Hindawi Publishing CorporationJournal of Biomedicine and BiotechnologyVolume 2012, Article ID 480289, 6 pagesdoi:10.1155/2012/480289
Review Article Autism Spectrum Disorders: Is Mesenchymal Stem Cell Personalized Therapy the Future? Dario Siniscalco,1, 2 Anna Sapone,3, 4 Alessandra Cirillo,5 Catia Giordano,1 Sabatino Maione,1 and Nicola Antonucci6 1 Division of Pharmacology “L. Donatelli”, Department of Experimental Medicine, Second University of Naples,Via S. Maria di Costantinopoli, 16-80138 Napoli, Italy2 Centre for Autism, La Forza del Silenzio, Caserta, 80138 Naples, Italy3 Department of Internal and Experimental Medicine “Magrassi-Lanzara”, Second University of Naples, 80138 Naples, Italy4 Center for Celiac Research and Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore,5 Division of Biotechnology and Molecular Biology “A. Cascino”, Department of Experimental Medicine, Second University of Naples,6 Biomedical Centre for Autism Research and Treatment, 70122 Bari, Italy
Correspondence should be addressed to Dario Siniscalco, email@example.com
Received 11 July 2011; Accepted 29 September 2011
Copyright 2012 Dario Siniscalco et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.
Autism and autism spectrum disorders (ASDs) are heterogeneous neurodevelopmental disorders. They are enigmatic conditionsthat have their origins in the interaction of genes and environmental factors. ASDs are characterized by dysfunctions in socialinteraction and communication skills, in addition to repetitive and stereotypic verbal and nonverbal behaviours. Immunedysfunction has been conﬁrmed with autistic children. There are no deﬁned mechanisms of pathogenesis or curative therapypresently available. Indeed, ASDs are still untreatable. Available treatments for autism can be divided into behavioural, nutritional,and medical approaches, although no deﬁned standard approach exists. Nowadays, stem cell therapy represents the great promisefor the future of molecular medicine. Among the stem cell population, mesenchymal stem cells (MSCs) show probably bestpotential good results in medical research. Due to the particular immune and neural dysregulation observed in ASDs, mesenchymalstem cell transplantation could oﬀer a unique tool to provide better resolution for this disease. 1. Autism Spectrum Disorders
of ASDs is unknown, likely it results from a complex combi-nation of genetic, environmental, and immunological factors
Autism and autism spectrum disorders (ASDs) are heteroge-
[5, 6]. This heritable disorder derives from genetic variations
neous neurodevelopmental disorders . They are enigmatic
in multiple genes , making its treatment particularly
conditions that have their origins in the interaction of
diﬃcult. Environment (i.e., air pollution, organophosphates,
genes and environmental factors. ASDs are characterized by
and heavy metals) also contributes to the incidence of ASDs
dysfunctions in social interaction and communication skills,
in addition to repetitive and stereotypic verbal and nonverbal
Frequency of these disorders is increasing: 56% reported
behaviours [2, 3]. Several biochemical events are associ-
increase in paediatric prevalence between 1991 and 1997
ated with ASDs: oxidative stress; endoplasmic reticulum
 until present rates of about 60 cases per 10,000 chil-
stress; decreased methylation capacity; limited production
dren, according to Center for Disease Control [10, 11].
of glutathione; mitochondrial dysfunction; intestinal dysbio-
ASDs are increasingly being recognized as a public health
sis; increased toxic metal burden; immune dysregulation;
problem . Pathophysiology and deﬁned mechanisms of
immune activation of neuroglial cells . The exact aetiology
pathogenesis of autism remain still unclear. There are no
drugs eﬀective for treatment of core symptoms of ASDs
surface of dishes when maintained in standard culture
. Indeed, ASDs are still untreatable. Current available
conditions; (2) express cytospeciﬁc cell surface markers, that
treatments for autism can be divided into behavioural,
is, CD105, CD90, and CD73, to be negative for other cell
nutritional, and pharmacological options, in addition to
surface markers, that is, CD45, CD34, CD14, and CD11b;
individual and family psychotherapy and other nonphar-
(3) possess the capacity to diﬀerentiate into mesenchymal
macologic interventions . However, no deﬁned stan-
lineages, under appropriate in vitro conditions . MSCs
dard approach exists . Pharmacological approaches are
can be isolated from diﬀerent tissues other than bone
direct towards neuropsychiatric disorders coassociated with
marrow: adipose tissue, liver, tendons, synovial membrane,
ASDs. Psycho-stimulants, alpha-2 agonists, beta blockers,
amniotic ﬂuid, placenta, umbilical cord, and teeth. MSCs
lithium, anticonvulsant mood stabilizers, atypical antipsy-
show a high expansion potential, genetic stability, stable
chotics, traditional antipsychotics, selective serotonin reup-
phenotype, high proliferation rate as adherent cells, and
take inhibitors, antidepressants, and antipsychotics, are
self-renew capacity and can be easily collected and shipped
drugs commonly prescribed [14–16]. Catatonia is treated
from the laboratory to the bedside and are compatible with
with lorazepam and bilateral electroconvulsive therapy .
diﬀerent delivery methods and formulations [38, 39]. In
Selective serotonin reuptake inhibitors are prescribed for the
addition, MSCs have two other extraordinary properties:
treatment of depression, anxiety, and obsessive-compulsive
they are able to migrate to sites of tissue injury, where they
are able to inhibit the release of proinﬂammatory cytokines
Other nonpsychotropic drugs which are supported by
and have strong immunosuppressive activity that renders
at least 1 or 2 prospective randomized controlled trials or
them a useful tool for successful autologous, as well as
1 systematic review include melatonin, acetylcholinesterase
heterologous, transplantations without requiring pharma-
inhibitors, naltrexone, carnitine, tetrahydrobiopterin, vita-
cological immunosuppression [40–43]. Besides, MSCs are
min C, hyperbaric oxygen treatment, immunomodulation
easily isolated from a small aspirate of bone marrow and
and anti-inﬂammatory treatments, oxytocin, and even music
expanded with high eﬃciency . Given that MSCs are
multipotent cells with a number of potential therapeutic
Alternative and complementary treatments, not suﬃ-
applications, and they represent a future powerful tool in
ciently supported by medical literature, include herbal reme-
regenerative medicine, including ASDs. Mesenchymal stem
dies, vitamin and mineral therapies, piracetam, elimina-
cells could be transplanted directly without genetic modiﬁ-
tion diets, chelation, cyproheptadine, famotidine, glutamate
cation or pretreatments. They simply eventually diﬀerentiate
antagonists, special dietary supplements, acupuncture, neu-
according to cues from the surrounding tissues and do
rofeedback, and sensory integration training [14, 19, 20]. On
not give uncontrollable growth or tumours. In clinical
the other hand, behavioural treatment could represent the
application, there is no problem with immune rejection
eﬀective intervention strategy for autism [21–23]. A plethora
because of their in vivo immunosuppressive properties [45,
of behavioural strategies and social skill trainings have been
46]. In addition, MSCs can readily be isolated from the
used [24–26]. However, it has been demonstrated that no
patients requiring transplant or from their parents. There is
deﬁnitive behavioural intervention completely improves all
also no tumour formation on transplantation . No moral
symptoms for all ASD patients [27, 28].
objection or ethical controversies are involved .
Summarizing, all these therapies indicate that further
In principle, mesenchymal stem cells can act through
research is needed to better address treatment of several
several possible mechanisms, that is, stimulating the plastic
medical conditions experienced by ASD patients .
response in the host damaged tissue, secreting survival-promoting growth factors, restoring synaptic transmitterrelease by providing local reinnervations, integrating into
2. Mesenchymal Stem Cells
existing neural and synaptic network, and reestablishingfunctional aﬀerent and eﬀerent connections . Since
Nowadays, stem cell therapy represents the great promise
MSCs have the capability to produce a large array of
for the future of molecular medicine. The progression of
trophic and growth factors both in vivo and in vitro. (MSCs
several diseases can be slowed or even blocked by stem cell
constitutively secrete interleukins (IL)-6, IL-7, IL-8, IL-11,
IL-12, IL-14, IL-15, macrophage colony-stimulating factor,
Among the stem cell population, mesenchymal stem cells
Flt-3 ligand, and stem-cell factor ). A more reasonable
(MSCs) show probably best potential good results in medical
explanation for the functional beneﬁt derived from MSC
research [31–33]. These cells are nonhematopoietic stem cells
transplantation is their paracrine activity, by which these
having a multilineage potential, as they have the capacity of
cells are able to produce factors that activate endogenous
diﬀerentiating into both mesenchymal and nonmesenchymal
restorative mechanisms within injured tissues contributing
lineages. MSCs are a population of progenitor cells of meso-
to recovery of function lost as a result of lesions [49, 51].
dermal origin found principally in the bone marrow ofadults, giving rise to skeletal muscle cells, blood, fat, vascular,
3. Autism, Personalized Therapy through
and urogenital systems, and to connective tissues throughout
Mesenchymal Stem Cells
the body [34–36]. According to the International Societyof Cellular Therapy, MSCs are deﬁned by the following
MSCs have a strong long-lasting immunosuppressive capac-
minimal set of criteria: (1) grown in adherence to plastic
ity . This extraordinary property is mediated via soluble
Anti-inﬂammatory cytokines overproduction
(IL-10) and IL-1β, TNF-α, and
Figure 1: Paracrine and immunomodulatory eﬀects as possible mechanisms of action of mesenchymal stem cells (MSCs) in autism spectrumdisorder (ASD) treatment. In humans, ASDs are associated with immune alterations and pro-inﬂammatory cytokines (i.e., IL-1β) over-production. These cytokines are able to trigger pro-inﬂammatory cellular events. Data from in vitro models show that MSCs are able to aﬀectnot only T cells, but also other cells of the immune system (i.e., NK cells). Immunoregulatory properties of MSCs are through secretionof large amounts of several bioactive molecules (paracrine activity), that is, PGE-2, IL-10. These molecules cause the inhibition or theunresponsiveness of T-cell mediated responses.
factors. MSCs are able to inhibit the proliferation of CD8+
It has been demonstrated that in postmortem brains
and CD4+ T lymphocytes and natural killer (NK) cells,
from ASD patients there is evidence of abnormal functioning
to suppress the immunoglobulin production by plasma
and cerebellum alterations [61–63]. Indeed, ASD subjects
cells, to inhibit the maturation of dendritic cells (DCs)
show a decreased number of Purkinje cells in the cere-
and the proliferation of regulatory T cells . It has
bellum . These changes could reﬂect defective cortical
been demonstrated that MSCs are also able to inhibit T
organization in ASDs development. In addition, autism is
lymphocyte pro-inﬂammatory cytokine production in vitro
associated with dysregulation in the maturation and plas-
[54, 55], as well as in vivo . Their ability to modulate
ticity of dendritic spine morphology . Restoring injured
the immune system opens a wide range of cell-mediated
brain functioning could be achieved by stem-cell-based cell
applications, not only for autoimmune diseases and graft-
replacement . Indeed, transplanted MSCs are able to
versus-host disease. Due to the particular immune system
promote synaptic plasticity and functional recovery and
dysregulation observed in ASDs [57, 58], mesenchymal stem
rescue cerebellar Purkinje cells [67, 68]. Challenging newest
cell transplantation could oﬀer a unique tool to provide
study from Deng et al. suggests that granulocyte colony-
better resolution for this disease. Indeed, in ASDs patho-
stimulating factor (G-CSF) is able to mobilize MSCs into
genesis, innate and adaptive immunity changes have been
peripheral blood. These mobilized MSCs are incorporated
reported . ASD patients show an imbalance in CD3+,
and integrate into damaged brain in craniocerebral injured
CD4+, and CD8+ T cells, as well as in NK cells. In addition,
mice, ameliorating the eﬀect of trauma . It is noteworthy
peripheral blood mononuclear cells (PBMCs) extracted from
that MSC ability to migrate to the sites of injury and
ASD patients are able to overproduce IL-1β resulting in
participate in the repair process is a key issue in tissue repair
long-term immune alterations . MSC-mediated immune
. Also by this way, MSC therapy could restore the altered
suppressive activity could restore this immune imbalance
brain organization seen in autistic subjects (Table 1).
(Figure 1). Indeed, MSC immunoregulatory eﬀects strongly
A key dilemma in stem-cell-based therapy for autism
inhibit T-cell recognition and expansion by inhibiting TNF-α
treatment is whether endogenous or exogenous MSC admin-
and INF-γ production and increasing IL-10 levels .
istration is the best way of stem cell delivery. Endogenous
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“Not being able to go home after • Postpoliosyndrome , after polio-infection 1945, weakness left • Mammacarcinoma 1988: mamma-amputation and post-• Medication: carbaspirin calcium, metformin, simvastatin, • Mobility: did walk with rollator outdoors for longer distances • Personal care: independent; shopping with neighbor/children; • Relations/occupancy: divorced in 1988, two