Psychiatric disorders are complex conditions that emerge from an interplay of genetic, neurochemical, and environmental factors. Despite significant advances, treatments remain largely symptom-targeted and do not fully address the underlying biological mechanisms. There is increasing interest in regenerative approaches that may modulate these mechanisms directly. This viewpoint aims to evaluate the potential of mesenchymal stem cells (MSCs) as a novel adjunctive strategy in psychiatry by integrating current pathophysiological models with emerging stem cell research [1].

The pathophysiology of psychiatric disorders is not yet fully understood, but it is believed to result from the interaction of multiple genetic, neurochemical, and environmental factors. To describe a few major psychiatric disorders, for instance, in the etiology of bipolar disorder (BD), it is thought that imbalances in monoaminergic neurotransmitter systems, particularly dopamine and serotonin, play a role. Furthermore, studies have shown alterations in brain-derived neurotrophic factor, nerve growth factor, neurotrophin-3, and neurotrophin-4 in patients diagnosed with BD, suggesting that reduced neurotrophic signaling is a molecular mechanism associated with decreased neuroplasticity [2]. Other proposed mechanisms include mitochondrial dysfunction, oxidative stress, immuneinflammatory imbalance, and disruption of the hypothalamicpituitary-adrenal axis. Additionally, neuroimaging studies have provided evidence of “changes in regional activity, functional connectivity, neuronal activity, and bioenergetics associated with BD,” while anatomical studies of post-mortem brain tissue from BD patients have revealed dendritic spine loss in the dorsolateral prefrontal cortex [3].

Studies on schizophrenia suggest that genetic factors may explain approximately 80% of schizophrenia risk. Specifically, about 30% of these genes play a role in the function of presynaptic and postsynaptic elements of the glutamatergic synapse by affecting N-methyl-D-aspartate receptor transmission [4]. In schizophrenia, there is approximately a 25% enlargement of the lateral ventricles and about a 2% reduction in total brain volume, predominantly in gray matter. This decrease in gray matter is primarily observed in the frontal and temporal lobes and the hippocampus. Evidence indicates decreased activity in the dorsolateral prefrontal cortex and increased activity in the medial frontal cortex both at rest and during executive tasks. Neurotransmitter abnormalities are also central to explaining the pathophysiology of schizophrenia, with dopamine, serotonin, glutamate, and gamma-aminobutyric acid (GABA) playing essential roles [5].

Major depressive disorder is caused by an imbalance of neurotransmitters (especially serotonin, norepinephrine, and dopamine) resulting from dysfunction in complex neuroregulation systems and neural circuits. GABA, an inhibitory neurotransmitter, and both glutamate and glycine, which are major excitatory neurotransmitters, have also been found to play a role in the etiology of depression. Depressed patients have been found to have lower plasma, cerebrospinal fluid, and brain GABA levels. GABA is believed to exert its antidepressant effect by inhibiting ascending monoaminergic pathways, including the mesocortical and mesolimbic systems [6].

This complexity in the etiology of psychiatric disorders presents challenges in treatment. While significant progress has been made with pharmacological treatments, patients’ responses to therapies remain highly heterogeneous. Therefore, the development of stem cell-based neuroregenerative approaches may have a significant impact.

Stem cells, with their ability to self-renew and differentiate into various cell types, hold great potential in regenerative medicine, disease treatment, and tissue repair [7]. These cells, classified into embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and MSCs, offer promising potential in tissue regeneration and the treatment of diseases [8]. ESCs derived from the inner cell mass of mammalian blastocysts retain pluripotency and can differentiate into cells of all three germ layers. However, the clinical use of ESCs is associated with ethical concerns and issues of immune rejection. To overcome these problems, iPSCs have been developed, which are alternative stem cells derived from the patient’s own somatic cells and reprogrammed to exhibit pluripotent properties [9].

MSC has emerged as one of the most suitable stem cell types for clinical applications without raising ethical concerns. MSCs, which can be obtained from various sources such as bone marrow, adipose tissue, placenta, and umbilical cord, have low immunogenicity, reducing the risk of rejection in patients and providing tissue compatibility advantages. Additionally, MSCs are known to be effective in tissue repair and reducing inflammation [10].

MSCs hold potential for regenerative therapy in neurological diseases [11]. Previous studies have shown that bone marrow MSCs express genes and proteins associated with the neural lineage and possess in vitro neurogenic differentiation potential [12]. Moreover, studies have demonstrated that brain MSC transplantation in animal models of Parkinson’s disease, Huntington’s disease, and multiple sclerosis results in migration to brain regions, integration into lesion sites, and, most importantly, improvements in neurobehavioral test results [13].

In experimental models of psychiatric disorders, MSCs and their extracellular vesicles (EVs) have demonstrated promising results. In an experimental study on mice with schizophrenia induced by phencyclidine, it was shown that the behavioral phenotypes of these mice improved following intracranial transplantation of MSCs [14]. In another study, EVs derived from MSCs were intranasally administered to phencyclidine-induced schizophrenic mouse models, and these vesicles were found to accumulate specifically in the prefrontal cortex, leading to behavioral improvements [15]. Experimental stem cell studies in BD and depression have not yet been reported in the literature.

Despite their promise, MSC-based therapies face significant translational challenges. These include optimal delivery methods (e.g., intranasal vs. intravenous vs. intracerebral), scalability of MSC production, long-term safety (e.g., tumorigenicity), and the lack of large-scale clinical trials. Moreover, ethical considerations remain, particularly regarding the use of fetal or perinatal tissue sources and the commercialization of unproven therapies [16].

In summary, while current clinical evidence for MSCs in psychiatric disorders remains limited, preclinical studies show potential for modulating key pathophysiological mechanisms such as inflammation, neurodegeneration, and neuroplasticity. Future research should focus on rigorous clinical trials, standardized protocols, and ethical deployment of MSC-based therapies. As our understanding grows, stem cell therapy may become a valuable component of integrative psychiatric care.