Mitochondria refine mesenchymal stem cell-based therapies

AdvancesM esenchymal stem cells (MSCs) have become a focus of interest in cell therapy and regenerative medicine due to their ability to differentiate into multiple cell types, modulate the immune system, and promote tissue repair.To fully achieve their therapeutic capabilities, it is crucial to understand the internal signaling mechanisms that regulate their decisions to differentiate, proliferate, age, or survive.In this context, mitochondria play a major role and act far beyond their traditional role in energy production.Mitochondrial metabolism and dynamics have direct impacts on MSC stemness, differentiation, migration, survival, paracrine functions, and therapeutic efficacy.In their undifferentiated state, the metabolism of MSCs depends on glycolysis for energy, which preserves reactive oxygen species (ROS) levels low and maintains a basic mitochondrial structure that supports their stem-like qualities.As MSCs begin to differentiate, their energy demands increase; a metabolic shift toward oxidative phosphorylation (OXPHOS), increased mitochondrial biogenesis, and the development of a more mature mitochondrial architecture occur. 1 The balance of mitochondrial dynamics, mediated by fission (Drp1/ DLP1) and fusion (Mfn1/2, OPA1), controls the MSC differentiation.Forni et al. showed that during MSC adipogenesis and osteogenesis, mitochondrial networks become elongated and fused via upregulation of Mfn1/2, while knockdown of Mfn2 impaired respiration and differentiation. 2Similarly, Feng et al. revealed that spontaneous differentiation is accompanied by reduced Drp1 and increased OPA1 expression. 3In this line, mitophagy, a cellular process where dysfunctional or damaged mitochondria are recycled, preserves mitochondrial homeostasis that is critical for MSC proliferation and differentiation potential.These studies highlight a mechanistic pattern: mitochondrial fusion shifts MSCs toward OXPHOS, enabling differentiation, whereas fission maintains a glycolytic, stem-like state.Beyond intrinsic dynamics, the most exciting discovery in MSC biology is their ability to transfer mitochondria Mitochondria refine mesenchymal stem cell-based therapies