Ma Xuan, Wei Wuhan, Zeng Han, Dong Miao
Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 33 Badachu Road, Shijingshan District, Beijing 100144, PR China.
Department of Breast Surgery, Beijing Chao-Yang Hospital, Capital Medical University, 5 Jingyuan Rd, Beijing 100043, PR China.
Tissue Cell. 2025 Dec;97:103049. doi: 10.1016/j.tice.2025.103049. Epub 2025 Jul 22.
Aging impairs the regenerative capacity of the skin, leading to delayed wound healing and chronic tissue damage. Recent advances have highlighted the therapeutic potential of dedifferentiated fat (DFAT) cells and their secreted exosomes. However, the bioactivity and molecular mechanisms of exosomes derived from DFAT spheroids (DFAT-Sps-Exos) in aging wound repair remain unclear. This study aims to evaluate the regenerative effects of DFAT-Sps-Exos on senescent fibroblasts and aging skin wounds, and to elucidate the underlying molecular mechanisms involved in their activity.
Human DFAT cells were cultured under three-dimensional conditions to form spheroids and produce DFAT-Sps-Exos. The effects of these exosomes were assessed using in vitro assays in senescent fibroblasts and in vivo full-thickness wound models in aged mice. Cellular senescence, proliferation, migration, and oxidative stress levels were evaluated. Transcriptome sequencing was conducted to investigate mechanistic pathways.
DFAT-Sps-Exos enhanced fibroblast proliferation and migration, reduced ROS, and downregulated senescence markers P16 and P21 more effectively than conventional DFAT-Exos. In vivo, they significantly accelerated wound healing and promoted neovascularization. Transcriptome analysis revealed suppression of the NF-κB/Serpine1 axis, and pathway interference assays confirmed this mechanism.
DFAT-Sps-Exos effectively recovered senescent fibroblast function and promoted aging wound repair by modulating the NF-κB/Serpine1 signaling pathway. These findings underscored their potential as a novel exosome-based therapeutic approach for aging wound healing.
衰老会损害皮肤的再生能力，导致伤口愈合延迟和慢性组织损伤。最近的进展突出了去分化脂肪（DFAT）细胞及其分泌的外泌体的治疗潜力。然而，源自DFAT球体（DFAT-Sps-Exos）的外泌体在衰老伤口修复中的生物活性和分子机制仍不清楚。本研究旨在评估DFAT-Sps-Exos对衰老成纤维细胞和衰老皮肤伤口的再生作用，并阐明其活性所涉及的潜在分子机制。
将人DFAT细胞在三维条件下培养以形成球体并产生DFAT-Sps-Exos。使用体外实验评估这些外泌体对衰老成纤维细胞的作用，并在老年小鼠体内进行全层伤口模型实验。评估细胞衰老、增殖、迁移和氧化应激水平。进行转录组测序以研究作用机制途径。
与传统的DFAT-Exos相比，DFAT-Sps-Exos更有效地增强了成纤维细胞的增殖和迁移，降低了活性氧，并下调了衰老标志物P16和P21。在体内，它们显著加速了伤口愈合并促进了新血管形成。转录组分析揭示了NF-κB/丝氨酸蛋白酶抑制剂1轴的抑制作用，并且通路干扰实验证实了这一机制。
DFAT-Sps-Exos通过调节NF-κB/丝氨酸蛋白酶抑制剂1信号通路有效地恢复了衰老成纤维细胞的功能并促进了衰老伤口修复。这些发现强调了它们作为一种基于外泌体的新型衰老伤口愈合治疗方法的潜力。
