低强度脉冲超声通过压电-ERK-血管内皮生长因子轴增强脂肪来源干细胞介导的血管生成以治疗糖尿病性勃起功能障碍
Low-Intensity Pulsed Ultrasound Enhanced Adipose-Derived Stem Cell-Mediated Angiogenesis in the Treatment of Diabetic Erectile Dysfunction through the Piezo-ERK-VEGF Axis.
作者信息
Liu Shiyun, Jiang Chenyi, Hu Jianlin, Chen Huixing, Han Bangmin, Xia Shujie
机构信息
Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
Department of Andrology, The Center for Men's Health, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
出版信息
Stem Cells Int. 2022 Jul 29;2022:6202842. doi: 10.1155/2022/6202842. eCollection 2022.
OBJECTIVES
Erectile dysfunction is a major comorbidity of diabetes. Stem cell transplantation is a promising method to treat diabetic erectile dysfunction. In this study, we evaluated whether low-intensity pulsed ultrasound (LIPUS) could enhance the efficacy of adipose-derived stem cells (ADSCs) and investigated the underlying molecular mechanism. . Sixty 8-week-old male Sprague-Dawley rats were randomly divided into the normal control (NC) cohort or the streptozocin-induced diabetic ED cohort, which was further subdivided into DM, ADSC, LIPUS, and ADSC+LIPUS groups. Rats in the ADSC or ADSC+LIPUS group received ADSC intracavernosal injection. Rats in the LIPUS or ADSC+LIPUS group were treated with LIPUS. The intracavernous pressure (ICP) and mean arterial pressure (MAP) were recorded at Day 28 after injection. The corpus cavernosum tissues were harvested and subjected to histologic analysis and ELISA. The effects of LIPUS on proliferation and cytokine secretion capacity of ADSCs were assessed in vitro. RNA sequencing and bioinformatic analysis were applied to predict the mechanism involved, and western blotting and ELISA were used for verification.
RESULTS
Rats in the ADSC+LIPUS group achieved significantly higher ICP and ICP/MAP ratios than those in the DM, ADSC, and LIPUS groups. In addition, the amount of cavernous endothelium and cGMP level also increased significantly in the ADSC+LIPUS group. In vitro experiments demonstrated that LIPUS promoted proliferation and cell cycle progression in ADSCs. The excretion of cytokines such as CXCL12, FGF2, and VEGF was also enhanced by LIPUS. Bioinformatic analysis based on RNA sequencing indicated that LIPUS stimulation might activate the MAPK pathway. We confirmed that LIPUS enhanced ADSC VEGF secretion through the Piezo-ERK pathway.
CONCLUSION
LIPUS enhanced the curative effects of ADSCs on diabetic erectile dysfunction through the activation of the Piezo-ERK-VEGF pathway. ADSC transplantation combined with LIPUS could be applied as a synergistic treatment for diabetic ED.
目的
勃起功能障碍是糖尿病的一种主要合并症。干细胞移植是治疗糖尿病性勃起功能障碍的一种有前景的方法。在本研究中，我们评估了低强度脉冲超声（LIPUS）是否能增强脂肪来源干细胞（ADSCs）的疗效，并研究其潜在的分子机制。60只8周龄雄性Sprague-Dawley大鼠被随机分为正常对照组（NC）或链脲佐菌素诱导的糖尿病性勃起功能障碍组，后者进一步细分为糖尿病组（DM）、脂肪来源干细胞组（ADSC）、低强度脉冲超声组（LIPUS）和脂肪来源干细胞+低强度脉冲超声组（ADSC+LIPUS）。ADSC组或ADSC+LIPUS组的大鼠接受阴茎海绵体内注射ADSCs。LIPUS组或ADSC+LIPUS组的大鼠接受LIPUS治疗。在注射后第28天记录阴茎海绵体内压（ICP）和平均动脉压（MAP）。采集阴茎海绵体组织并进行组织学分析和酶联免疫吸附测定（ELISA）。在体外评估LIPUS对ADSCs增殖和细胞因子分泌能力的影响。应用RNA测序和生物信息学分析预测其中涉及的机制，并使用蛋白质免疫印迹法和ELISA进行验证。
结果
ADSC+LIPUS组大鼠的ICP和ICP/MAP比值显著高于DM组、ADSC组和LIPUS组。此外，ADSC+LIPUS组的海绵体内皮细胞数量和环磷酸鸟苷（cGMP）水平也显著增加。体外实验表明，LIPUS促进了ADSCs的增殖和细胞周期进程。LIPUS还增强了趋化因子配体12（CXCL12）、成纤维细胞生长因子2（FGF2）和血管内皮生长因子（VEGF）等细胞因子的分泌。基于RNA测序的生物信息学分析表明，LIPUS刺激可能激活丝裂原活化蛋白激酶（MAPK）通路。我们证实LIPUS通过Piezo-细胞外信号调节激酶（ERK）通路增强了ADSCs的VEGF分泌。
结论
LIPUS通过激活Piezo-ERK-VEGF通路增强了ADSCs对糖尿病性勃起功能障碍的治疗效果。ADSC移植联合LIPUS可作为糖尿病性勃起功能障碍的一种协同治疗方法。
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