Autism spectrum disorders
Autism spectrum disorders (ASDs) are multiple heterogeneous neurodevelopmental disorders.16 Neuroinflammation and immune dysregulation influence the origin of ASDs. Due to the neurobiologic changes underlying ASD development, cell-based therapies, including the use of mesenchymal stem cells (MSCs), have been applied to ASDs.16 Stem cells show specific immunologic properties that make them promising candidates for treating ASDs.17
The exact mechanisms of action of MSCs to restore function in patients with ASDs are largely unknown, but proposed mechanisms include:
- synthesizing and releasing anti-inflammatory cytokines and survival-promoting growth factors
- integrating into the existing neural and synaptic network
- restoring plasticity.18
In a study of transplantation of human cord blood cells and umbilical cord–derived MSCs for patients with ASDs, Bradstreet et al19 found a statistically significant difference on scores for domains of speech, sociability, sensory, and overall health, as well as reductions in the total scores, in those who received transplants compared to their pretreatment values.
In another study of stem cell therapy for ASDs, Lv et al20 demonstrated the safety and efficacy of combined transplantation of human cord blood cells and umbilical cord–derived MSCs in treating children with ASDs. The transplantations included 4 stem cell IV infusions and intrathecal injections once a week. Statistically significant differences were shown at 24 weeks post-treatment. Although this nonrandomized, open-label, single-center Phase I/II trial cannot be relied on for any definitive conclusions, it suggests an important area of investigation.20
The vascular aspects of ASDs’ pathogenesis should not be overlooked. For example, specific temporal lobe areas associated with facial recognition, social interaction, and language comprehension have been demonstrated to be hypoperfused in children with ASDs, but not in controls. The degree of hypoperfusion and resulting hypoxia correlates with the severity of ASD symptoms. The damage causing hypoperfusion of temporal areas was associated with the onset of autism-like disorders. Damage of the amygdala, hippocampus, or other temporal structures induces permanent or transient autistic-like characteristics, such as unexpressive faces, little eye contact, and motor stereotypes. Clinically, temporal lobe damage by viral and other means has been implicated in the development of ASD in children and adults. Hypoperfusion may contribute to defects, not only by inducing hypoxia, but also by allowing for abnormal metabolite or neurotransmitter accumulation. This is one of the reasons glutamate toxicity has been implicated in ASD. The augmentation of perfusion through stimulation of angiogenesis by stem cells should allow for metabolite clearance and restoration of functionality. Vargas et al21 compared brain autopsy samples from 11 children with ASDs to those of 7 age-matched controls. They demonstrated an active neuroinflammatory process in the cerebral cortex, white matter, and cerebellum of patients with ASDs, both by immunohistochemistry and morphology.21
Multiple studies have confirmed that the systemic administration of cord blood cells is sufficient to induce neuroregeneration.22,23 Angiogenesis has been experimentally demonstrated in peripheral artery disease, myocardial ischemia, and stroke, and has direct implications on brain repair.24 Immune dysregulation25,26 and immune modulation27 also are addressed by stem cell treatment, which provides a promising avenue for battling ASDs.
Like attention-deficit/hyperactivity disorder and obsessive-compulsive disorder, ASDs are neurodevelopmental conditions. Advances based on the use of stem cells hold great promise for understanding, diagnosing and, possibly, treating these psychiatric disorders.28,29
Depression
Neuropsychiatric disorders arise from deviations from the regular differentiation process of the CNS, leading to altered neuronal connectivity. Relatively subtle abnormalities in the size and number of cells in the prefrontal cortex and basal ganglia have been observed in patients with depressive disorder and Tourette syndrome.30 Fibroblast-derived iPSCs generate serotonergic neurons through the exposure of the cells to growth factors and modulators of signaling pathways. If these serotonergic neurons are made from the patients’ own cells, they can be used to screen for new therapeutics and elucidate the unknown mechanisms through which current medications may function.31 This development could lead to the discovery of new medication targets and new insights into the molecular biology of depression.32
Deficiencies of brain-derived neurotrophic factor (BDNF) have a role in depression, anxiety, and other neuropsychiatric illnesses. The acute behavioral effects of selective serotonin reuptake inhibitors and tricyclic antidepressants seem to require BDNF signaling, which suggests that BDNF holds great potential as a therapeutic agent. Cell therapies focused on correcting BDNF deficiencies in mice have had some success.33
Dysregulation of GABAergic neurons has also been implicated in depression and anxiety. Patients with major depressive disorder have reduced gamma aminobutyric acid (GABA) receptors in the parahippocampal and lateral temporal lobes.34
Ultimately, the development of differentiation protocols for serotonergic and GABAergic neuronal populations will pave the way for examining the role of these populations in the pathogenesis of depression and anxiety, and may eventually open the door for cell-based therapies in humans.35
Studies have demonstrated a reduction in the density of pyramidal and nonpyramidal neurons in the anterior cingulate cortex of patients with schizophrenia and bipolar disorder,36 glial reduction in the subgenual prefrontal cortex in mood disorders,37 and morphometric evidence for neuronal and glial prefrontal cell pathology in major depressive disorder.38 The potential for stem cells to repair such pathology may be of clinical benefit to many patients.
Aside from their other suggested clinical uses, iPSCs may be utilized in new pathways for research on the biology and pharmacology of major depressive disorder.39
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