脂肪间充质干细胞来源外泌体通过 miR-106a-5p 和 FGF4/p38MAPK 通路促进糖尿病足溃疡的血管生成。

Exosomes from mmu_circ_0001052-modified adipose-derived stem cells promote angiogenesis of DFU via miR-106a-5p and FGF4/p38MAPK pathway.

机构信息

Department of Burn and Skin Repair Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), No.19, Xiuhua Road, Xiuying District, Haikou, 570311, Hainan Province, People's Republic of China.

Department of Burn Plastic Surgery, Guangzhou Red Cross Hospital Affiliated to Jinan University, No.396, Tongfu Middle Road, Guangzhou, 510632, Guangdong Province, People's Republic of China.

出版信息

Stem Cell Res Ther. 2022 Jul 23;13(1):336. doi: 10.1186/s13287-022-03015-7.

BACKGROUND

Diabetic foot ulcer (DFU) is a chronic infectious disease caused by diabetes mellitus (DM). Angiogenesis plays the decisive role in wound healing of DFU. Adipose-derived stem cells (ADSCs) can ameliorate angiogenesis in DFU by exosomes. This study aims to determine the mechanism of exosomes from mmu_circ_0001052-modified ADSCs in angiogenesis of DFU.

METHODS

HUVECs were induced by high glucose and mice stimulated using STZ injection during high-fat feeding, which were treated with exosomes derived from mmu_circ_0001052-modified ADSCs. Real-time PCR determined the expression of gene and western blot determined protein levels. Proliferation, migration, apoptosis and angiogenesis of HUVECs were studied by MTT assay, transwell test, flow cytometry and tube formation experiment, respectively. Histological lesion of wound was determined by HE staining.

RESULTS

The expression of circ_0001052 was upregulated in ADSCs and miR-106a-5p elevated in high glucose-induced HUVECs. Exosomal mmu_circ_0001052 significantly accelerated wound healing in mice with DFU. Also, exosomal mmu_circ_0001052 evoked the reduction of miR-106a-5p and the elevation of FGF4 in high glucose-induced HUVECs and wound tissue of DFU mice. Exosomal mmu_circ_0001052 was determined to sponge miR-106a-5p that targeted FGF4 in DFU. In high glucose-induced HUVECs, exosomal mmu_circ_0001052 inhibited apoptosis and miR-106a-5p expression, and meanwhile promoted proliferation, migration, angiogenesis and expressions of FGF4, VEGF and p-p38/p38, which were reversed by miR-106a-5p elevation.

CONCLUSION

Mmu_circ_0001052 in ADSCs-derived exosomes promote angiogenesis of DFU via miR-106a-5p and FGF4/p38MAPK pathway.

背景

糖尿病足溃疡（DFU）是一种由糖尿病（DM）引起的慢性感染性疾病。血管生成在 DFU 的伤口愈合中起决定性作用。脂肪来源的干细胞（ADSCs）可以通过外泌体改善 DFU 的血管生成。本研究旨在确定 mmu_circ_0001052 修饰的 ADSCs 来源的外泌体在 DFU 血管生成中的作用机制。

方法

用高糖诱导 HUVECs，并用 STZ 注射在高脂喂养下刺激小鼠，然后用 mmu_circ_0001052 修饰的 ADSCs 来源的外泌体处理。实时 PCR 检测基因表达，Western blot 检测蛋白水平。MTT 法检测 HUVECs 的增殖、迁移、凋亡和血管生成，Transwell 检测、流式细胞术和管形成实验分别检测。HE 染色检测伤口组织学损伤。

结果

ADSCs 中 circ_0001052 的表达上调，高糖诱导的 HUVECs 中 miR-106a-5p 水平升高。DFU 小鼠外泌体 mmu_circ_0001052 明显加速了伤口愈合。此外，外泌体 mmu_circ_0001052 可降低高糖诱导的 HUVECs 和 DFU 小鼠伤口组织中的 miR-106a-5p 水平，升高 FGF4 水平。外泌体 mmu_circ_0001052 被确定为 DFU 中的 miR-106a-5p 海绵，靶向 FGF4。在高糖诱导的 HUVECs 中，外泌体 mmu_circ_0001052 抑制凋亡和 miR-106a-5p 的表达，同时促进增殖、迁移、血管生成和 FGF4、VEGF 和 p-p38/p38 的表达，这些作用可被 miR-106a-5p 升高所逆转。