Dynamic Interplay Between Autophagy and Oxidative Stress in Stem Cells: Implications for Regenerative Medicine

Abstract

The crosstalk between autophagy and oxidative stress is a cornerstone of stem cell biology. These processes are tightly interwoven, forming a regulatory network that impacts stem cell survival, self-renewal, and differentiation. Autophagy, a cellular recycling mechanism, ensures the removal of damaged organelles and proteins, thereby maintaining cellular integrity and metabolic balance. Oxidative stress, driven by the accumulation of reactive oxygen species (ROS), can act as both a signalling molecule and a source of cellular damage, depending on its levels and context. The interplay between autophagy and oxidative stress shapes stem cell fate by either promoting survival under stress conditions or triggering senescence and apoptosis when dysregulated. Recent evidence underscores the bidirectional relationship between these processes, where autophagy mitigates oxidative damage by degrading ROS-generating organelles, and oxidative stress can induce autophagy as a protective response. This crosstalk is critical not only for preserving stem cell function but also for addressing age-related decline and enhancing regenerative potential. Understanding the molecular mechanisms that govern this interplay offers novel insights into stem cell biology and therapeutic strategies. This review delves into the intricate molecular dynamics of autophagy and oxidative stress in stem cells, emphasizing their synergistic roles in health, disease, and regenerative medicine applications.

Keywords: ROS; ageing; antioxidant; autophagy; mitophagy; regenerative medicine; stem cell.

Figure 1

The phases of autophagy in stem cells. AMPK initiates the autophagic process by activation of the ULK1 complex and removing the inhibitory effect of mTOR. During nucleation, the activated ULK1/2 complex orchestrates the recruitment of the class III PI3K complex, which includes VPS34, VPS15, Beclin-1, and ATG14, with Tat-Beclin1 functioning as an mTORC1-independent autophagy inducer. The phagophore expands into the isolation membrane, which elongates and closes to form the autophagosome. This process is driven by two ubiquitin-like conjugation systems: one involving the ATG12–ATG5–ATG16L1 complex, and the other mediating the lipidation of LC3-I with phosphatidylethanolamine (PE) to generate LC3-II, a hallmark of autophagosome maturation. Both conjugation pathways critically depend on the E1-like enzyme ATG7.

Figure 2

Oxidative stress gradient regulates stem cell fate. Low levels of oxidative stress promote stem cell self-renewal, while moderate levels drive differentiation. However, excessive oxidative stress leads to cellular damage and senescence, impairing stem cell function and regenerative potential. Maintaining an optimal oxidative balance is crucial for sustaining stem cell homeostasis and function.

Figure 3

Redox balance triggered by FOXO3 and Nrf2 in stem cells. In response to oxidative stress, the transcription factors FOXO3 and Nrf2 are activated and orchestrate distinct yet complementary cryoprotective programmes. FOXO3 enhances the expression of different autophagy-related genes (e.g., LC3, BNIP3, MAP1LC3B, GABA, RAPL1, and PARK2) and antioxidant enzymes (e.g., catalase and SOD). Nrf2 upregulates antioxidant defences (e.g., HO-1, GPx, and SOD) and promotes autophagy via p62/SQSTM1. Together, the autophagy and antioxidant defences promote stem cell resistance to oxidative stress and limit cell death. This coordinated response preserves redox homeostasis and counteracts premature stem cell ageing. FOXO3 and Nrf2 thus represent promising therapeutic targets in age-related and oxidative stress-driven pathologies.

Figure 4

Pharmacological interventions targeting oxidative stress and autophagy to enhance tissue regenerative potential. Impaired autophagic activity and excessive oxidative stress in aged stem cells negatively impact their ability to regenerate. Elevated levels of ROS lead to mitochondrial dysfunction, as well as the oxidation of proteins and lipids, and DNA damage, ultimately resulting in stem cell senescence. In contrast, lower ROS levels combined with sufficient autophagic activity promote mitophagy and bolster antioxidant defences, which support stem cell renewal and differentiation, thereby enhancing tissue regeneration. Therapeutic agents such as NAC, MitoQ, Trolox, rapamycin, and 3-MA can help reduce oxidative stress and promote autophagy, ultimately restoring the homeostasis and regenerative capacity of stem cells.