Research Insight - A Fibrous Scaffold Loaded with BMSC-Derived Apoptotic Bodies Promotes Wound Healing via Inducing Macrophage Polarization

Recently, Ning Hu and Leilei Qin from the First Affiliated Hospital of Chongqing Medical University, together with Yonghua Yuan from Chongqing Medical University, have made new progress in the field of skin wound repair and regenerative medicine. The related findings have been published in the internationally recognized journal *Genes & Diseases* (IF = 9.4, Q1 journal).

The skin is the largest organ of the human body and serves as the first line of defense against external injury. Upon skin damage, the body initiates a series of precisely regulated repair processes, in which macrophages play a critical role. These immune cells exhibit high plasticity and can differentiate into pro-inflammatory M1 phenotypes or anti-inflammatory, pro-repair M2 phenotypes in response to different microenvironmental signals. During normal wound healing, macrophages gradually transition from an early pro-inflammatory state to a later anti-inflammatory reparative state, thereby coordinating inflammation resolution, angiogenesis, and tissue remodeling. However, disruption of this polarization process can lead to persistent inflammation, delayed healing, or even chronic wounds. Therefore, effective regulation of macrophage polarization toward the reparative M2 phenotype has become a key strategy for promoting wound healing.

In recent years, mesenchymal stem cells (MSCs) have attracted considerable attention in tissue repair due to their strong paracrine and immunomodulatory capabilities. Extracellular vesicles released by MSCs, particularly apoptotic bodies generated during apoptosis, have been shown to efficiently deliver bioactive molecules and regulate recipient cell functions. Previous studies have demonstrated that apoptotic bodies can be recognized and internalized by macrophages, promoting their polarization toward the M2 phenotype; however, the underlying mechanisms remain unclear. Meanwhile, achieving sustained release and targeted delivery of apoptotic bodies at wound sites remains a major challenge for translational applications.

Based on this, the present study successfully constructed a polycaprolactone fibrous scaffold loaded with bone marrow mesenchymal stem cell–derived apoptotic bodies (BMSC-ABs) and systematically elucidated its mechanism in promoting wound healing through regulation of macrophage polarization. The study demonstrated that the scaffold enables localized sustained release of apoptotic bodies via electrospinning. Enriched microRNA miR-21a-5p within the apoptotic bodies targets and suppresses the expression of the CCL-1 gene in macrophages, thereby driving the polarization of M0 macrophages toward the reparative M2 phenotype. The polarized M2 macrophages not only secrete anti-inflammatory factors such as IL-10 and TGF-β to effectively alleviate local inflammation, but also upregulate pro-angiogenic factors such as vascular endothelial growth factor, thereby synergistically promoting collagen deposition and neovascularization. In animal models, this scaffold significantly accelerated the healing process of full-thickness skin defects, demonstrating favorable biocompatibility and therapeutic safety.

This study, for the first time, reveals the molecular pathway by which apoptotic bodies regulate macrophage polarization via the miR-21a-5p/CCL-1 axis, and develops a novel composite material with both sustained-release and synergistic functions, providing important experimental evidence and strategic insights for the treatment of chronic wounds and immune dysregulation–related diseases.

In this study, the research team employed the AniView multimodal in vivo imaging system (Guangzhou Biolight Biotechnology Co., Ltd.) to monitor the dynamic distribution and retention time of BMSC-ABs at wound sites and surrounding tissues in mice. The results showed that fluorescence signals of Cy7-NHS–labeled BMSC-ABs at the wound site remained clearly detectable within 2 days after injury and gradually decreased over time. By 2 days post-injection, the signal intensity declined to below 10% of the initial level, indicating that locally injected BMSC-ABs can be effectively retained at the wound site for a sufficient duration.

Article Link：

https://doi.org/10.1016/j.gendis.2024.101388