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Stem Cell Reviews and Reports

, Volume 13, Issue 5, pp 686–698 | Cite as

Pericytes Extend Survival of ALS SOD1 Mice and Induce the Expression of Antioxidant Enzymes in the Murine Model and in IPSCs Derived Neuronal Cells from an ALS Patient

  • Giuliana Castello Coatti
  • Miriam Frangini
  • Marcos C. Valadares
  • Juliana Plat Gomes
  • Natalia O. Lima
  • Natale Cavaçana
  • Amanda F. Assoni
  • Mayra V. Pelatti
  • Alexander Birbrair
  • Antonio Carlos Pedroso de Lima
  • Julio M. Singer
  • Francisco Marcelo M. Rocha
  • Giovani Loiola Da Silva
  • Mario Sergio Mantovani
  • Lucia Inês Macedo-Souza
  • Merari F. R. Ferrari
  • Mayana ZatzEmail author
Article

Abstract

Amyotrophic Lateral Sclerosis (ALS) is one of the most common adult-onset motor neuron disease causing a progressive, rapid and irreversible degeneration of motor neurons in the cortex, brain stem and spinal cord. No effective treatment is available and cell therapy clinical trials are currently being tested in ALS affected patients. It is well known that in ALS patients, approximately 50% of pericytes from the spinal cord barrier are lost. In the central nervous system, pericytes act in the formation and maintenance of the blood-brain barrier, a natural defense that slows the progression of symptoms in neurodegenerative diseases. Here we evaluated, for the first time, the therapeutic effect of human pericytes in vivo in SOD1 mice and in vitro in motor neurons and other neuronal cells derived from one ALS patient. Pericytes and mesenchymal stromal cells (MSCs) were derived from the same adipose tissue sample and were administered to SOD1 mice intraperitoneally. The effect of the two treatments was compared. Treatment with pericytes extended significantly animals survival in SOD1 males, but not in females that usually have a milder phenotype with higher survival rates. No significant differences were observed in the survival of mice treated with MSCs. Gene expression analysis in brain and spinal cord of end-stage animals showed that treatment with pericytes can stimulate the host antioxidant system. Additionally, pericytes induced the expression of SOD1 and CAT in motor neurons and other neuronal cells derived from one ALS patient carrying a mutation in FUS. Overall, treatment with pericytes was more effective than treatment with MSCs. Our results encourage further investigations and suggest that pericytes may be a good option for ALS treatment in the future.

Graphical Abstract

Keywords

Amyotrophic lateral sclerosis Pericytes Mesenchymal stromal cells SOD1 mice IPSCs Motor neurons 

Abbreviations

ACTB

Beta Actin

ALS

Amyotrophic Lateral Sclerosis

basic FGF

Basic fibroblast; growth factor

BBB

Blood Brain Barrier

BNDF

Brain-derived Neurotrophic Factor

BSA

Bovine serum albumin

CAT

catalase

CD11b

cluster of differentiation; molecule 11B

CFDA-SE

carboxyfluorescein diacetate succinimidyl ester

CHAT

Choline acetyltransferase

c-Myc

Proto-oncogene c-Myc

DAPI

4′,6-Diamidino-2-phenylindole dihydrochloride

DMEM

Dulbecco’s Modified Eagle Medium

EB

Embryoid bodies

EBM

Endothelial Cell Growth Medium

EGF

Epidermal growth factor

FBS

Fetal Bovine Serum

FDA

Food and Drug Administration

FGF

Fibroblast growth factors

GAPDH

Glyceraldehyde 3-phosphate dehydrogenase

G-CSF

Granulocyte colony-stimulating factor

GDNF

glial cell derived neurotrophic factor

GFAP

Glial fibrillary acidic protein

GLP-1

Glucagon-like Peptide 1

GM-CSF

Granulocyte-macrophage colony-stimulating factor

GPX

glutathione peroxidase

GSR

Glutathione reductase

HBSS

Hanks’ Balanced Salt Solution

IFN-g

Interferon gamma

IGF-1

Insulin-like growth factor 1

IL-10

Interleukin 10

IL-12p70

Interleukin 12p70

IL-13

Interleukin 13

IL-15

Interleukin 15

IL-17A

Interleukin 17A

IL-1ra

Interleukin 1ra

IL-1β

Interleukin 1β

IL-2

Interleukin

IL-4

Interleukin 4

IL-5

Interleukin 5

IL-6

Interleukin 6

IL-7

Interleukin 7

IL-8

Interleukin 8

IL-9

Interleukin 9

IP-10

C-X-C motif chemokine 10

IPSC

Induced Pluripotent Stem Cells

Klf4

Kruppel-like factor 4

MCP-1

Monocyte chemoattractant protein-1

MIP-1α

Macrophage Inflammatory Proteins −1α

MIP-1β

Macrophage Inflammatory Proteins -1 β

MND

Motor neuron diseases

MNX1/HB9

Motor neuron and pancreas homeobox 1/Homeobox HB9

MSCs

Mesenchymal stromal cells

NB media

Neuro Basal Media

NF-kB

factor nuclear kappa B

NGF

Nerve Growth Factor

NPCs

neural progenitor cells

NSCs

Neural Stem Cells

Oct4

octamer-binding transcription factor 4

PaGE

paw grip endurance

PBS

Phosphate-buffered saline

PDGF –BB

Platelet-derived growth factor C

RANTES

Regulated on Activation, Normal T Cell Expressed and Secreted

Ri

ROCK inhibitor

RT-qPCR

Real Time Quantitative Polymerase Chain Reaction

SHH

Sonic Hedgehog

SOD1

superoxide dismutase 1

Sox2

SRY (sex determining region Y)-box 2

TNF-α

Tumor necrosis fator α

VEGF

Vascular endothelial growth factor

Notes

Acknowledgments

This work was supported by CEPID/FAPESP, INCT and CNPq.

Compliance with Ethical Standards

Disclosure of Interest

The authors indicate no potential conflicts of interest.

Supplementary material

12015_2017_9752_MOESM1_ESM.pdf (3.8 mb)
Figure S1 Cell lines characterization performed in the 8th passage, the same used for in vivo experiments. (A) In vitro differentiation potential of MSCs and pericytes into adipocytes, osteoblasts and chondroblasts. (B) Immunophenotypic profile of MSCs and pericytes after 8 passages in culture, assessed by flow cytometry. (C) Multiplex ligation-dependent probe amplification (MLPA) analysis using SALSA P070 and SALSA P036 subtelomeric probes, evaluated in MSCs and pericytes. (PDF 3905 kb)
12015_2017_9752_MOESM2_ESM.pdf (18.8 mb)
Figure S2 Macrophage phagocytosis assay. (A, C) Anti-human lamin A/C (green) immunostaining of human cells (MSCs, or pericytes, respectively) co-cultured with macrophages (unlabeled, obtained from one SOD1 female). (B, D) Anti-human lamin A/C (green) immunostaining of human cells (MSCs, or pericytes, respectively) without macrophage co-culture. (E) DAPI nuclei staining in macrophages cultured alone. Magnification 200X. (F) positive control showing India Ink internalization by macrophages, 400X magnification. (H) Graphical representation of human MSCs and pericytes quantification with or without co-culture with macrophages (p = 0.3024 and p = 0.0906, respectively). The experiment was carried out in triplicate. (PDF 19208 kb)
12015_2017_9752_MOESM3_ESM.pdf (476 kb)
Figure S3 Dose-dependent immunosuppressive potential of MSCs and pericytes in CFDA-labeled SOD1 mice PBMCs and lymphocytes, after 5 days of co-culture with increasing doses of MSCs and pericytes. Bars represent the mean fluorescence of peak area of CFDA-labeled activated PBMCs and lymphocytes (obtained from one SOD1 female), evaluated by flow cytometry after the co-culture period. Increasing concentrations of human cells and a fixed amount of 1.104 activated PBMCs and lymphocytes were used. Activated PBMCs and lymphocytes cultured alone were used as a control. No differences were found between MSCs and pericytes. ***p < 0.001. The experiment was carried out in triplicate. (PDF 475 kb)
12015_2017_9752_MOESM4_ESM.pdf (192 kb)
Figure S4 Individual and average smoothed profiles (bold curve) of the longitudinal data relating to weight (A), motor score (B), rotarod (C) e PaGE (D). n = 22 mice per group, being 11 males and 11 females. (PDF 192 kb)
12015_2017_9752_MOESM5_ESM.pdf (737 kb)
Figure S5 Cytokine quantification by the 27-human cytokine plex (luminex) in culture media of co-cultured ALS patient derived motor neurons and other neuronal cells (NMs) with MSCs or pericytes. Only differentially secreted cytokines were represented. IL-2 IL-4 IL-5, IL-7 IL-9 IL-10, MIP-1a, were not detected in this assay and levels of basic-FGF, Eotaxin, GM-CSF, IFN-γ, IL-1β, IL-12p70, IL-13, IL-17a, MP-1β and PDGF-bb were not altered in comparison to the control (MNNs alone). *p < 0.05 **p < 0.01. For neuronal differentiation, iPSCs from one ALS patient was used. The experiment was carried out in four replicas. (PDF 736 kb)
12015_2017_9752_MOESM6_ESM.pdf (1.3 mb)
Figure S6 Validation of iPSC derived motor neurons and other neuronal cells. Amplification curves obtained after RT-qPCR, evaluating the expression of neuronal markers (ISL1, CHAT and MNX1) and the expression of the endogenous gene (BACT), with taqman probes. (PDF 1356 kb)
12015_2017_9752_MOESM7_ESM.pdf (493 kb)
Table S1 Primers for qRT-PCR. (PDF 492 kb)
12015_2017_9752_MOESM8_ESM.pdf (616 kb)
Table S2 Results of the mixed model analysis for physical performance tests assessed weekly in SOD1 treated mice (n = 22 mice per group, being 11 males and 11 females), for weight, PaGE, rotarod and motor score evaluations. (PDF 615 kb)

References

  1. 1.
    Goodall, E. F., & Morrison, K. E. (2006). Amyotrophic lateral sclerosis (motor neuron disease): Proposed mechanisms and pathways to treatment. Expert Reviews in Molecular Medicine. doi: 10.1111/j.1467-9639.2006.00001.x.
  2. 2.
    Guégan, C., & Przedborski, S. (2003). Programmed cell death in amyotrophic lateral sclerosis. Journal of Clinical Investigation. doi: 10.1172/JCI200317610.
  3. 3.
    Pasinelli, P., & Brown, R. H. (2006). Molecular biology of amyotrophic lateral sclerosis: Insights from genetics. Nature Reviews. Neuroscience, 7, 710–723. doi: 10.1038/nrn1971.CrossRefPubMedGoogle Scholar
  4. 4.
    Proctor, E. A., Fee, L., Tao, Y., Redler, R. L., Fay, J. M., Zhang, Y., et al. (2015). Nonnative SOD1 trimer is toxic to motor neurons in a model of amyotrophic lateral sclerosis. Proceedings of the National Academy of Sciences of the United States of America, 113(3), 614–619. doi: 10.1073/pnas.1516725113.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Bensimon, G., Lacomblez, L., & Meininger, V. (1994). A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. The New England journal of medicine, 330. doi: 10.1056/NEJM199403033300901.
  6. 6.
    Miller, R. G., Mitchell, J. D., Lyon, M., & Moore, D. H. (2007). Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database of Systematic Reviews. doi: 10.1002/14651858.CD001447.pub2.
  7. 7.
    Mitchell, J. D., & Borasio, G. D. (2007). Amyotrophic lateral sclerosis. Lancet, 369, 2031–2041. doi: 10.1016/S0140-6736(07)60944-1.CrossRefPubMedGoogle Scholar
  8. 8.
    Coatti, G. C., Beccari, M. S., Olávio, T. R., Mitne-Neto, M., Okamoto, O. K., & Zatz, M. (2015). Stem cells for amyotrophic lateral sclerosis modeling and therapy: Myth or fact? Cytometry Part A, 87(3), 197–211. doi: 10.1002/cyto.a.22630.CrossRefGoogle Scholar
  9. 9.
    Dellavalle, A., Sampaolesi, M., Tonlorenzi, R., Tagliafico, E., Sacchetti, B., Perani, L., et al. (2007). Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells. Nature Cell Biology, 9(3), 255–267. doi: 10.1038/ncb1542.CrossRefPubMedGoogle Scholar
  10. 10.
    Valadares, M. C., Gomes, J. P., Castello, G., Assoni, A., Pellati, M., Bueno, C., et al. (2014). Human adipose tissue derived Pericytes increase life span in Utrn (tm1Ked) Dmd (mdx) /J mice. Stem cell reviews. doi: 10.1007/s12015-014-9537-9.
  11. 11.
    Chen, C.-W., Okada, M., Proto, J. D., Gao, X., Sekiya, N., Beckman, S. A., et al. (2013). Human pericytes for ischemic heart repair. Stem cells (Dayton, Ohio), 31(2), 305–316. doi: 10.1002/stem.1285.CrossRefGoogle Scholar
  12. 12.
    Birbrair, A., Zhang, T., Wang, Z.-M., Messi, M. L., Mintz, A., & Delbono, O. (2014). Pericytes: Multitasking cells in the regeneration of injured, diseased, and aged skeletal muscle. Frontiers in Aging Neuroscience, 6, 245. doi: 10.3389/fnagi.2014.00245.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Corselli, M., Chen, C.-W., Crisan, M., Lazzari, L., & Péault, B. (2010). Perivascular ancestors of adult multipotent stem cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 30(6), 1104–1109. doi: 10.1161/ATVBAHA.109.191643.CrossRefPubMedGoogle Scholar
  14. 14.
    Crisan, M., Yap, S., Casteilla, L., Chen, C.-W., Corselli, M., Park, T. S., et al. (2008). A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell, 3(3), 301–313. doi: 10.1016/j.stem.2008.07.003.CrossRefPubMedGoogle Scholar
  15. 15.
    Caplan, A. I., & Sorrell, J. M. (2015). The MSC curtain that stops the immune system. Immunology Letters, 168(2), 136–139. doi: 10.1016/j.imlet.2015.06.005.CrossRefPubMedGoogle Scholar
  16. 16.
    Winkler, E. A, Bell, R. D., & Zlokovic, B. V. (2011). Central nervous system pericytes in health and disease. Nature Neuroscience, 14(11), 1398–1405. doi: 10.1038/nn.2946.
  17. 17.
    Winkler, E. A., Sengillo, J. D., Sagare, A. P., Zhao, Z., Ma, Q., Zuniga, E., et al. (2014). Blood-spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice. Proceedings of the National Academy of Sciences of the United States of America, 111(11), E1035–E1042. doi: 10.1073/pnas.1401595111.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Winkler, E. A., Sengillo, J. D., Sullivan, J. S., Henkel, J. S., Appel, S. H., & Zlokovic, B. V. (2013). Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis. Acta Neuropathologica, 125(1), 111–120. doi: 10.1007/s00401-012-1039-8.CrossRefPubMedGoogle Scholar
  19. 19.
    Assoni, A., Coatti, G., Valadares, M. C., Beccari, M., Gomes, J., Pelatti, M., … Zatz, M. (2016). Different donors mesenchymal stromal cells Secretomes reveal heterogeneous profile of relevance for therapeutic use. Stem Cells and Development, scd.2016.0218. doi: 10.1089/scd.2016.0218.
  20. 20.
    Ray, A., & Dittel, B. N. (2010). Isolation of mouse peritoneal cavity cells. Journal of visualized experiments : JoVE. doi: 10.3791/1488.
  21. 21.
    Gurney, M. E., Pu, H., Chiu, A. Y., Canto, M. C. D., Polchow, C. Y., Alexander, D. D., et al. (1994). Motor neuron degeneration in mice that express a human cu, Zn superoxide dismutase mutation. Science, 264(18), 1–4.Google Scholar
  22. 22.
    Barnéoud, P., Lolivier, J., Sanger, D. J., Scatton, B., & Moser, P. (1997). Quantitative motor assessment in FALS mice: A longitudinal study. Neuroreport, 8(13), 2861–5. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9376520.
  23. 23.
    Doble, A., & Kennel, P. (2000). Animal models of amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis, 1(5), 301–312. doi: 10.1080/146608200300079545.CrossRefPubMedGoogle Scholar
  24. 24.
    Pfohl, S. R., Halicek, M. T., & Mitchell, C. S. (2015). Characterization of the contribution of genetic background and gender to disease progression in the SOD1 G93A mouse model of amyotrophic lateral sclerosis: A meta-analysis. Journal of Neuromuscular Diseases, 2, 137–150. doi: 10.3233/JND-140068.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Heiman-Patterson, T. D., Deitch, J. S., Blankenhorn, E. P., Erwin, K. L., Perreault, M. J., Alexander, B. K., et al. (2005). Background and gender effects on survival in the TgN(SOD1-G93A)1Gur mouse model of ALS. Journal of the Neurological Sciences, 236(1–2), 1–7. doi: 10.1016/j.jns.2005.02.006.CrossRefPubMedGoogle Scholar
  26. 26.
    McCombe, P. A., & Henderson, R. D. (2010). Effects of gender in amyotrophic lateral sclerosis. Gender Medicine, 7(6), 557–570. doi: 10.1016/j.genm.2010.11.010.CrossRefPubMedGoogle Scholar
  27. 27.
    Scott, S., Kranz, J. E., Cole, J., Lincecum, J. M., Thompson, K., Kelly, N., et al. (2008). Design, power, and interpretation of studies in the standard murine model of ALS. Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases, 9(1), 4–15. doi: 10.1080/17482960701856300.CrossRefGoogle Scholar
  28. 28.
    Weydt, P., Hong, S. Y., Kliot, M., & Möller, T. (2003). Assessing disease onset and progression in the SOD1 mouse model of ALS. Neuroreport, 14(7), 1051–1054. doi: 10.1097/01.wnr.0000073685.00308.89.CrossRefPubMedGoogle Scholar
  29. 29.
    Liscic, R. M., & Breljak, D. (2011). Molecular basis of amyotrophic lateral sclerosis. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 35(2), 370–372. doi: 10.1016/j.pnpbp.2010.07.017.CrossRefGoogle Scholar
  30. 30.
    Marchetto, M. C. N. N., Carromeu, C., Acab, A., Yu, D., Yeo, G. W., Mu, Y., et al. (2010). A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell, 143(4), 527–539. doi: 10.1016/j.cell.2010.10.016.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Melo, U. S., Macedo-Souza, L. I., Figueiredo, T., Muotri, A. R., Gleeson, J. G., Coux, G., … Santos, S. (2015). Overexpression of KLC2 due to a homozygous deletion in the non-coding region causes SPOAN syndrome. Human Molecular Genetics, 24(24), ddv388. doi: 10.1093/hmg/ddv388.
  32. 32.
    Mitne-Neto, M., Machado-Costa, M., Marchetto, M. C. N. M., Bengtson, M. H. M., Joazeiro, C. C. A., Tsuda, H., et al. (2011). Downregulation of VAPB expression in motor neurons derived from induced pluripotent stem cells of ALS8 patients. Human Molecular Genetics, 20(18), 3642–3652.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Aranda, P. S., LaJoie, D. M., & Jorcyk, C. L. (2013). Bleach gel: A simple agarose gel for analyzing RNA quality. Electrophoresis, 33(2), 366–369. doi: 10.1002/elps.201100335.Bleach.CrossRefGoogle Scholar
  34. 34.
    Pfaffl, M. (2006). Relative quantification. In T. Dorak (Ed.), Real-time PCR (1st ed., pp. 63–82). International University Line.Google Scholar
  35. 35.
    Collett, D. (2003). Modelling survival data in medical research.Google Scholar
  36. 36.
    Cox, D. R. (1972). Regression models and life tables. Journal of the Royal Statistical Society. Series B (Methodological), 34(2), 187–220.Google Scholar
  37. 37.
    Singer, J. M., & Andrade, D. F. (2000). Analysis of longitudinal data. In P. K. Sen & C. R. Rao (Eds.), Handbook of statistics, volume 18: Bio-environmental and public health statistics (pp. 115–160). Amsterdam: North Holland.Google Scholar
  38. 38.
    Muggeo, V. M. R. (2003). Estimating regression models with unknown break-points. Statistics in Medicine, 22(19), 3055–3071. doi: 10.1002/sim.1545.CrossRefPubMedGoogle Scholar
  39. 39.
    Dominici, M., Le Blanc, K., Mueller, I., Slaper-Cortenbach, I., Marini, F., Krause, D., et al. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 8(4), 315–317. doi: 10.1080/14653240600855905.CrossRefPubMedGoogle Scholar
  40. 40.
    Alves, C. J., de Santana, L. P., dos Santos, A. J. D., de Oliveira, G. P., Duobles, T., Scorisa, J. M., et al. (2011). Early motor and electrophysiological changes in transgenic mouse model of amyotrophic lateral sclerosis and gender differences on clinical outcome. Brain Research, 1394, 90–104. doi: 10.1016/j.brainres.2011.02.060.CrossRefPubMedGoogle Scholar
  41. 41.
    Peron, J. P. S., Jazedje, T., Brandão, W. N., Perin, P. M., Maluf, M., Evangelista, L. P., et al. (2012). Human endometrial-derived mesenchymal stem cells suppress inflammation in the central nervous system of EAE mice. Stem Cell Reviews, 8(3), 940–952. doi: 10.1007/s12015-011-9338-3.CrossRefPubMedGoogle Scholar
  42. 42.
    Ohshima, M., Taguchi, A., Tsuda, H., Sato, Y., Yamahara, K., Harada-Shiba, M., et al. (2014). Intraperitoneal and intravenous deliveries are not comparable in terms of drug efficacy and cell distribution in neonatal mice with hypoxia-ischemia. Brain & Development, 5–7. doi: 10.1016/j.braindev.2014.06.010.
  43. 43.
    James, A. W., Zara, J. N., Zhang, X., Askarinam, A., Goyal, R., Chiang, M., et al. (2012). Perivascular stem cells: A prospectively purified mesenchymal stem cell population for bone tissue engineering. Stem Cells Translational Medicine, 1(6), 510–519. doi: 10.5966/sctm.2012-0002.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Birbrair, A., Zhang, T., Wang, Z.-M., Messi, M. L., Enikolopov, G. N., Mintz, A., & Delbono, O. (2013). Role of pericytes in skeletal muscle regeneration and fat accumulation. Stem Cells and Development, 22(16), 2298–2314. doi: 10.1089/scd.2012.0647.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Starling, A., Rocco, P., Passos-Bueno, M. R., Hazan, J., Marie, S. K., & Zatz, M. (2002). Autosomal dominant (AD) pure spastic paraplegia (HSP) linked to locus SPG4 affects almost exclusively males in a large pedigree. Journal of medical genetics. doi: 10.1136/jmg.39.12.e77.
  46. 46.
    Tonini, M. M. O., Pavanello, R. C. M., Gurgel-Giannetti, J., Lemmers, R. J., van der Maarel, S. M., Frants, R. R., & Zatz, M. (2004). Homozygosity for autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) does not result in a more severe phenotype. Journal of Medical Genetics, 41(2), e17 Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1735661&tool=pmcentrez&rendertype=abstract.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    de Paula, F., Vainzof, M., Passos-Bueno, M. R., de Cássia, M., Pavanello, R., Matioli, S. R., VB Anderson, L., et al. (2002). Clinical variability in calpainopathy: What makes the difference? European journal of human genetics : EJHG, 10(12), 825–832. doi: 10.1038/sj.ejhg.5200888.CrossRefPubMedGoogle Scholar
  48. 48.
    Prockop, D. J., & Youn Oh, J. (2012). Mesenchymal stem/stromal cells (MSCs): Role as guardians of inflammation. Molecular Therapy, 20(1), 14–20. doi: 10.1038/mt.2011.211.CrossRefPubMedGoogle Scholar
  49. 49.
    Kota, D. J., DiCarlo, B., Hetz, R. A., Smith, P., Cox, C. S., & Olson, S. D. (2014). Differential MSC activation leads to distinct mononuclear leukocyte binding mechanisms. Scientific Reports, 4, 4565. doi: 10.1038/srep04565.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Waterman, R. S., Henkle, S. L., & Betancourt, A. M. (2012). Mesenchymal stem cell 1 (MSC1)-based therapy attenuates tumor growth whereas MSC2-treatment promotes tumor growth and metastasis. PloS One, 7(9), e45590. doi: 10.1371/journal.pone.0045590.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Waterman, R. S., Tomchuck, S. L., Henkle, S. L., & Betancourt, A. M. (2010). A new mesenchymal stem cell (MSC) paradigm: Polarization into a pro-inflammatory MSC1 or an immunosuppressive MSC2 phenotype. PloS One, 5(4), e10088. doi: 10.1371/journal.pone.0010088.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Kyurkchiev, D., Bochev, I., Ivanova-Todorova, E., Mourdjeva, M., Oreshkova, T., Belemezova, K., & Kyurkchiev, S. (2014). Secretion of immunoregulatory cytokines by mesenchymal stem cells. World journal of stem cells, 6(5), 552–570. doi: 10.4252/wjsc.v6.i5.552.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Admyre, C., Axelsson, L.-G., von Stein, O., & Zargari, A. (2015). Immunomodulatory oligonucleotides inhibit neutrophil migration by decreasing the surface expression of interleukin-8 and leukotriene B 4 receptors. Immunology, 144(2), 206–217. doi: 10.1111/imm.12368.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Shibata, N., Nagai, R., Uchida, K., Horiuchi, S., Yamada, S., Hirano, A., et al. (2001). Morphological evidence for lipid peroxidation and protein glycoxidation in spinal cords from sporadic amyotrophic lateral sclerosis patients. Brain Research, 917(1), 97–104. doi: 10.1016/S0006-8993(01)02926-2.CrossRefPubMedGoogle Scholar
  55. 55.
    Shaw, P. J., Ince, P. G., Falkous, G., & Mantle, D. (1995). Oxidative damage to protein in sporadic motor neuron disease spinal cord. Annals of Neurology, 38(4), 691–695. doi: 10.1002/ana.410380424.CrossRefPubMedGoogle Scholar
  56. 56.
    Ferrante, R. J., Browne, S. E., Shinobu, L. A., Bowling, A. C., Baik, M. J., MacGarvey, U., … Beal, M. F. (1997). Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. Journal of neurochemistry.Google Scholar
  57. 57.
    Robelin, L., & Gonzalez De Aguilar, J. L. (2014). Blood biomarkers for amyotrophic lateral sclerosis: Myth or reality? BioMed Research International, 2014. doi: 10.1155/2014/525097.
  58. 58.
    Patel, B. P., & Hamadeh, M. J. (2009). Nutritional and exercise-based interventions in the treatment of amyotrophic lateral sclerosis. Clinical nutrition (Edinburgh, Scotland), 28(6), 604–617. doi: 10.1016/j.clnu.2009.06.002.CrossRefGoogle Scholar
  59. 59.
    Reinholz, M. M., Merkle, C. M., & Poduslo, J. F. (1999). Therapeutic benefits of putrescine-modified catalase in a transgenic mouse model of familial amyotrophic lateral sclerosis. Experimental Neurology, 159(1), 204–216. doi: 10.1006/exnr.1999.7142.CrossRefPubMedGoogle Scholar
  60. 60.
    Williams, J. R., Trias, E., Beilby, P. R., Lopez, N. I., Labut, E. M., Samuel Bradford, C., et al. (2016). Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SODG93A mice co-expressing the copper-chaperone-for-SOD. Neurobiology of Disease. doi: 10.1016/j.nbd.2016.01.020.
  61. 61.
    Egawa, N., Kitaoka, S., Tsukita, K., Naitoh, M., Takahashi, K., Yamamoto, T., et al. (2012). Drug screening for ALS using patient-specific induced pluripotent stem cells. Science Translational Medicine, 4(145). doi: 10.1126/scitranslmed.3004052.
  62. 62.
    Wainger, B. J., Kiskinis, E., Mellin, C., Wiskow, O., Han, S. S. W., Sandoe, J., et al. (2014). Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Reports, 7(1), 1–11. doi: 10.1016/j.celrep.2014.03.019.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Kemp, K., Mallam, E., Hares, K., Witherick, J., Scolding, N., & Wilkins, A. (2011). Mesenchymal stem cells restore frataxin expression and increase hydrogen peroxide scavenging enzymes in Friedreich ataxia fibroblasts. PloS One, 6(10), e26098. doi: 10.1371/journal.pone.0026098.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Dey, R., Kemp, K., Gray, E., Rice, C., Scolding, N., & Wilkins, A. (2012). Human mesenchymal stem cells increase anti-oxidant Defences in cells derived from patients with Friedreich’s ataxia. The Cerebellum, 861–871. doi: 10.1007/s12311-012-0406-2.
  65. 65.
    Levy, O., Mortensen, L. J., Boquet, G., Tong, Z., Perrault, C., Benhamou, B., … Karp, J. M. (2015). A small-molecule screen for enhanced homing of systemically infused cells. Cell Reports, 1–8. doi: 10.1016/j.celrep.2015.01.057.
  66. 66.
    Zeng, W., Xiao, J., Zheng, G., Xing, F., Tipoe, G. L., & Wang, X. (2015). Antioxidant treatment enhances human mesenchymal stem cell anti-stress ability and therapeutic efficacy in an acute liver failure model. Nature Publishing Group, 1–17. doi: 10.1038/srep11100.

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Giuliana Castello Coatti
    • 1
  • Miriam Frangini
    • 2
  • Marcos C. Valadares
    • 1
  • Juliana Plat Gomes
    • 1
  • Natalia O. Lima
    • 1
  • Natale Cavaçana
    • 1
  • Amanda F. Assoni
    • 1
  • Mayra V. Pelatti
    • 1
  • Alexander Birbrair
    • 3
    • 4
  • Antonio Carlos Pedroso de Lima
    • 5
  • Julio M. Singer
    • 5
  • Francisco Marcelo M. Rocha
    • 5
  • Giovani Loiola Da Silva
    • 5
  • Mario Sergio Mantovani
    • 6
  • Lucia Inês Macedo-Souza
    • 1
  • Merari F. R. Ferrari
    • 1
  • Mayana Zatz
    • 1
    Email author
  1. 1.Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Biosciences InstituteUniversity of Sao Paulo (USP)São PauloBrazil
  2. 2.Department of Epidemiology and BiostatisticsCase Western Reserve UniversityClevelandUSA
  3. 3.Department of Cell BiologyAlbert Einstein College of MedicineBronxUSA
  4. 4.Department of PathologyUniversity Federal of Minas GeraisBelo HorizonteBrazil
  5. 5.Department of StatisticsUniversity of Sao Paulo (USP)Sao PauloBrazil
  6. 6.Departament of BiologyUniversity of LondrinaLondrinaBrazil

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