Numerous studies have identified mitochondrial dysfunction in certain individuals with depression, characterized by altered mitochondrial structure and function, including decreased ATP production. This dysfunction is accompanied by the generation of free radicals and oxidative stress, which escalate as the disease progresses (Singh et al., 2019). While reactive oxygen species (ROS) at normal levels serve as important signaling molecules in neuronal function, excessive ROS in the presence of low antioxidant levels can be harmful to neurons. Heightened oxidative stress may exacerbate mitochondrial damage, leading to increased apoptosis and the release of inflammatory signals, thereby damaging cells in the brain (Sies and Jones, 2020). Overall, mitochondrial dysfunction may trigger the activation of apoptosis, releasing damage-associated molecular patterns and amplifying inflammatory mechanisms. The resulting oxidative stress may contribute to the accelerated cellular senescence observed in patients with depression.

Mounting evidence indicates the pivotal role of neuroimmunity in mood disorder development and remission (Koo and Wohleb, 2021). Microglia, among the central nervous system’s (CNS) most diverse cell types, exhibit heterogeneity across developmental stages, colonization sites, and disease states. They perform various functions, including phagocytosis of cellular debris, promotion of neurogenesis, and synaptic pruning, as well as release cytokines and chemokines (Tan et al., 2020; Ceasrine and Bilbo, 2021). Microglial activation, traditionally categorized as neurotoxic (M1-phenotype microglia) or neuroprotective (M2-phenotype microglia), is heterogeneous. Microglia are divided into the M1 (classical activation) and M2 (alternative activation) phenotypes based on their activation status (Glass et al., 2010; Luo and Chen, 2012). M1 microglia, expressing proinflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin [IL]-1β, IL-6, inducible nitric oxide synthase [iNOS], and CCL2), may contribute to neurotoxic outcomes by disrupting the neurotrophic system (Kwon and Koh, 2020). Conversely, M2-phenotype microglia release different mediators (Ym1, Arg1, IL-10, IL-4, and TGF-β) to counteract inflammation-induced CNS damage (Liu et al., 2020). Pathological studies have observed increased expression of TNF-α, IL, IL-1β, IL-6, and C-X3-C modality chemokine receptor 1 (CX3CR1) in the brain of patients with depression (Rahimian et al., 2021). Studies have also reported a significant increase in mRNA expression of Toll-like receptors (TLRs) TLR3, TLR4, and TLR7 in the prefrontal cortex of individuals with depression, suggesting microglial activation toward a proinflammatory state and an enhanced inflammatory response (Pandey et al., 2019). Additionally, heightened microglia activation has been observed in the white matter region of the dorsal anterior cingulate gyrus in suicidal patients with depression, although the expression levels of IL-1β, TNF-α, and IL-10 were not elevated (Torres-Platas et al., 2014).

T helper 17 cells (Th17) play a crucial role in regulatory T-cell (Treg) development and function, with the balance between these cell types crucial for immune homeostasis (Cui et al., 2021). Under normal physiological conditions, Th17 cells regulate hippocampal growth and maintain the structural integrity of the brain without detrimental effects on the CNS. However, in individuals with depression, peripheral T cells exhibit poor adaptability to the proinflammatory environment, correlating positively with Th17 cells (Davami et al., 2016). Patients with depression show elevated levels of IL-17 and reduced Treg cell numbers, leading to an increased Th17/Treg ratio. Furthermore, a study encompassing 33 cohort or case-control studies examined changes in absolute versus relative peripheral blood immune cell counts between individuals with depression and matched controls. A meta-analysis of 27 of these studies, involving 1,286 patients with depression and 991 controls, found that compared with controls, patients with depression have significantly higher absolute counts of CD4⁺ T cells, significantly lower relative counts of Th1 and Th2, and significantly higher mean absolute counts of B lymphocytes (Foley É et al., 2023). Taken together, the bidirectional communication network between the CNS and immune system plays a pivotal role in the pathological process of depression, with both acute and chronic stress contributing to the development of depression through neuroimmune mechanisms.

Evidence suggests that the brains of patients with depression have a lower antioxidant capacity and higher oxidative damage than those of healthy controls. Mitochondrial dysfunction, often associated with depression and other neuropsychiatric disorders, serves as a significant source of oxidative damage. In addition, neuroinflammation, prevalent in the brains of patients with depression, contributes significantly to ROS production (Riveros et al., 2022). MSCs have been shown to reduce inflammation and oxidative stress in numerous diseases, including colitis, pancreatitis, arthritis, sepsis, stroke, myocardial infarction, and hyperoxic lung injury (Stavely and Nurgali, 2020). Hydrogen sulfide (H2S), known for its potent anti-inflammatory and antioxidant properties, exhibits reduced plasma levels in patients with depression and directly correlates with the severity of depression (Yang et al., 2021). MSCs possess the ability to generate H2S, which is essential for maintaining MSCs function and increasing their survival and proliferation under inflammatory and oxidative conditions (Yang et al., 2016). Furthermore, H2S has been demonstrated to upregulate Sirt1 expression and alleviate depression-like symptoms induced by sleep deprivation in rats, attenuating levels of proinflammatory cytokines (IL-1β, IL-6, TNF-α, and CCL2), and augmenting anti-inflammatory cytokines in the hippocampus (Kang et al., 2021). Several studies have indicated that MSCs increase the expression of anti-inflammatory factors, enhance antioxidant defenses, and improve the behavioral manifestations of depression (Salem et al., 2018; Cui et al., 2019; Wang et al., 2024). However, no reports directly link MSCs to ROS or mitochondrial function modulation for improving depressive symptoms. Due to the complexity of the brain microenvironment, the precise mechanism by which MSCs protect patients with depression from inflammation-induced oxidative stress remains to be explored.

Cytokines, including interleukins, tumor necrosis factors, and interferons, are important regulators of depression-associated inflammation. Prior research suggests that the implantation of SCs and their secretory properties contribute to the production and downregulation of a large number of anti-inflammatory factors (Cui et al., 2019), exerting anti-inflammatory and neuroprotective effects akin to antidepressants. For example Salem et al. (2018), bone marrow-derived MSCs (BMSCs) ameliorate brain inflammation by decreasing immunoreactivity to insulin growth factor-1 receptor, synaptophysin, and cachectomycin-3, thereby mitigating inflammation and oxidative damage. Furthermore, SC transplantation improves the inflammatory environment of the brain by downregulating the levels of inflammatory factors such as IL-6, IL-1 and upregulating the anti-inflammatory factor IL- 10. In a recent study by Wang et al., using a rat model of depression induced by chronic unpredictable mild stress and lipopolysaccharide (LPS) co-stimulation, human umbilical cord blood MSC (hUC-MSC) treatment led to decreased expression of proinflammatory cytokines, such as IL-6 and TNF-α, and increased expression of anti-inflammatory cytokines, such as IL-10 and TNF-β. Notably, a unique feature of this study was that rats with depression reliably maintained their depressive behavior owing to continuous LPS administration during hUC-MSC treatment. The study demonstrated that hUC-MSC treatment induced the expression of anti-inflammatory cytokines, effectively counteracting LPS-induced hippocampal injury (Wang et al., 2024).

Microglia, resident immune cells of the CNS, play a key role in maintaining brain homeostasis. Overactivation of microglia is implicated in the pathogenesis of depression (Aguzzi et al., 2013), with activated microglia typically categorized into the M1 and M2 types. M1 microglia, through the expression of proinflammatory cytokines, can induce neurotrophic system dysfunction, leading to neurotoxicity (Kwon and Koh, 2020). Conversely, M2 microglia, considered the neuroprotective phenotype, release various mediators (Ym1, Arg1, IL-10, IL-4, and TGF- β) to counteract inflammation-induced CNS damage (Liu et al., 2020). A growing body of evidence suggests that neuroinflammation mediated by M1-type polarized microglia plays a key role in the pathogenesis of depression. MSCs possess immunomodulatory properties that induce reprogramming of microglia from a proinflammatory (M1) to an anti-inflammatory (M2) phenotype (Li et al., 2020; Liu et al., 2021). In a rat model of subarachnoid hemorrhage, immunomodulatory MSCs promoted the differentiation of microglial cells into the anti-inflammatory M2 phenotype, significantly improving the inflammatory environment in the brain (Na et al., 2020). This “calming” effect may involve the chemokine axis CX3CR1/CX3CL1, released by activated MSCs, which upregulates the expression of the CX3CR1/CX3CL1 axis, inhibits microglial activation, and converts activated cells to a quiescent state. SC-derived exosomes (Exos) exhibit immunomodulatory functions; in a model of cerebral ischemia/reperfusion injury, BMSC-Exos induced a shift from M1-type polarized microglia to the M2 phenotype. In vitro models confirmed that BMSC-Exos attenuate neuronal death by modulating microglial polarization. Moreover, Li et al. confirmed that in a mouse model of chronic unpredictable stress-induced depression, hUC-MSCs altered the polarization of microglia to improve depressive symptoms by reducing the activation of complement C3a-C3aR signaling (Li et al., 2020).

Studies have shown that patients with depression have increased numbers of natural (neutrophils and monocytes) and adaptive immune cells (Th1, Th17, and plasma cells) in their peripheral circulatory system (Drevets et al., 2022). In addition, a recent study established, for the first time, a link between depression and the mechanical characteristics of all major blood cell types. This study showed that depression, especially persistent depression lasting more than 2 years, is associated with increased blood cell deformability. Although all major blood cells tended to exhibit increased deformability, lymphocytes, monocytes, and neutrophils were the most affected. This may indicate deterioration in cellular function and further explain the generalized lethargy observed in many patients with depression (Walther et al., 2022). MSCs exhibit immunomodulatory functions, capable of enhancing or inhibiting immune cell proliferation and responses, thus influencing immune reconstitution.

The immunosuppressive mechanism of SCs mainly regulates a variety of immune cells by secreting IDO, TGF-β, NO and other factors (Li et al., 2023). MSCs have been found to maintain macrophages and dendritic cells in an immature or anti-inflammatory state, thereby preventing the activation of effector T cells and promoting the production of Tregs (Gao et al., 2016; Jiang and Xu, 2020). BMSCs acquire T-cell suppressive properties in the presence of IFN-γ produced by CD4⁺ helper T cells and cytotoxic CD8⁺ T lymphocytes (Rivera-Cruz et al., 2017). Huc-MSCs inhibit T lymphocyte proliferation, downregulate RORγt mRNA and protein expression, decrease the proportion of Th17 cells, and increase the proportion of Tregs in the spleen. Furthermore, they downregulate RORγt and Foxp3 expression in the joints. Nevertheless, research elucidating the mechanism of MSC-mediated immune microenvironment remodeling in depression models remains limited. Despite a growing body of research on the immunomodulatory effects of MSCs and depression, the precise molecular mechanisms underlying their interactions require further study.