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
- 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
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
- 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
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
- Atladóttir HO, Pedersen MG, Thorsen P, et al. Association of family
history of autoimmune diseases and autism spectrum disorders. Pediatrics
- Stigler K, Sweeten T, Posey D, McDougle C. Autism and immune factors: a
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- Enstrom AM, Van de Water JA, Ashwood P. Autoimmunity in autism. Curr Opin
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- Gesundheit B, Rosenzweig JP, Naor D, et al. Immunological and autoimmune
considerations of autism spectrum disorders. J Autoimmun 2013; 44:1–7.
- 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.
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- Torres AR, Sweeten TL, Cutler A, et al. The association and linkage of
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- Torres AR, Westover JB, Gibbons C, Johnson RC, Ward DC. Activating killer-cell
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significantly increased in autism. Brain Behav Immun 2012; 26:1122–7.
- Torres AR, Westover JB, Rosenspire AJ. HLA immune function genes in autism.
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- Diamond B, Honig G, Mader S, Brimberg L, Volpe BT. Brain-reactive antibodies
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- 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
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- Wang P, Lin M, Pedrosa E, Hrabovsky A, Zhang Z, Guo W, Lachman HM, Zheng
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