Mesenchymal stem cell senescence as a potency brake: causes, consequences, and cures

Abstract

Mesenchymal stem cells (MSCs) are widely investigated for regenerative medicine, tissue repair, immunomodulation, and selected cancer-related applications because of their multilineage differentiation potential, paracrine activity, immunoregulatory properties, and capacity to home to sites of injury. However, the therapeutic potential of MSCs depends not only on their tissue source or surface-marker expression but also on their functional state. MSC senescence is not a single phenotypic alteration; rather, it reflects the combined effects of persistent DNA damage response activation, disruption of mitochondrial and metabolic homeostasis, remodeling of epigenetic and secretory networks, and loss of proteostasis. Collectively, these changes drive MSCs toward reduced proliferative capacity, dysregulated paracrine signaling, impaired immunomodulatory activity, and diminished tissue-repair potential, thereby compromising cell-product potency and batch-to-batch consistency. This review summarizes the molecular mechanisms underlying MSC senescence, its source-specific functional consequences, and emerging rejuvenation strategies, with an emphasis on MSC quality control, potency assessment, and clinical translation.