Department of Plastic and Reconstructive Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea.
Department of Plastic and Reconstructive Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
Int J Mol Sci. 2021 Mar 5;22(5):2632. doi: 10.3390/ijms22052632.
Chronic inflammation and impaired neovascularization play critical roles in delayed wound healing in diabetic patients. To overcome the limitations of current diabetic wound (DBW) management interventions, we investigated the effects of a catechol-functionalized hyaluronic acid (HA-CA) patch combined with adipose-derived mesenchymal stem cells (ADSCs) in DBW mouse models.
Diabetes in mice (C57BL/6, male) was induced by streptozotocin (50 mg/kg, >250 mg/dL). Mice were divided into four groups: control (DBW) group, ADSCs group, HA-CA group, and HA-CA + ADSCs group ( = 10 per group). Fluorescently labeled ADSCs (5 × 10 cells/100 µL) were transplanted into healthy tissues at the wound boundary or deposited at the HA-CA patch at the wound site. The wound area was visually examined. Collagen content, granulation tissue thickness and vascularity, cell apoptosis, and re-epithelialization were assessed. Angiogenesis was evaluated by immunohistochemistry, quantitative real-time polymerase chain reaction, and Western blot.
DBW size was significantly smaller in the HA-CA + ADSCs group (8% ± 2%) compared with the control (16% ± 5%, < 0.01) and ADSCs (24% ± 17%, < 0.05) groups. In mice treated with HA-CA + ADSCs, the epidermis was regenerated, and skin thickness was restored. CD31 and von Willebrand factor-positive vessels were detected in mice treated with HA-CA + ADSCs. The mRNA and protein levels of , , , , , and in the HA-CA + ADSCs group were the highest among all groups, although the and expression levels remained unchanged.
The combination of HA-CA and ADSCs provided synergistic wound healing effects by maximizing paracrine signaling and angiogenesis via the PI3K/AKT pathway. Therefore, ADSC-loaded HA-CA might represent a novel strategy for the treatment of DBW.
慢性炎症和新生血管形成受损在糖尿病患者的伤口愈合延迟中起着关键作用。为了克服当前糖尿病创面（DBW）管理干预的局限性，我们研究了儿茶酚功能化透明质酸（HA-CA）贴片与脂肪间充质干细胞（ADSCs）联合应用于 DBW 小鼠模型的效果。
通过链脲佐菌素（50mg/kg，>250mg/dL）诱导小鼠糖尿病（C57BL/6，雄性）。将小鼠分为四组：对照组（DBW 组）、ADSCs 组、HA-CA 组和 HA-CA+ADSCs 组（每组=10 只）。将荧光标记的 ADSCs（5×10 个细胞/100μL）移植到伤口边界的健康组织中，或沉积在伤口部位的 HA-CA 贴片上。通过肉眼观察伤口面积。评估胶原含量、肉芽组织厚度和血管生成、细胞凋亡和再上皮化。通过免疫组织化学、实时定量聚合酶链反应和 Western blot 评估血管生成。
HA-CA+ADSCs 组的 DBW 面积明显小于对照组（16%±5%， < 0.01）和 ADSCs 组（24%±17%， < 0.05）。在接受 HA-CA+ADSCs 治疗的小鼠中，表皮得到再生，皮肤厚度得到恢复。在接受 HA-CA+ADSCs 治疗的小鼠中检测到 CD31 和血管假性血友病因子阳性血管。HA-CA+ADSCs 组的 、 、 、 、和 mRNA 和蛋白水平在所有组中最高，尽管 和 的表达水平保持不变。
HA-CA 和 ADSCs 的联合应用通过最大限度地发挥旁分泌信号和血管生成作用，通过 PI3K/AKT 途径提供协同的伤口愈合效果。因此，负载 ADSC 的 HA-CA 可能代表治疗 DBW 的一种新策略。
