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


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


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



Beta Actin


Amyotrophic Lateral Sclerosis

basic FGF

Basic fibroblast; growth factor


Blood Brain Barrier


Brain-derived Neurotrophic Factor


Bovine serum albumin




cluster of differentiation; molecule 11B


carboxyfluorescein diacetate succinimidyl ester


Choline acetyltransferase


Proto-oncogene c-Myc


4′,6-Diamidino-2-phenylindole dihydrochloride


Dulbecco’s Modified Eagle Medium


Embryoid bodies


Endothelial Cell Growth Medium


Epidermal growth factor


Fetal Bovine Serum


Food and Drug Administration


Fibroblast growth factors


Glyceraldehyde 3-phosphate dehydrogenase


Granulocyte colony-stimulating factor


glial cell derived neurotrophic factor


Glial fibrillary acidic protein


Glucagon-like Peptide 1


Granulocyte-macrophage colony-stimulating factor


glutathione peroxidase


Glutathione reductase


Hanks’ Balanced Salt Solution


Interferon gamma


Insulin-like growth factor 1


Interleukin 10


Interleukin 12p70


Interleukin 13


Interleukin 15


Interleukin 17A


Interleukin 1ra


Interleukin 1β




Interleukin 4


Interleukin 5


Interleukin 6


Interleukin 7


Interleukin 8


Interleukin 9


C-X-C motif chemokine 10


Induced Pluripotent Stem Cells


Kruppel-like factor 4


Monocyte chemoattractant protein-1


Macrophage Inflammatory Proteins −1α


Macrophage Inflammatory Proteins -1 β


Motor neuron diseases


Motor neuron and pancreas homeobox 1/Homeobox HB9


Mesenchymal stromal cells

NB media

Neuro Basal Media


factor nuclear kappa B


Nerve Growth Factor


neural progenitor cells


Neural Stem Cells


octamer-binding transcription factor 4


paw grip endurance


Phosphate-buffered saline


Platelet-derived growth factor C


Regulated on Activation, Normal T Cell Expressed and Secreted


ROCK inhibitor


Real Time Quantitative Polymerase Chain Reaction


Sonic Hedgehog


superoxide dismutase 1


SRY (sex determining region Y)-box 2


Tumor necrosis fator α


Vascular endothelial growth factor



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)


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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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