Frostbite is the most common cold injury and is caused by both immediate cold-induced cell death and the gradual development of localized inflammation and tissue ischemia. Delayed healing of frostbite often leads to scar formation, which not only causes psychological distress but also tends to result in the development of secondary malignant tumors. Therefore, a rapid healing method for frostbite wounds is urgently needed. Herein, we used a mouse skin model of frostbite injury to evaluate the recovery process after frostbite. Moreover, single-cell transcriptomics was used to determine the patterns of changes in monocytes, macrophages, epidermal cells and fibroblasts during frostbite. Most importantly, human-induced pluripotent stem cell (hiPSC) -derived skin organoids combining with gelatin-hydrogel were constructed for the treatment of frostbite. The results showed that skin organoid treatment significantly accelerated wound healing by reducing early inflammation after frostbite and increasing the proportions of epidermal stem cells. Moreover, in the later stage of wound healing, skin organoids reduced the overall proportions of fibroblasts, significantly reduced fibroblast-to-myofibroblast transition by regulating the integrin α5β1-FAK pathway, and remodeled the extracellular matrix (ECM) through degradation and reassembly mechanisms, facilitating the restoration of physiological ECM and reducing the abundance of ECM associated with abnormal scar formation. These results highlight the potential application of organoids for promoting the reversal of frostbite-related injury and the recovery of skin functions. This study provides a new therapeutic alternative for patients suffering from disfigurement and skin dysfunction caused by frostbite.

中文翻译：

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皮肤类器官移植促进组织修复，冻伤时无疤痕。


冻伤是最常见的冷损伤，由即刻寒冷诱导的细胞死亡和局部炎症和组织缺血的逐渐发展引起。冻伤愈合延迟往往导致瘢痕形成，这不仅会引起心理困扰，还往往会导致继发性恶性肿瘤的发展。因此，迫切需要一种快速愈合的冻伤伤口方法。在此，我们使用冻伤小鼠皮肤模型来评估冻伤后的恢复过程。此外，单细胞转录组学用于确定冻伤过程中单核细胞、巨噬细胞、表皮细胞和成纤维细胞的变化模式。最重要的是，构建了人诱导多能干细胞 （hiPSC） 衍生的皮肤类器官与明胶水凝胶相结合，用于治疗冻伤。结果表明，皮肤类器官治疗通过减少冻伤后的早期炎症和增加表皮干细胞的比例，显着加速伤口愈合。此外，在伤口愈合后期，皮肤类器官降低了成纤维细胞的总体比例，通过调节整合素 α5β1-FAK 通路显着减少了成纤维细胞向肌成纤维细胞的转变，并通过降解和重组机制重塑细胞外基质 （ECM），促进生理 ECM 的恢复，减少与异常疤痕形成相关的 ECM 丰度。这些结果突出了类器官在促进冻伤相关损伤逆转和皮肤功能恢复方面的潜在应用。本研究为冻伤引起的毁容和皮肤功能障碍患者提供了一种新的治疗选择。