Innovative Stem Cell-Based Therapeutic Modalities to Address Major Depression and Treatment-Resistant Depression: A Review.

Depression is among the most widespread mental health conditions worldwide, with a significant number of patients showing inadequate responses to pharmacological treatments. Despite the development of numerous pharmacological therapies over the past six decades, a substantial proportion of patients with major depressive disorder (MDD) remain unresponsive to conventional therapies, prompting the exploration of innovative therapeutic strategies. This review critically examines the potential of stem cell-based therapies as a novel alternative to conventional antidepressant treatments, with a particular focus on individuals diagnosed with MDD. This study explores the molecular pathways that mediate neuroinflammatory responses in MDD, emphasizing the contributions of key pro-inflammatory cytokines to impaired neuroplasticity, mitochondrial dysfunction, and heightened oxidative stress. In addition, this study discusses the immunomodulatory properties of mesenchymal stromal cells (MSCs), highlighting their capacity to enhance antiinflammatory signaling, promote neurogenesis, and restore neurotransmitter homeostasis. Moreover, this review underscores the neuroprotective role of MSCs in mitigating oxidative stress-induced neuronal injury, with particular emphasis on their ability to secrete neurotrophic factors such as brain-derived neurotrophic factor (BDNF), which support neuronal integrity and survival.