Forostyak S, Homola A, Turnovcova K, Svitil P, Jendelova P, Sykova E. Intrathecal delivery of mesenchymal stromal cells protects the structure of altered perineuronal nets in SOD1 rats and amends the course of ALS. Stem Cells. 2014;32(12):3163–72.PubMedPubMedCentralCrossRef

67.

Zhou C, Zhang C, Zhao R, Chi S, Ge P. Human marrow stromal cells reduce microglial activation to protect motor neurons in a transgenic mouse model of amyotrophic lateral sclerosis. J Neuroinflammation. 2013;10:52.PubMedPubMedCentralCrossRef

68.

Boido M, Piras A, Valsecchi V, Spigolon G, Mareschi K, Ferrero I, et al. Human mesenchymal stromal cell transplantation modulates neuroinflammatory milieu in a mouse model of amyotrophic lateral sclerosis. Cytotherapy. 2014;16(8):1059–72.PubMedCrossRef

69.

Iwashita Y, Crang AJ, Blakemore WF. Redistribution of bisbenzimide Hoechst 33342 from transplanted cells to host cells. Neuroreport. 2000;11(5):1013–6. Epub 2000/05/03PubMedCrossRef

70.

Vercelli A, Mereuta OM, Garbossa D, Muraca G, Mareschi K, Rustichelli D, et al. Human mesenchymal stem cell transplantation extends survival, improves motor performance and decreases neuroinflammation in mouse model of amyotrophic lateral sclerosis. Neurobiol Dis. 2008;31(3):395–405.PubMedCrossRef

71.

Knippenberg S, Thau N, Schwabe K, Dengler R, Schambach A, Hass R, et al. Intraspinal injection of human umbilical cord blood-derived cells is neuroprotective in a transgenic mouse model of amyotrophic lateral sclerosis. Neurodegener Dis. 2012;9(3):107–20.PubMedCrossRef

72.

Suzuki M, McHugh J, Tork C, Shelley B, Hayes A, Bellantuono I, et al. Direct muscle delivery of GDNF with human mesenchymal stem cells improves motor neuron survival and function in a rat model of familial ALS. Mol Ther. 2008;16(12):2002–10.PubMedPubMedCentralCrossRef

73.

Mazzini L, Fagioli F, Boccaletti R, Mareschi K, Oliveri G, Olivieri C, et al. Stem cell therapy in amyotrophic lateral sclerosis: a methodological approach in humans. Amyotroph Lateral Scler Other Motor Neuron Disord. 2003;4(3):158–61.PubMedCrossRef

74.

Mazzini L, Mareschi K, Ferrero I, Vassallo E, Oliveri G, Nasuelli N, et al. Stem cell treatment in amyotrophic lateral sclerosis. J Neurol Sci. 2008;265(1–2):78–83.PubMedCrossRef

75.

Mazzini L, Ferrero I, Luparello V, Rustichelli D, Gunetti M, Mareschi K, et al. Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis: a phase I clinical trial. Exp Neurol. 2010;223(1):229–37.PubMedCrossRef

76.

Mazzini L, Mareschi K, Ferrero I, Miglioretti M, Stecco A, Servo S, et al. Mesenchymal stromal cell transplantation in amyotrophic lateral sclerosis: a long-term safety study. Cytotherapy. 2012;14(1):56–60.PubMedCrossRef

77.

Cabanes C, Bonilla S, Tabares L, Martinez S. Neuroprotective effect of adult hematopoietic stem cells in a mouse model of motoneuron degeneration. Neurobiol Dis. 2007;26(2):408–18.PubMedCrossRef

78.

Blanquer M, Moraleda JM, Iniesta F, Gomez-Espuch J, Meca-Lallana J, Villaverde R, et al. Neurotrophic bone marrow cellular nests prevent spinal motoneuron degeneration in amyotrophic lateral sclerosis patients: a pilot safety study. Stem Cells. 2012;30(6):1277–85.PubMedCrossRef

79.

Blanquer M, Perez-Espejo MA, Martinez-Lage JF, Iniesta F, Martinez S, Moraleda JMA. Surgical technique of spinal cord cell transplantation in amyotrophic lateral sclerosis. J Neurosci Methods. 2010;191(2):255–7.PubMedCrossRef

80.

Karussis D, Karageorgiou C, Vaknin-Dembinsky A, Gowda-Kurkalli B, Gomori JM, Kassis I, et al. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol. 2010;67(10):1187–94.PubMedPubMedCentralCrossRef

81.

KW O, Moon C, Kim HY, SI O, Park J, Lee JH, et al. Phase I trial of repeated intrathecal autologous bone marrow-derived mesenchymal stromal cells in amyotrophic lateral sclerosis. Stem Cells Transl Med. 2015;4(6):590–7.CrossRef

82.

Kim HY, Kim H, KW O, SI O, Koh SH, Baik W, et al. Biological markers of mesenchymal stromal cells as predictors of response to autologous stem cell transplantation in patients with amyotrophic lateral sclerosis: an investigator-initiated trial and in vivo study. Stem Cells. 2014;32(10):2724–31.PubMedCrossRef

83.

Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7(2):211–28.PubMedCrossRef

84.

Meyer J, Salamon A, Herzmann N, Adam S, Kleine HD, Matthiesen I, et al. Isolation and differentiation potential of human Mesenchymal stem cells from adipose tissue harvested by water jet-assisted liposuction. Aesthet Surg J. 2015;35(8):1030–9.PubMedCrossRef

85.

Baglioni S, Francalanci M, Squecco R, Lombardi A, Cantini G, Angeli R, et al. Characterization of human adult stem-cell populations isolated from visceral and subcutaneous adipose tissue. FASEB J. 2009;23(10):3494–505.PubMedCrossRef

86.

Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7.PubMedCrossRef

87.

Han C, Zhang L, Song L, Liu Y, Zou W, Piao H, et al. Human adipose-derived mesenchymal stem cells: a better cell source for nervous system regeneration. Chin Med J. 2014;127(2):329–37.PubMed

88.

Safford KM, Hicok KC, Safford SD, Halvorsen YD, Wilkison WO, Gimble JM, et al. Neurogenic differentiation of murine and human adipose-derived stromal cells. Biochem Biophys Res Commun. 2002;294(2):371–9.PubMedCrossRef

89.

Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002;13(12):4279–95.PubMedPubMedCentralCrossRef

90.

Ashjian PH, Elbarbary AS, Edmonds B, DeUgarte D, Zhu M, Zuk PA, et al. Vitro differentiation of human processed lipoaspirate cells into early neural progenitors. Plast Reconstr Surg. 2003;111(6):1922–31.PubMedCrossRef

91.

Krampera M, Marconi S, Pasini A, Galie M, Rigotti G, Mosna F, et al. Induction of neural-like differentiation in human mesenchymal stem cells derived from bone marrow, fat, spleen and thymus. Bone. 2007;40(2):382–90.PubMedCrossRef

92.

Jang S, Cho HH, Cho YB, Park JS, Jeong HS. Functional neural differentiation of human adipose tissue-derived stem cells using bFGF and forskolin. BMC Cell Biol. 2010;11:25.PubMedPubMedCentralCrossRef

93.

Qian DX, Zhang HT, Ma X, Jiang XD, Comparison XRX. Of the efficiencies of three neural induction protocols in human adipose stromal cells. Neurochem Res. 2010;35(4):572–9.PubMedCrossRef

94.

Ahmadi N, Razavi S, Kazemi M, Oryan S. Stability of neural differentiation in human adipose derived stem cells by two induction protocols. Tissue Cell. 2012;44(2):87–94.PubMedCrossRef

95.

Feng N, Han Q, Li J, Wang S, Li H, Yao X, et al. Generation of highly purified neural stem cells from human adipose-derived mesenchymal stem cells by Sox1 activation. Stem Cells Dev. 2014;23(5):515–29.PubMedCrossRef

96.

Bahmani L, Taha MF, Javeri A. Coculture with embryonic stem cells improves neural differentiation of adipose tissue-derived stem cells. Neuroscience. 2014;272:229–39.PubMedCrossRef

97.

Abdanipour A, Tiraihi T. Induction of adipose-derived stem cell into motoneuron-like cells using selegiline as preinducer. Brain Res. 2012;1440:23–33.PubMedCrossRef

98.

Darvishi M, Tiraihi T, Mesbah-Namin SA, Delshad A, Taheri T. Motor neuron Transdifferentiation of neural stem cell from adipose-derived stem cell characterized by differential gene expression. Cell Mol Neurobiol. 2016;

99.

Neuhuber B, Gallo G, Howard L, Kostura L, Mackay A, Fischer I. Reevaluation of in vitro differentiation protocols for bone marrow stromal cells: disruption of actin cytoskeleton induces rapid morphological changes and mimics neuronal phenotype. J Neurosci Res. 2004;77(2):192–204.PubMedCrossRef

100.

Lu P, Blesch A, Tuszynski MH. Induction of bone marrow stromal cells to neurons: differentiation, transdifferentiation, or artifact? J Neurosci Res. 2004;77(2):174–91.PubMedCrossRef

101.

Woodbury D, Reynolds K, Black IB. Adult bone marrow stromal stem cells express germline, ectodermal, endodermal, and mesodermal genes prior to neurogenesis. J Neurosci Res. 2002;69(6):908–17.PubMedCrossRef

102.

Fu L, Zhu L, Huang Y, Lee TD, Forman SJ, Shih CC. Derivation of neural stem cells from mesenchymal stem cells: evidence for a bipotential stem cell population. Stem Cells Dev. 2008;17(6):1109–21.PubMedPubMedCentralCrossRef

103.

Kalinina N, Kharlampieva D, Loguinova M, Butenko I, Pobeguts O, Efimenko A, et al. Characterization of secretomes provides evidence for adipose-derived mesenchymal stromal cells subtypes. Stem Cell Res Ther. 2015;6:221.PubMedPubMedCentralCrossRef

104.

Marconi S, Bonaconsa M, Scambi I, Squintani GM, Rui W, Turano E, et al. Systemic treatment with adipose-derived mesenchymal stem cells ameliorates clinical and pathological features in the amyotrophic lateral sclerosis murine model. Neuroscience. 2013;248:333–43.PubMedCrossRef

105.

Kim KS, Lee HJ, An J, Kim YB, Ra JC, Lim I, et al. Transplantation of human adipose tissue-derived stem cells delays clinical onset and prolongs life span in ALS mouse model. Cell Transplant. 2014;23(12):1585–97.PubMedCrossRef

106.

Kim JM, Lee ST, Chu K, Jung KH, Song EC, Kim SJ, et al. Systemic transplantation of human adipose stem cells attenuated cerebral inflammation and degeneration in a hemorrhagic stroke model. Brain Res. 2007;1183:43–50.PubMedCrossRef

107.

Park D, Yang G, Bae DK, Lee SH, Yang YH, Kyung J, et al. Human adipose tissue-derived mesenchymal stem cells improve cognitive function and physical activity in ageing mice. J Neurosci Res. 2013;91(5):660–70.PubMedCrossRef

108.

Yan Y, Ma T, Gong K, Ao Q, Zhang X, Gong Y. Adipose-derived mesenchymal stem cell transplantation promotes adult neurogenesis in the brains of Alzheimer's disease mice. Neural Regen Res. 2014;9(8):798–805.PubMedPubMedCentralCrossRef

109.

Schwerk A, Altschuler J, Roch M, Gossen M, Winter C, Berg J, et al. Adipose-derived human mesenchymal stem cells induce long-term neurogenic and anti-inflammatory effects and improve cognitive but not motor performance in a rat model of Parkinson's disease. Regen Med. 2015;10(4):431–46.PubMedCrossRef

110.

Ilieva H, Polymenidou M, Cleveland DW. Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J Cell Biol. 2009;187(6):761–72.PubMedPubMedCentralCrossRef

111.

Kingham PJ, Kolar MK, Novikova LN, Novikov LN, Wiberg M. Stimulating the neurotrophic and angiogenic properties of human adipose-derived stem cells enhances nerve repair. Stem Cells Dev. 2014;23(7):741–54.PubMedCrossRef

112.

Henriques A, Pitzer C, Schneider A. Neurotrophic growth factors for the treatment of amyotrophic lateral sclerosis: where do we stand? Front Neurosci. 2010;4:32.PubMedPubMedCentral

113.

Krakora D, Mulcrone P, Meyer M, Lewis C, Bernau K, Gowing G, et al. Synergistic effects of GDNF and VEGF on lifespan and disease progression in a familial ALS rat model. Mol Ther. 2013;21(8):1602–10.PubMedPubMedCentralCrossRef

114.

Knippenberg S, Thau N, Dengler R, Brinker T, Petri S. Intracerebroventricular injection of encapsulated human mesenchymal cells producing glucagon-like peptide 1 prolongs survival in a mouse model of ALS. PLoS One. 2012;7(6):e36857.PubMedPubMedCentralCrossRef

115.

Sun H, Benardais K, Stanslowsky N, Thau-Habermann N, Hensel N, Huang D, et al. Therapeutic potential of mesenchymal stromal cells and MSC conditioned medium in amyotrophic lateral sclerosis (ALS)--in vitro evidence from primary motor neuron cultures, NSC-34 cells, astrocytes and microglia. PLoS One. 2013;8(9):e72926.PubMedPubMedCentralCrossRef

116.

Han C, Sun X, Liu L, Jiang H, Shen Y, Xu X, et al. Exosomes and their therapeutic potentials of stem cells. Stem Cells Int. 2016;2016:7653489.PubMed

117.

Bonafede R, Scambi I, Peroni D, Potrich V, Boschi F, Benati D, et al. Exosome derived from murine adipose-derived stromal cells: Neuroprotective effect on in vitro model of amyotrophic lateral sclerosis. Exp Cell Res. 2015;340(1):150–8.PubMedCrossRef

118.

119.

Gu R, Hou X, Pang R, Li L, Chen F, Geng J, et al. Human adipose-derived stem cells enhance the glutamate uptake function of GLT1 in SOD1(G93A)-bearing astrocytes. Biochem Biophys Res Commun. 2010;393(3):481–6.PubMedCrossRef

120.

Kwon MS, Noh MY, KW O, Cho KA, Kang BY, Kim KS, et al. The immunomodulatory effects of human mesenchymal stem cells on peripheral blood mononuclear cells in ALS patients. J Neurochem. 2014;131(2):206–18.PubMedCrossRef

121.

Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, Gerdoni E, et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood. 2005;106(5):1755–61.PubMedCrossRef

122.

Ramasamy R, Fazekasova H, Lam EW, Soeiro I, Lombardi G, Dazzi F. Mesenchymal stem cells inhibit dendritic cell differentiation and function by preventing entry into the cell cycle. Transplantation. 2007;83(1):71–6.PubMedCrossRef

123.

Luz-Crawford P, Kurte M, Bravo-Alegría J, Contreras R, Nova-Lamperti E, Tejedor G, et al. Mesenchymal stem cells generate a CD4+CD25+Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells. Stem Cell Res Ther. 2013;4(3):65.PubMedPubMedCentralCrossRef

124.

Henkel JS, Beers DR, Wen S, Rivera AL, Toennis KM, Appel JE, et al. Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival. EMBO Mol Med. 2013;5(1):64–79.PubMedCrossRef

125.

Brites D, Vaz AR. Microglia centered pathogenesis in ALS: insights in cell interconnectivity. Front Cell Neurosci. 2014;8:117.PubMedPubMedCentralCrossRef

126.

Ooi YY, Dheen ST, Tay SS. Paracrine effects of mesenchymal stem cells-conditioned medium on microglial cytokines expression and nitric oxide production. Neuroimmunomodulation. 2015;22(4):233–42.PubMedCrossRef

127.

Noh MY, Lim SM, KW O, Cho KA, Park J, Kim KS, et al. Mesenchymal stem cells modulate the functional properties of microglia via TGF-beta secretion. Stem Cells Transl Med. 2016;5(11):1538–49.PubMedPubMedCentralCrossRef

128.

Knippenberg S, Rath KJ, Boselt S, Thau-Habermann N, Schwarz SC, Dengler R, et al. Intraspinal administration of human spinal cord-derived neural progenitor cells in the G93A–SOD1 mouse model of ALS delays symptom progression, prolongs survival and increases expression of endogenous neurotrophic factors. J Tissue Eng Regen Med. 2015;11(3):751–64.PubMedCrossRef

129.

Riley J, Glass J, Feldman EL, Polak M, Bordeau J, Federici T, et al. Intraspinal stem cell transplantation in amyotrophic lateral sclerosis: a phase I trial, cervical microinjection, and final surgical safety outcomes. Neurosurgery. 2014;74(1):77–87.PubMedCrossRef

130.

Wilson EH, Weninger W, Hunter CA. Trafficking of immune cells in the central nervous system. J Clin Invest. 2010;120(5):1368–79.PubMedPubMedCentralCrossRef

131.

McCandless EE, Wang Q, Woerner BM, Harper JM, Klein RS. CXCL12 limits inflammation by localizing mononuclear infiltrates to the perivascular space during experimental autoimmune encephalomyelitis. J Immunol. 2006;177(11):8053–64.PubMedCrossRef

132.

Muller M, Carter SL, Hofer MJ, Manders P, Getts DR, Getts MT, et al. CXCR3 signaling reduces the severity of experimental autoimmune encephalomyelitis by controlling the parenchymal distribution of effector and regulatory T cells in the central nervous system. J Immunol. 2007;179(5):2774–86.PubMedCrossRef

133.

Agrawal S, Anderson P, Durbeej M, van Rooijen N, Ivars F, Opdenakker G, et al. Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. J Exp Med. 2006;203(4):1007–19.PubMedPubMedCentralCrossRef

134.

Corti S, Locatelli F, Papadimitriou D, Donadoni C, Del Bo R, Fortunato F, et al. Multipotentiality, homing properties, and pyramidal neurogenesis of CNS-derived LeX(ssea-1)+/CXCR4+ stem cells. FASEB J. 2005;19(13):1860–2.PubMed

135.

Appel SH, Armon C. Stem cells in amyotrophic lateral sclerosis: Ready for prime time? Neurology. 2016;87:348–9. United States.

136.

Abdul Wahid SF, Law ZK, Ismail NA, Azman Ali R, Lai NM. Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev. 2016;11:Cd011742.PubMed

137.

Guidance for Industry Drug Development for Amyotrophic Lateral Sclerosis. 2016. [Internet] http://www.alsa.org/advocacy/fda/assets/als-drug-development-guidance-for-public-comment-5-2-16.pdf. Accessed 23 Aug 2017.

138.

Bryson JB, Machado CB, Crossley M, Stevenson D, Bros-Facer V, Burrone J, et al. Optical control of muscle function by transplantation of stem cell-derived motor neurons in mice. Science. 2014;344(6179):94–7.PubMedCrossRef

139.

Robberecht W, Philips T. The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci. 2013;14(4):248–64.PubMedCrossRef

140.

Abel O, Powell JF, Andersen PM, Al-Chalabi A. ALSoD: a user-friendly online bioinformatics tool for amyotrophic lateral sclerosis genetics. Hum Mutat. 2012;33(9):1345–51.PubMedCrossRef

141.

Arnold ES, Ling SC, Huelga SC, Lagier-Tourenne C, Polymenidou M, Ditsworth D, et al. ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43. Proc Natl Acad Sci U S A. 2013;110(8):E736–45.PubMedPubMedCentralCrossRef

142.

Mead RJ, Bennett EJ, Kennerley AJ, Sharp P, Sunyach C, Kasher P, et al. Optimised and rapid pre-clinical screening in the SOD1(G93A) transgenic mouse model of amyotrophic lateral sclerosis (ALS). PLoS One. 2011;6(8):e23244.PubMedPubMedCentralCrossRef

143.

Bennett EJ, Mead RJ, Azzouz M, Shaw PJ, Grierson AJ. Early detection of motor dysfunction in the SOD1G93A mouse model of amyotrophic lateral sclerosis (ALS) using home cage running wheels. PLoS One. 2014;9(9):e107918.PubMedPubMedCentralCrossRef

144.

Scott MK, Akinduro O, Lo CC. In vivo 4-dimensional tracking of hematopoietic stem and progenitor cells in adult mouse calvarial bone marrow. J Vis Exp. 2014;91:e51683.

145.

Malide D, Metais JY, Dunbar CE. In vivo clonal tracking of hematopoietic stem and progenitor cells marked by five fluorescent proteins using confocal and multiphoton microscopy. J Vis Exp. 2014;90:e51669.

146.

Cheng NC, Wang S, Young TH. The influence of spheroid formation of human adipose-derived stem cells on chitosan films on stemness and differentiation capabilities. Biomaterials. 2012;33(6):1748–58.PubMedCrossRef

147.

Gao S, Zhao P, Lin C, Sun Y, Wang Y, Zhou Z, et al. Differentiation of human adipose-derived stem cells into neuron-like cells which are compatible with photocurable three-dimensional scaffolds. Tissue Eng Part A. 2014;20(7–8):1271–84.PubMedPubMedCentralCrossRef

148.

Cheng NC, Chen SY, Li JR, Young TH. Short-term spheroid formation enhances the regenerative capacity of adipose-derived stem cells by promoting stemness, angiogenesis, and chemotaxis. Stem Cells Transl Med. 2013;2(8):584–94.PubMedPubMedCentralCrossRef

149.

Shen CC, Yang YC, Liu BS. Peripheral nerve repair of transplanted undifferentiated adipose tissue-derived stem cells in a biodegradable reinforced nerve conduit. J Biomed Mater Res A. 2012;100(1):48–63.PubMedCrossRef

150.

Shrestha B, Coykendall K, Li Y, Moon A, Priyadarshani P, Yao L. Repair of injured spinal cord using biomaterial scaffolds and stem cells. Stem Cell Res Ther. 2014;5(4):91.PubMedPubMedCentralCrossRef

151.

Koh SH, Baik W, Noh MY, Cho GW, Kim HY, Kim KS, et al. The functional deficiency of bone marrow mesenchymal stromal cells in ALS patients is proportional to disease progression rate. Exp Neurol. 2012;233(1):472–80.PubMedCrossRef

152.

Cho GW, Noh MY, Kim HY, Koh SH, Kim KS, Kim SH. Bone marrow-derived stromal cells from amyotrophic lateral sclerosis patients have diminished stem cell capacity. Stem Cells Dev. 2010;19(7):1035–42.PubMedCrossRef

153.

Ferrero I, Mazzini L, Rustichelli D, Gunetti M, Mareschi K, Testa L, et al. Bone marrow mesenchymal stem cells from healthy donors and sporadic amyotrophic lateral sclerosis patients. Cell Transplant. 2008;17(3):255–66.PubMedCrossRef

154.

YS O, Kim SH, Cho GW. Functional restoration of amyotrophic lateral sclerosis patient-derived Mesenchymal stromal cells through inhibition of DNA Methyltransferase. Cell Mol Neurobiol. 2016;36(4):613–20.CrossRef

155.

Wu Y, Zhou H, Fan X, Zhang Y, Zhang M, Wang Y, et al. Correction of a genetic disease by CRISPR-Cas9-mediated gene editing in mouse spermatogonial stem cells. Cell Res. 2015;25(1):67–79.PubMedCrossRef

Title: Advances, challenges and future directions for stem cell therapy in amyotrophic lateral sclerosis
Authors: Yuri Ciervo
Ke Ning
Xu Jun
Pamela J. Shaw
Richard J. Mead
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Molecular Neurodegeneration / Issue 1/2017
Electronic ISSN: 1750-1326
DOI: https://doi.org/10.1186/s13024-017-0227-3

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Advances, challenges and future directions for stem cell therapy in amyotrophic lateral sclerosis

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2017

Depletion of adult neurogenesis exacerbates cognitive deficits in Alzheimer’s disease by compromising hippocampal inhibition

Targeting psychologic stress signaling pathways in Alzheimer’s disease

Glial contributions to neurodegeneration in tauopathies

Gad67 haploinsufficiency reduces amyloid pathology and rescues olfactory memory deficits in a mouse model of Alzheimer’s disease

The Trojan horse - neuroinflammatory impact of T cells in neurodegenerative diseases

Caspase vinyl sulfone small molecule inhibitors prevent axonal degeneration in human neurons and reverse cognitive impairment in Caspase-6-overexpressing mice