Department of Dermatology, China Academy of Chinese Medical Science, Xiyuan Hospital, Beijing, 100091, China.
Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division, The 4th Medical Center of Chinese PLA General Hospital, Beijing, 100048, China.
Adv Sci (Weinh). 2023 Sep;10(25):e2300414. doi: 10.1002/advs.202300414. Epub 2023 Jun 30.
Ferroptosis plays an essential role in the development of diabetes and its complications, suggesting potential therapeutic strategies targeting ferroptosis. Secretory autophagosomes (SAPs) carrying cytoplasmic cargoes have been recognized as novel nano-warrior to defeat diseases. Here, it is hypothesized that SAPs derived from human umbilical vein endothelial cells (HUVECs) can restore the function of skin repair cells by inhibiting ferroptosis to promote diabetic wound healing. High glucose (HG)-caused ferroptosis in human dermal fibroblasts (HDFs) is observed in vitro, which results in impaired cellular function. SAPs successfully inhibit ferroptosis in HG-HDFs, thereby improving their proliferation and migration. Further research show that the inhibitory effect of SAPs on ferroptosis resulted from a decrease in endoplasmic reticulum (ER) stress-regulated generation of free ferrous ions (Fe ) in HG-HDFs and an increase in exosome release to discharge free Fe from HG-HDFs. Additionally, SAPs promote the proliferation, migration, and tube formation of HG-HUVECs. Then the SAPs are loaded into gelatin-methacryloyl (GelMA) hydrogels to fabricate functional wound dressings. The results demonstrate the therapeutic effect of Gel-SAPs on diabetic wounds by restoring the normal behavior of skin repair cells. These findings suggest a promising SAP-based strategy for the treatment of ferroptosis-associated diseases.
铁死亡在糖尿病及其并发症的发生发展中起着重要作用，这提示针对铁死亡的治疗策略可能具有潜在的疗效。携带细胞质 cargo 的分泌型自噬体（SAPs）已被认为是一种新型的纳米战士，可用于对抗疾病。在这里，我们假设来源于人脐静脉内皮细胞（HUVECs）的 SAPs 可以通过抑制铁死亡来恢复皮肤修复细胞的功能，从而促进糖尿病伤口愈合。在体外观察到高葡萄糖（HG）引起的人真皮成纤维细胞（HDFs）发生铁死亡，导致细胞功能受损。SAPs 成功抑制了 HG-HDFs 中的铁死亡，从而提高了它们的增殖和迁移能力。进一步的研究表明，SAPs 抑制铁死亡的作用是由于 HG-HDFs 中内质网（ER）应激调节的游离亚铁离子（Fe ）生成减少，以及外泌体释放增加，从而将游离 Fe 从 HG-HDFs 中排出。此外，SAPs 还促进了 HG-HUVECs 的增殖、迁移和管腔形成。然后，将 SAPs 载入明胶甲基丙烯酰（GelMA）水凝胶中，构建功能性伤口敷料。结果表明，Gel-SAPs 通过恢复皮肤修复细胞的正常行为，对糖尿病伤口具有治疗作用。这些发现提示基于 SAP 的策略可能为治疗与铁死亡相关的疾病提供新的思路。
