Overview
Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by difficulties in social communication, repetitive behaviors, and restricted interests. The global prevalence continues to rise, with significant medical and socioeconomic burden. Traditional interventions — including behavioral, speech, and occupational therapy — target symptoms but do not address the underlying biological dysfunctions.
Recent studies highlight neuroinflammation as a key contributor to ASD pathophysiology, opening new therapeutic pathways through mesenchymal stem cell (MSC)–based therapy. MSCs’ immunomodulatory and neuroprotective properties make them a promising regenerative option to restore cellular balance in the brain.
Etiology of Autism Spectrum Disorder
ASD arises from a multifactorial interaction of genetic, epigenetic, environmental, and immunological factors.
- Genetic influence accounts for up to 80% of susceptibility, with hundreds of implicated genes affecting synaptic connectivity, neurotransmitter signaling, and immune regulation.
- Environmental factors such as maternal infections, toxin exposure, and advanced parental age increase risk.
- Maternal immune activation (MIA) has gained attention as inflammation during pregnancy alters fetal brain development. Elevated maternal cytokines, including IL-6 and IL-17A, can influence neuronal migration and cortical formation, potentially predisposing offspring to autistic behavior.
While the exact trigger remains unclear, converging evidence indicates that neuroinflammatory processes are a central mechanism connecting genetic vulnerability and environmental exposure.
Neuroinflammation in Autism
Neuroinflammation refers to chronic immune activation in the central nervous system (CNS), primarily mediated by microglia, astrocytes, and cytokines. In ASD, numerous post-mortem and imaging studies demonstrate persistent inflammatory activity in the brain:
- Activation of microglia and astroglia in the cerebral cortex, white matter, and cerebellum.
- Elevated inflammatory cytokines such as IL-6, TNF-α, MCP-1, and TGF-β in cerebrospinal fluid and serum.
- PET and MR-PET imaging reveal abnormal microglial activation across multiple brain regions, including the anterior cingulate cortex, fusiform gyrus, cerebellum, and orbitofrontal cortex.
These findings suggest that immune dysregulation and oxidative stress disrupt normal neural development, leading to synaptic dysfunction, impaired connectivity, and behavioral deficits typical of ASD. However, it remains uncertain whether neuroinflammation is a cause or a downstream effect of the disorder — likely, it plays both roles at different stages of neurodevelopment.
Rationale for Mesenchymal Stem Cell Therapy
Mesenchymal stem cells (MSC stem cells) are multipotent cells derived from sources such as bone marrow, adipose tissue, placenta, and umbilical cord. They possess powerful anti-inflammatory, immunomodulatory, and neuroprotective effects, making them ideal candidates for treating neuroinflammatory conditions.
Key biological mechanisms include:
- Secretion of growth factors, cytokines, and chemokines that regulate immune balance and stimulate tissue repair.
- Release of extracellular vesicles (EVs) and exosomes that transfer RNA, proteins, and signaling molecules to promote neurogenesis and synaptic restoration.
- Ability to cross the blood–brain barrier (BBB) indirectly through systemic signaling and paracrine communication.
Importantly, MSC stem cells adapt their function based on the immune environment: they exhibit pro-inflammatory activity when immune signaling is low, and anti-inflammatory behavior when inflammation is excessive. This dynamic response supports immune homeostasis in chronic neuroinflammatory disorders like ASD.
Preclinical Evidence
Multiple animal and cellular studies demonstrate MSC stem cells’ capacity to modulate inflammation and improve autistic-like behaviors:
- Cell culture studies show that MSC-conditioned medium reduces inflammatory cytokines (TNF-α, IL-6) and suppresses activation pathways such as NF-κB and JNK in microglial cells, confirming strong paracrine anti-inflammatory action.
- MSC-derived microvesicles and exosomes inhibit microglial activation and decrease proinflammatory signaling while promoting production of anti-inflammatory molecules like IL-10.
- In BTBR and valproic acid (VPA) mouse models of autism, MSC transplantation or intranasal administration of MSC-derived exosomes significantly improved sociability, reduced repetitive behaviors, and enhanced vocalization.
- These improvements correlated with increased brain-derived neurotrophic factor (BDNF) levels, greater hippocampal neurogenesis, and restoration of GABA receptor expression.
Collectively, these findings suggest that MSC stem cells and their secretory products restore neurological function through immune modulation, neurotrophic support, and synaptic plasticity.
Clinical Evidence
Although limited, early human studies indicate that MSC stem cells therapy is both safe and potentially effective in children with ASD:
- Phase I/II clinical trial using umbilical cord MSC stem cells (UC-MSC stem cells) and cord blood mononuclear cells showed significant behavioral improvement compared to rehabilitation therapy alone.
- Combination therapy achieved the highest reduction in Autism Behavior Checklist (ABC) and Childhood Autism Rating Scale (CARS) scores.
- Improvements included better eye contact, social interaction, and reduced repetitive actions.
- No severe adverse events were observed, confirming treatment safety.
- Phase I study with intravenous allogeneic cord-tissue MSC infusions in children aged 4–9 years showed measurable progress in socialization and reduced symptom severity across standardized assessments.
- Case studies of UC-MSC infusions demonstrated improved verbal communication, emotional expression, and decreased behavioral rigidity, without any significant side effects.
Together, these results highlight MSC therapy’s ability to improve core symptoms while maintaining an excellent safety profile. Still, researchers emphasize the need for larger, randomized controlled trials to validate efficacy and optimize dosage, frequency, and administration route (intravenous, intrathecal, or intranasal).
Potential Mechanisms of Improvement
MSC-based therapy addresses multiple biological pathways implicated in autism:
- Reduction of neuroinflammation and microglial overactivation.
- Regulation of cytokine imbalance, shifting from pro-inflammatory (IL-6, TNF-α) to anti-inflammatory profiles (IL-10, TGF-β).
- Promotion of synaptic repair and neurogenesis, improving cognitive and behavioral function.
- Support of mitochondrial activity and oxidative stress balance.
- Secretion of neurotrophic factors such as BDNF and NGF, enhancing neuronal survival and communication.
This multi-target mechanism explains why stem cell therapy can achieve broad symptomatic improvements beyond behavioral interventions alone.
Limitations and Future Directions
While findings are promising, limitations include small sample sizes, variability in cell types and administration protocols, and short follow-up durations. Future research should focus on:
- Establishing standardized treatment guidelines for UC-MSC dosage and delivery.
- Long-term monitoring of cognitive and neurological outcomes.
- Investigating exosome-based therapies as non-cell alternatives for easier clinical translation.
- Exploring combination protocols integrating stem cell therapy with behavioral and rehabilitative programs for maximal benefit.
Conclusion
This literature review underscores the critical role of neuroinflammation in autism and the emerging therapeutic potential of mesenchymal stem cell therapy to restore immune balance and neural connectivity.
Preclinical and early clinical data consistently show that MSC and UC-MSC treatments can reduce inflammation, enhance brain function, and improve behavioral outcomes safely.
With continued progress in stem cell therapy in Thailand and global research efforts, MSC-based regenerative medicine could soon become a cornerstone in managing ASD — moving treatment from symptom control to true biological repair.