Innovative Strategies for Efferocytosis in Tissue Repair

The Role of Efferocytosis in Tissue Regeneration Processes

Efferocytosis, the process by which phagocytes clear apoptotic cells, plays a fundamental role in tissue repair and regeneration. This process is critical for maintaining tissue homeostasis and preventing chronic inflammation, which can hinder effective healing. In healthy tissues, the timely clearance of apoptotic cells by macrophages and other phagocytes promotes resolution of inflammation and facilitates the transition from the inflammatory phase to tissue regeneration (Zhang et al., 2025). Efferocytosis not only prevents secondary necrosis but also triggers pro-resolving signals that enhance tissue repair mechanisms.

During the early phases of tissue repair, efferocytosis helps to modulate the inflammatory response. The recognition of apoptotic cells involves the release of “find-me” signals, such as ATP and LPC, which recruit phagocytes to the site of injury. Upon arrival, phagocytes recognize “eat-me” signals on the surface of apoptotic cells, primarily phosphatidylserine (PS), leading to their engulfment (Zhang et al., 2025). A failure in this process can lead to chronic inflammation and impaired healing, underscoring the significance of efferocytosis in regenerative medicine.

Mechanisms of Efferocytosis and Its Impact on Inflammation

Efferocytosis occurs in three distinct phases: recognition, engulfment, and degradation. In the recognition phase, apoptotic cells release signaling molecules that attract phagocytes. During engulfment, phagocytes recognize apoptotic cells through surface receptors that interact with PS and other markers. The degradation phase involves the internalization of apoptotic cells into phagosomes, which fuse with lysosomes for degradation (Zhang et al., 2025).

The significance of efferocytosis extends beyond mere cell clearance. It also plays a critical role in modulating inflammation. For instance, efferocytosis can suppress the production of pro-inflammatory cytokines, such as TNF-α and IL-6, while promoting the secretion of anti-inflammatory cytokines, including IL-10 and TGF-β (Zhang et al., 2025). This shift in cytokine profiles facilitates the transition from an inflammatory to a reparative state, enhancing tissue regeneration following injury.

Enhancing Efferocytosis through Tissue Engineering Approaches

Tissue engineering has emerged as a promising strategy to enhance efferocytosis and promote tissue repair. By integrating bioactive factors, scaffold materials, and cellular components, researchers have developed innovative approaches to modulate efferocytosis and improve therapeutic outcomes.

Bioactive Factors

Bioactive factors can be utilized to stimulate efferocytosis by enhancing the phagocytic capacity of macrophages. For example, the incorporation of pro-resolving mediators, such as resolvins and lipoxins, into tissue scaffolds can improve macrophage function and promote efferocytosis (Zhang et al., 2025). These mediators not only enhance apoptotic cell clearance but also facilitate macrophage polarization towards an anti-inflammatory phenotype, creating a beneficial environment for tissue repair.

Scaffold Materials

Scaffold materials play a vital role in tissue engineering by providing structural support and facilitating cell interactions. Biodegradable scaffolds can be designed to mimic the extracellular matrix, enhancing macrophage infiltration and promoting efferocytosis. Recent studies have shown that scaffolds incorporated with signaling molecules can significantly increase the efficiency of efferocytosis and improve healing outcomes in various tissues (Zhang et al., 2025).

For instance, scaffolds that release specific apoptotic signals can enhance the clearance of senescent cells, promoting a more favorable microenvironment for tissue regeneration. In bone tissue repair, the regulation of efferocytosis through scaffold design has been shown to accelerate healing processes and improve overall outcomes (Zhang et al., 2025).

Applications of Efferocytosis in Bone and Skin Repair

Bone Repair

In bone tissue, efferocytosis is essential for maintaining homeostasis and facilitating repair following injury. The clearance of apoptotic osteoblasts and other cellular debris by macrophages promotes a pro-repair environment, supporting osteogenesis and angiogenesis. Recent advances have demonstrated that enhancing efferocytosis through biomaterials and bioactive factors can significantly improve bone healing outcomes (Zhang et al., 2025).

For example, scaffolds designed to release bioactive molecules such as BMP-2 have shown promise in regulating macrophage efferocytosis and promoting osteogenic differentiation, leading to enhanced bone repair. Additionally, the manipulation of macrophage polarization towards an M2 phenotype through efferocytosis has been linked to improved bone regeneration, suggesting that targeted strategies to enhance this process may be beneficial in clinical settings (Zhang et al., 2025).

Skin Repair

Efferocytosis also plays a crucial role in skin wound healing. The timely clearance of apoptotic neutrophils by macrophages not only prevents secondary necrosis but also promotes the transition from inflammation to tissue regeneration. Studies have shown that enhancing efferocytosis in the wound microenvironment can improve healing rates and reduce scar formation (Zhang et al., 2025).

Biomaterials that facilitate efferocytosis in skin repair have been developed, demonstrating the potential for improved therapeutic outcomes. By promoting macrophage polarization and enhancing the clearance of apoptotic cells, these materials can effectively modulate the inflammatory response and accelerate wound healing (Zhang et al., 2025).

Future Perspectives on Efferocytosis Regulation in Therapeutics

The potential of efferocytosis as a therapeutic target in regenerative medicine is vast. Future research should aim to further elucidate the molecular mechanisms governing efferocytosis and explore innovative strategies for enhancing this process in various tissues. By developing advanced biomaterials and therapeutic interventions that modulate efferocytosis, it may be possible to address chronic inflammatory conditions and improve tissue repair outcomes.

Moreover, the integration of personalized medicine approaches, such as tailoring efferocytosis-enhancing therapies to individual patient profiles, holds promise for optimizing treatment efficacy and reducing adverse effects. Continued collaboration between researchers, clinicians, and engineers will be essential for translating these findings into clinical practice, ultimately improving patient outcomes and quality of life.

FAQ

What is efferocytosis?

Efferocytosis is the process by which phagocytes, such as macrophages, clear apoptotic cells from tissues, preventing secondary necrosis and chronic inflammation.

How does efferocytosis impact tissue repair?

Efferocytosis promotes the resolution of inflammation, enhances macrophage polarization towards an anti-inflammatory phenotype, and facilitates tissue regeneration by clearing cellular debris.

What are some strategies for enhancing efferocytosis in tissue engineering?

Strategies for enhancing efferocytosis include the incorporation of bioactive factors, the design of scaffold materials that mimic the extracellular matrix, and the modulation of macrophage function through targeted therapies.

What role does efferocytosis play in bone repair?

Efferocytosis is critical for bone repair, as it helps clear apoptotic cells, supports osteogenesis, and promotes a pro-repair environment, ultimately enhancing healing outcomes.

How is efferocytosis relevant to skin healing?

In skin healing, efferocytosis of apoptotic neutrophils by macrophages prevents secondary necrosis and facilitates the transition from inflammation to tissue regeneration, improving wound healing rates.

References

1. Zhang, Y.-Q., Nie, R., Feng, Z.-Y., Fan, M.-H., Shen, Z.-X., Zhang, X.-Z., Zhang, Q.-Y., Zou, C.-Y., Zhang, J.-Y., Huang, K., Mou, L.-P., Xie, H.-Q. (2025). Efferocytosis in tissue engineering: A comprehensive review of emerging therapeutic strategies for enhanced tissue repair and regeneration. Bioactive Materials, 3, 413-425. https://doi.org/10.1016/j.bioactmat.2025.05.026

2. Zhang, Y.-Q., Nie, R., Feng, Z.-Y., Fan, M.-H., Shen, Z.-X., Zhang, X.-Z., Zhang, Q.-Y., Zou, C.-Y., Zhang, J.-Y., Huang, K., Mou, L.-P., Xie, H.-Q. (2025). Efferocytosis in tissue engineering: A comprehensive review of emerging therapeutic strategies for enhanced tissue repair and regeneration. Bioactive Materials, 3, 413-425. https://doi.org/10.1016/j.bioactmat.2025.05.026

3. Zhang, Y.-Q., Nie, R., Feng, Z.-Y., Fan, M.-H., Shen, Z.-X., Zhang, X.-Z., Zhang, Q.-Y., Zou, C.-Y., Zhang, J.-Y., Huang, K., Mou, L.-P., Xie, H.-Q. (2025). Efferocytosis in tissue engineering: A comprehensive review of emerging therapeutic strategies for enhanced tissue repair and regeneration. Bioactive Materials, 3, 413-425. https://doi.org/10.1016/j.bioactmat.2025.05.026

4. Zhang, Y.-Q., Nie, R., Feng, Z.-Y., Fan, M.-H., Shen, Z.-X., Zhang, X.-Z., Zhang, Q.-Y., Zou, C.-Y., Zhang, J.-Y., Huang, K., Mou, L.-P., Xie, H.-Q. (2025). Efferocytosis in tissue engineering: A comprehensive review of emerging therapeutic strategies for enhanced tissue repair and regeneration. Bioactive Materials, 3, 413-425. https://doi.org/10.1016/j.bioactmat.2025.05.026

5. Zhang, Y.-Q., Nie, R., Feng, Z.-Y., Fan, M.-H., Shen, Z.-X., Zhang, X.-Z., Zhang, Q.-Y., Zou, C.-Y., Zhang, J.-Y., Huang, K., Mou, L.-P., Xie, H.-Q. (2025). Efferocytosis in tissue engineering: A comprehensive review of emerging therapeutic strategies for enhanced tissue repair and regeneration. Bioactive Materials, 3, 413-425. https://doi.org/10.1016/j.bioactmat.2025.05.026