School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, People's Republic of China.
Cell Resource Bank and Integrated Cell Preparation Center of Xiaoshan District, Hangzhou Regional Cell Preparation Center (Shangyu Biotechnology Co., Ltd), Hangzhou, People's Republic of China.
Stem Cells Transl Med. 2023 Oct 5;12(10):689-706. doi: 10.1093/stcltm/szad050.
Diabetic foot ulcer (DFU) is a main diabetic complication with unmet treatment needs. This study applied human umbilical cord-derived mesenchymal stem cells-hyaluronic acid (hucMSCs-HA) gel to treat DFU in a noninvasive external way and investigated its paracrine action and mechanism. In this study, after analyzing the physical and biological properties of HA gel, hucMSCs-HA gel was applied in 2 in vivo models (types I and II DFU), and a molecular mechanism was investigated. To evaluate the paracrine action of hucMSCs, hucMSCs-conditional medium (MSC-CM) was collected to treat 1 in vivo model (type I DFU) and 2 in vitro models (high glucose (HG)-injured human umbilical vein endothelial cells (HUVECs) and human skin fibroblasts (HSFs)). The results indicated that HA gel with a porous microstructure underwent over 90% degradation and swelled to the maximum value within 48 h. In vivo, hucMSCs-HA gel accelerated wound healing of DFU rats by improving re-epithelialization, collagen deposition, and angiogenesis, in which a paracrine action of hucMSCs was confirmed and the phosphorylation of p38, ERK1/2, JNK, and Akt was increased. In vitro, MSC-CM improved cell viability, wound healing, migration, tube formation, cell senescence, and abnormal expressions (TNF-α, IL-1β, IL-6, ET-1, p16 genes, and PCNA protein) of HUVECs, also improved cell viability, wound healing, antioxidant stress, and abnormal expressions (COL1, COL3, COL4, SOD1, SOD2 genes, and PCNA protein) of HSFs. Summarily, noninvasive external application of hucMSCs-HA gel shows great perspective against DFU and exerts wound healing effects through the MAPK and Akt pathways-mediated paracrine mechanism.
糖尿病足溃疡（DFU）是一种主要的糖尿病并发症，存在未满足的治疗需求。本研究采用人脐带间充质干细胞-透明质酸（hucMSCs-HA）凝胶以无创的外部方式治疗 DFU，并研究其旁分泌作用及其机制。在这项研究中，在分析了 HA 凝胶的物理和生物学特性后，将 hucMSCs-HA 凝胶应用于 2 种体内模型（I 型和 II 型 DFU），并研究了其分子机制。为了评估 hucMSCs 的旁分泌作用，收集了 hucMSCs 条件培养基（MSC-CM）来治疗 1 种体内模型（I 型 DFU）和 2 种体外模型（高糖（HG）损伤的人脐静脉内皮细胞（HUVECs）和人皮肤成纤维细胞（HSFs））。结果表明，具有多孔微结构的 HA 凝胶经历了超过 90%的降解，并在 48 h 内膨胀至最大值。在体内，hucMSCs-HA 凝胶通过改善再上皮化、胶原沉积和血管生成来加速 DFU 大鼠的伤口愈合，其中证实了 hucMSCs 的旁分泌作用，并且 p38、ERK1/2、JNK 和 Akt 的磷酸化增加。在体外，MSC-CM 提高了细胞活力、伤口愈合、迁移、管形成、细胞衰老和异常表达（TNF-α、IL-1β、IL-6、ET-1、p16 基因和 PCNA 蛋白）的 HUVECs，也提高了细胞活力、伤口愈合、抗氧化应激和异常表达（COL1、COL3、COL4、SOD1、SOD2 基因和 PCNA 蛋白）的 HSFs。总之，hucMSCs-HA 凝胶的无创外部应用对 DFU 具有很大的前景，并通过 MAPK 和 Akt 通路介导的旁分泌机制发挥伤口愈合作用。
