Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
Department 4, State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing, 400042, China.
Stem Cell Res Ther. 2020 Jan 28;11(1):39. doi: 10.1186/s13287-020-1561-x.
Chronic nonhealing wounds represent one of the most common complications of diabetes and require advanced treatment strategies. Increasing evidence supports the important role of mesenchymal stem cells in diabetic wound healing; however, the underlying mechanism remains unclear. Here, we explored the effects of umbilical cord-matrix stem cells (UCMSCs) on diabetic wound healing and the underlying mechanism.
UCMSCs or conditioned medium (UCMSC-CM) were injected into the cutaneous wounds of streptozotocin-induced diabetic mice. The effects of this treatment on macrophages and diabetic vascular endothelial cells were investigated in vivo and in vitro.
Our results reveal that UCMSCs or UCMSC-CM accelerated wound healing by enhancing angiogenesis. The number of host macrophages recruited to the wound tissue by local infusion of UCMSCs was greater than that recruited by fibroblast transplantation or control. The frequency of M2 macrophages was increased by UCMSC transplantation or UCMSC-CM injection, which promoted the expression of cytokines derived from M2 macrophages. Furthermore, when cocultured with UCMSCs or UCMSC-CM, lipopolysaccharide-induced macrophages acquired an anti-inflammatory M2 phenotype characterized by the increased secretion of the cytokines interleukin (IL)-10 and vascular endothelial growth factor and the suppressed production of tumor necrosis factor-α and IL-6. UCMSC-CM-activated macrophages significantly enhanced diabetic vascular endothelial cell functions, including angiogenesis, migration, and chemotaxis. Moreover, the action of UCMSC-CM on macrophages or vascular endothelial cells was abrogated by the administration of neutralizing antibodies against prostaglandin E2 (PGE2) or by the inhibition of PGE2 secretion from UCMSCs.
Our findings demonstrate that UCMSCs can induce the functional restoration of vascular endothelial cells via the remodeling of macrophage phenotypes, which might contribute to the marked acceleration of wound healing in diabetic mice.
慢性难愈性创面是糖尿病最常见的并发症之一，需要采用先进的治疗策略。越来越多的证据表明间充质干细胞在糖尿病创面愈合中起着重要作用，但潜在机制尚不清楚。在此，我们探讨了脐带基质干细胞（UCMSCs）对糖尿病创面愈合的影响及其潜在机制。
将 UCMSCs 或条件培养基（UCMSC-CM）注射到链脲佐菌素诱导的糖尿病小鼠的皮肤创面中。在体内和体外研究了这种治疗方法对巨噬细胞和糖尿病血管内皮细胞的影响。
我们的结果表明，UCMSCs 或 UCMSC-CM 通过促进血管生成加速了创面愈合。通过局部注射 UCMSCs 募集到创面组织中的宿主巨噬细胞数量多于成纤维细胞移植或对照组。UCMSC 移植或 UCMSC-CM 注射增加了 M2 巨噬细胞的频率，促进了 M2 巨噬细胞来源细胞因子的表达。此外，与 UCMSCs 或 UCMSC-CM 共培养时，脂多糖诱导的巨噬细胞获得抗炎 M2 表型，其特征是细胞因子白细胞介素（IL）-10 和血管内皮生长因子的分泌增加，肿瘤坏死因子-α和 IL-6 的产生减少。UCMSC-CM 激活的巨噬细胞显著增强了糖尿病血管内皮细胞的功能，包括血管生成、迁移和趋化性。此外，用前列腺素 E2（PGE2）中和抗体或抑制 UCMSC 分泌 PGE2 可阻断 UCMSC-CM 对巨噬细胞或血管内皮细胞的作用。
我们的研究结果表明，UCMSCs 可以通过重塑巨噬细胞表型诱导血管内皮细胞的功能恢复，这可能有助于加速糖尿病小鼠的创面愈合。
