Stem Cells & Autism

New tool to better understand the causes leading to Autism
A promising therapy to treat Autism

Autism spectrum disorder (ASD) is a developmental disorder affecting the brain, with social and communication skills impairment that occur during the three first years of life.

It is a fast-growing disorder affecting 1 in 45 children as recently published by the Centers for Disease Control and Prevention (Zablotsky_2015.pdf). There are currently no medical cures or FDA approved therapies for ASD. Only symptoms associated with ASD can be treated.

Stem cell therapies represent a cell-type of choice to study ex-vivo the possible causes of Autism development. In addition, they constitute a promising alternative in regenerative medicine to treat diseases that would have been untreatable otherwise such as Autism.

Immunology in the pathogenesis of Autism

An accumulation of evidences show that immune dysfunctions may play a key role in the etiologies of Autism. These indications can be grouped in four categories:

  • Epidemiological studies: many works demonstrate an association between family history of autoimmune diseases and ASD (1).
  • Immune markers of inflammation such as cytokines were found in the blood of children with ASD (2) and in postmortem brain specimens (3-4).
  • Immunogenetic: some study showed an association between Human Leukocyte Antigen (HLA) and ASD (5-8).
  • Maternal immune alteration have also been linked to ASD where immune dysfunction in the mothers during pregnancy could alter brain development as seen in affected children (9-11). As an example, in utero, exposure to maternal autoantibodies can also target fetal brain and disrupt its development (12).

For more information, read the section “Maternal inflammation and Autism” on our website www.preventautism.com.

Stem cells: a new tool to better understand autism etiology

What are stem cells?

Stem cells are present in all the tissue of your body.

They all have:

- the potential to self-renew: stem cells can generate more identical stem cells

- the potential to differentiate: a stem cell can differentiate into a particular cell type to become a specialized cell with specific functions.

Depending on their origin, stem cells have some specificity.

Stem cells as a tool to study the causes leading to Autism

To assess the dysregulation occurring in human brain and potentially responsible for autism symptoms and development, studies were focusing on post mortem specimen from autistic patients. Because, their number is limited and offer little insight into a disorder that arises through the course of development, it is crucial to find alternative cells source to study autism.

A new category of stem cells localized in teeth namely Stem cells of human exfoliated deciduous teeth (SHEDs) has been recently used as a source of very accessible cells to study Autism. These SHED cells express neuronal markers upon differentiation, which makes them functionally related to nervous tissue cells.

In a study, the authors compared the expression profile of SHEDs from autistic patients with those of non-affected control patients (13).

They found that SHED cells from autistic patients are:

- enriched in genes expressed in brain.

- enriched in genes that were shown to be involved in autism development.

- SHED cells showed the same pattern of gene expression than the one found in brain specimen from ASD patients.

These cells are a good alternative to study ASD because several factors and pathways known to be dysregulated in ASD were also found in SHEDs cells from autistic patients.

In another study, stem cell models of ASD were generated by performing skin biopsies of ASD patients and then dedifferentiating these fibroblasts into human-induced pluripotent stem cells (hiPSCs) that can then give rise to any cells of the organism including brain cells. These cells retain the unique genetic signature of the individual from whom they were originally derived from (14).

An abundance of work has been recently published with the same scientific approach:

  • Identifying genes whose expression is altered in autistic patient versus matched controls using hiPSCs (15).
  • Knocking out a candidate gene (silencing its expression) and looking at the effects on neuronal progenitors. As an example, a recent study showed that CHD8 gene deletion impacts multiple pathways related to neural development thus directly regulating the brain volume (16).

Stem cells as a treatment for immune alterations linked to autism

Besides their self-renewal ability and differentiation potential, stem cells can also synthesize and release many factors regulating cell differentiation and tissue repair. Most importantly, stem cells have immune modulatory properties with anti-inflammatory actions that could be beneficial to Autism treatment:

  • They inhibit T cell proliferation (17).
  • They decrease pro-inflammatory cytokine production such as tumor necrosis factor-alpha (TNF-a) or interferon gamma (IFN-Υ) (18).
  • They inhibit natural killer (NK) cell proliferation, NK cell cytokine production (19).

Mesenchymal stem cells (MSCs) seem to be the most promising cells for therapies to treat ASD, due to their immunomodulatory actions that can restore the immune imbalance existing in ASD patients and their capacity to integrate into neural networks and restore neuronal plasticity (20).

In other neurological disorders such as Multiple Sclerosis (MS), therapy using MSCs have shown promising results with the induction of neuronal plasticity and remodeling of the brain (21).

Is MSCs therapy safe?

A systematic review and meta-analysis of clinical trials using MSCs including over a thousand participants concluded that MSCs are safe (22), with no significant adverse effects (23), including in children (24).

What are the outcomes in ASD patients?

Recently, a clinical trial examined the safety and efficacy of the transplantation of human cord blood mononuclear cell (CBMNCs) and/or human umbilical cord-derived mesenchymal stem cells (UCMSCs) in children with autism (25).

After the stem cell transplantation, the children affected by autism were followed for 24 weeks with no long term side effects (allergic or immunological reactions). The treatment showed efficacy with improvement in children behavior and increased beneficial effects when these stems cells were used together.

Nevertheless, this study should be considered with caution as it was a non-blinded and a non-randomized study. Furthermore, children behavior and abilities were scored using tests that were not included in Autism Diagnostic Observation Schedule (ADOS), the current gold standard for ASD diagnosis.

References

  1. Atladóttir HO, Pedersen MG, Thorsen P, et al. Association of family history of autoimmune diseases and autism spectrum disorders. Pediatrics 2009; 124(2):687–94.
  2. Stigler K, Sweeten T, Posey D, McDougle C. Autism and immune factors: a comprehensive review. Res Autism Spectr Disord 2009; 3:840–60.
  3. Enstrom AM, Van de Water JA, Ashwood P. Autoimmunity in autism. Curr Opin Investig Drugs 2009; 10: 463–73.
  4. Gesundheit B, Rosenzweig JP, Naor D, et al. Immunological and autoimmune considerations of autism spectrum disorders. J Autoimmun 2013; 44:1–7.
  5. Torres AR, Maciulis A, Stubbs EG, Cutler A, Odell D. The transmission disequilibrium test suggests that HLA-DR4 and DR13 are linked to autism spectrum disorder. Hum Immunol 2002; 63:311–6.
  6. Torres AR, Sweeten TL, Cutler A, et al. The association and linkage of the HLA-A2 class I allele with autism. Hum Immunol 2006; 67:346–51.
  7. Torres AR, Westover JB, Gibbons C, Johnson RC, Ward DC. Activating killer-cell immunoglobulin-like receptors (KIR) and their cognate HLA ligands are significantly increased in autism. Brain Behav Immun 2012; 26:1122–7.
  8. Torres AR, Westover JB, Rosenspire AJ. HLA immune function genes in autism. Autism Res Treat 2012; 2012: 959073.
  9. Jonakait GM. The effects of maternal inflammation on neuronal development: possible mechanisms. Int J Dev Neurosci. 2007; 25: 415-425
  10. Ashwood P, Wills S, Van de Water J. The immune response in autism: a new frontier for autism research. J Leukoc Biol. 2006; 80: 1-15.
  11. Patterson PH. Maternal infection and immune involvement in autism. Trends Mol Med. 2011; 17: 389-394.
  12. Diamond B, Honig G, Mader S, Brimberg L, Volpe BT. Brain-reactive antibodies and disease. Annu Rev Immunol 2013; 31: 345-385.
  13. Griesi-Oliveira K, Sunaga DY, Alvizi L, Vadasz E, Passos-Bueno MR. Stem cells as a good tool to investigate dysregulated biological systems in autism spectrum disorders. Autism Res. 2013 Oct; 6(5):354-61.
  14. Ardhanareeswaran K, Coppola G, Vaccarino F. The use of stem cells to study autism spectrum disorder. Yale J Biol Med. 2015 Mar 4; 88(1):5-16. eCollection 2015 Mar. Review.
  15. Germain ND, Chen PF, Plocik AM, Glatt-Deeley H, Brown J, Fink JJ, Bolduc KA, Robinson TM, Levine ES, Reiter LT, Graveley BR, Lalande M, Chamberlain SJ. Gene expression analysis of human induced pluripotent stem cell-derived neurons carrying copy number variants of chromosome 15q11-q13.1. Mol Autism. 2014 Aug 20; 5:44.
  16. Wang P, Lin M, Pedrosa E, Hrabovsky A, Zhang Z, Guo W, Lachman HM, Zheng D. CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in neurodevelopment. Mol Autism. 2015 Oct 19; 6:55.
  17. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105:1815–22.
  18. English K, Barry FP, Field-Corbett CP, Mahon BP. IFN-gamma and TNF-alpha differentially regulate immunomodulation by murine mesenchymal stem cells. Immunol Lett 2007; 110:91–100.
  19. Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, Moretta L. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 2008; 111:1327–33.
  20. Siniscalco D, Bradstreet JJ, Sych N, Antonucci N. Perspectives on the use of stem cells for autism treatment. Stem Cells Int. 2013; 2013:262438. Review.
  21. Freedman MS, Bar-Or A, Atkins HL, et al. The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group. Mult Scler 2010; 16(4):503–10.
  22. Lv YT, Zhang Y, Liu M, et al. Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism. J Transl Med 2013; 11:196.
  23. Prockop DJ, Brenner M, Fibbe WE, Horwitz E, Le Blanc K, Phinney DG, Simmons PJ, Sensebe L, Keating A. Defining the risks of mesenchymal stromal cell therapy. Cytotherapy. 2010 Sep; 12(5):576-8.
  24. Prasad VK, Lucas KG, Kleiner GI, et al. Efficacy and safety of ex vivo cultured adult human mesenchymal stem cells (Prochymal™) in pediatric patients with severe refractory acute graft-versus-host disease in a compassionate use study. Biol Blood Marrow Transplant 2011; 17(4):534–41.
  25. Lv YT, Zhang Y, Liu M, Qiuwaxi JN, Ashwood P, Cho SC, Huan Y, Ge RC, Chen XW, Wang ZJ, Kim BJ, Hu X. Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism. J Transl Med 2013; 11: 196
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