Probiotics promote cellular wound healing responses by modulating the PI3K and TGF-β/Smad signaling pathways.

IF 8.2 2区生物学 Q1 CELL BIOLOGY

Cell Communication and Signaling Pub Date : 2025-04-23 DOI:10.1186/s12964-025-02179-y

Sixuan Zhang, Yvonne Elbs-Glatz, Siyuan Tao, Steven Schmitt, Zhihao Li, Markus Rottmar, Katharina Maniura-Weber, Qun Ren

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引用次数: 0

Abstract

Background: Skin wound healing represents a dynamic and intricate biological process involving the coordinated efforts of various cellular and molecular components to restore tissue integrity and functionality. Among the myriads of cellular events orchestrating wound closure, fibroblast migration and the regulation of fibrosis play pivotal roles in determining the outcome of wound healing. In recent years, probiotic therapy has emerged as a promising strategy for modulating wound healing and fibrosis. Here, we aim to investigate the effect of bacterial probiotics on cell migration and anti-fibrotic response of human dermal fibroblast (HDFs).

Methods: Probiotic mixture BioK was co-cultured with HDFs in vitro to assess its impact on fibroblast migration, gene expression, and protein production associated with important processes in wound healing. Gene expression was investigated by transcriptomic analysis and confirmed by RT-qPCR. Protein levels of the identified genes were evaluated by ELISA. The role of lactic acid, produced by BioK, in mediating pH-related effects on fibroblast activity was further examined.

Results: We observed that BioK effectively promoted HDFs migration in vitro, which was found to be related to the up-regulation of genes involved in the phosphoinositide 3-kinase (PI3K) signaling pathways such as Paxillin, PI3K, PKC and ITG-β1. Interestingly, we also found that BioK down-regulated the expression of Nox-4, α-SMA and Col-I in TGF-Smad signaling pathways, which are involved in the differentiation of fibroblasts to myofibroblasts, and extracellular matrix type I collagen production, demonstrating its potential in reducing formation of fibrosis and scars. One of the acting factors for such down-regulation was identified to be BioK-produced lactic acid, which is known to lower the surrounding pH and to play a major role in fibroblast activity and wound healing.

Conclusions: This study demonstrates BioK's beneficial effects on fibroblast migration and its potential to mitigate fibrosis through pH modulation and pathway-specific gene regulation. These findings enhance our understanding of probiotic action on wound healing and offer promising therapeutic insights for the reduction of scar formation.

Clinical trial number: Not applicable.

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益生菌通过调节PI3K和TGF-β/Smad信号通路促进细胞伤口愈合反应。

背景：皮肤伤口愈合是一个动态和复杂的生物学过程，涉及各种细胞和分子成分的协调努力，以恢复组织的完整性和功能。在介导伤口愈合的众多细胞事件中，成纤维细胞迁移和纤维化调节在决定伤口愈合的结果中起着关键作用。近年来，益生菌治疗已成为一种有前途的策略，以调节伤口愈合和纤维化。在此，我们旨在研究细菌益生菌对人真皮成纤维细胞（HDFs）细胞迁移和抗纤维化反应的影响。方法：益生菌混合物BioK与HDFs体外共培养，以评估其对成纤维细胞迁移、基因表达和与伤口愈合相关的重要过程的蛋白质产生的影响。转录组学分析和RT-qPCR证实基因表达。ELISA法检测鉴定基因的蛋白水平。进一步研究了由BioK产生的乳酸在ph相关的成纤维细胞活性调节中的作用。结果：我们发现BioK能有效促进HDFs在体外的迁移，这与Paxillin、PI3K、PKC和ITG-β1等参与PI3K信号通路的基因上调有关。有趣的是，我们还发现BioK下调TGF-Smad信号通路中Nox-4、α-SMA和col - 1的表达，这些信号通路参与成纤维细胞向肌成纤维细胞的分化，以及细胞外基质I型胶原的产生，这表明BioK在减少纤维化和疤痕形成方面具有潜力。这种下调的作用因子之一被确定为biok产生的乳酸，它可以降低周围的pH值，并在成纤维细胞活性和伤口愈合中发挥重要作用。结论：本研究证明了BioK对成纤维细胞迁移的有益作用，以及其通过pH调节和通路特异性基因调控减轻纤维化的潜力。这些发现增强了我们对益生菌在伤口愈合中的作用的理解，并为减少疤痕形成提供了有希望的治疗见解。临床试验号：不适用。

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来源期刊

Cell Communication and Signaling CELL BIOLOGY-

CiteScore

11.00

自引率

0.00%

发文量

180

期刊介绍： Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.