Autophagy in Tissue Repair and Regeneration

Abstract

Autophagy is a cellular recycling system that, through the sequestration and degradation of intracellular components regulates multiple cellular functions to maintain cellular homeostasis and survival. Dysregulation of autophagy is closely associated with the development of physiological alterations and human diseases, including the loss of regenerative capacity. Tissue regeneration is a highly complex process that relies on the coordinated interplay of several cellular processes, such as injury sensing, defense responses, cell proliferation, differentiation, migration, and cellular senescence. These processes act synergistically to repair or replace damaged tissues and restore their morphology and function. In this review, we examine the evidence supporting the involvement of the autophagy pathway in the different cellular mechanisms comprising the processes of regeneration and repair across different regenerative contexts. Additionally, we explore how modulating autophagy can enhance or accelerate regeneration and repair, highlighting autophagy as a promising therapeutic target in regenerative medicine for the development of autophagy-based treatments for human diseases.

Keywords: autophagy; injury; planarian; regeneration; senescence; stem cell; tissue repair.

Figure 1

Overview of Autophagy Pathways. Autophagy utilizes distinct pathways to degrade intracellular components, including damaged proteins, organelles, and pathogens, ensuring cellular homeostasis. (a) Macroautophagy involves the sequestration of cytoplasmic material within a double-membrane vesicle known as the autophagosome. The autophagosome subsequently fuses with the lysosome, where lysosomal enzymes degrade its contents. (b) Chaperone-mediated autophagy (CMA) selectively targets individual proteins containing the KFERQ-like motif. These proteins are recognized by the chaperone Hsc70, transported to the lysosomal membrane, and translocated into the lysosomal lumen through the receptor LAMP2A for degradation. (c) Microautophagy involves the direct uptake of cargo by lysosomes or late endosomes through membrane invagination or protrusion. Once internalized, the autophagic cargo is delivered to the lysosomal lumen, where it undergoes enzymatic degradation. Created in BioRender. Gonzalez Estevez, C. (2025) https://BioRender.com/a77a953.

Figure 2

Key Molecular Steps in the Autophagy Pathway. Autophagy is initiated in response to various stimuli, such as nutrient deprivation, misfolded proteins, reactive oxygen species (ROS), or infections. These signals activate the ULK1 complex, which triggers the formation of the isolation membrane (phagophore) in the cytosol. As the phagophore elongates, cytosolic cargo—including misfolded proteins, damaged organelles, and pathogens—is sequestered through the coordinated action of ATG proteins, which function as a ubiquitin-like conjugation system. Upon elongation and closure, the phagophore matures into a double-membrane vesicle known as the autophagosome. The autophagosome then fuses with the lysosome to form the autolysosome, where lysosomal hydrolytic enzymes degrade the cargo and the inner autophagosomal membrane, facilitating recycling of the breakdown products. Created in BioRender. Gonzalez Estevez, C. (2025) https://BioRender.com/d35c194.

Figure 3

Regeneration. Regeneration is a biological process in which organisms restore lost tissues, structures, or even entire bodies. Certain species, such as planarians and Hydra, exhibit whole-body regeneration, where they can regenerate an entire organism from a small body fragment. Structural regeneration occurs after limb or fin resection in axolotl and zebrafish, respectively. Some organs, such as our skin after superficial damage (deep wounds can only be repaired) and zebrafish heart after cryoinjury or transection, possess notable regenerative capacities, allowing them to restore their structure and function following injury. Additionally, specific cells, such as neurons, can regenerate damaged components, like axons, through a process known as axonal regeneration. Created in BioRender. Gonzalez Estevez, C. (2025) https://BioRender.com/n86y859.

Figure 4

Autophagy: a Potential Player in Regeneration. In this model, autophagy serves as a central mechanism driving tissue regeneration and repair across diverse regenerative species. It orchestrates multiple processes critical to regeneration, including injury sensing and damage response, rapid immune activation, and clearance of invading pathogens. Autophagy further promotes cellular proliferation, migration, and cell cycle re-entry necessary for tissue repair. Additionally, it facilitates tissue remodeling to ensure correct proportions and size during regeneration. Importantly, autophagy also regulates cellular senescence, a key biological process in successful tissue regeneration. Created in BioRender. Gonzalez Estevez, C. (2025) https://BioRender.com/n98d270 and edited with Adobe Illustrator.

Figure 5

Pharmacological Modulation of Autophagy Enhances Tissue Regeneration. Pharmacological targeting of the autophagy pathway represents a promising therapeutic strategy for promoting tissue repair and regeneration due to the critical role of autophagy in regulating various components of the regenerative process. Several well-established autophagy inducers, including rapamycin, resveratrol, metformin, and trehalose, have demonstrated significant efficacy in enhancing muscle regeneration, accelerating wound healing, and promoting axonal and cardiac tissue repair. Created in BioRender. Gonzalez Estevez, C. (2025) https://BioRender.com/y97n890 and edited with Adobe Illustrator.