Mesenchymal stem cell with enhanced antioxidant capacity integrates into smooth muscle cells in diabetic detrusor underactivity (RNA-Seq)

Diabetic cystopathy, affecting half of individuals with diabetes, often progresses to detrusor underactivity (DUA), a late and irreversible stage of bladder dysfunction. Despite its prevalence, the etiology of diabetic DUA remains elusive, with no established treatments. Mesenchymal stem cell (MSC) transplantation, demonstrated as a promising therapeutic avenue in preclinical studies, lacks comprehensive analyses of its mechanisms, tumorigenic risks, and optimal protocols for diabetic DUA. This study addresses these gaps, exploring transcriptome changes post-MSC treatment in a diabetic DUA preclinical model. Oxidative injury emerged as a significant pathological mechanism, with N-acetylcysteine (NAC) enhancing MSC synergistic effects, potentially reducing the amount of required MSCs . Additionally, human umbilical cord-derived MSCs with high antioxidant capacity (PFO-MSCs) exhibited improved and sustained therapeutic efficacy, integrating into myocytes within bladder muscle bundles or neighboring pericytes. Single-cell transcriptome analysis of engrafted cells revealed expression changes in pathways related to muscle development and immune responses, emphasizing the pivotal roles of cMET and PD-L1 in muscle regeneration and immune modulation within diabetic DUA. This study provides a comprehensive overview of the pathogenesis and repair processes following MSC therapy for diabetic DUA, enhancing our understanding of its mode of action, efficacy, and safety for future clinical applications.糖尿病性膀胱病（Diabetic cystopathy）累及半数糖尿病患者，常进展至逼尿肌活动低下（detrusor underactivity, DUA）——这一膀胱功能障碍的晚期不可逆阶段。尽管该病患病率较高，但其致病机制仍不明确，目前尚无获批的治疗方案。间充质干细胞（mesenchymal stem cell, MSC）移植在临床前研究中被证实是极具潜力的治疗途径，但针对其治疗糖尿病性DUA的作用机制、致瘤风险及最优方案，仍缺乏全面系统的分析。本研究针对上述空白展开探索，在糖尿病性DUA临床前模型中探究了间充质干细胞移植后的转录组变化。研究发现氧化损伤是关键病理机制之一，而N-乙酰半胱氨酸（N-acetylcysteine, NAC）可增强间充质干细胞的协同治疗效果，有望降低所需的细胞用量。此外，高抗氧化能力人脐带来源间充质干细胞（PFO-MSCs）展现出更优且持久的治疗效能，可整合至膀胱肌束内的肌细胞或邻近的周细胞中。对移植细胞的单细胞转录组分析（single-cell transcriptome analysis）显示，其肌肉发育与免疫应答相关通路的表达发生显著改变，凸显了cMET与程序性死亡受体配体1（PD-L1）在糖尿病性DUA肌肉再生及免疫调控中的核心作用。本研究全面阐明了间充质干细胞治疗糖尿病性DUA后的发病机制与修复过程，加深了我们对其作用模式、疗效及安全性的认知，可为后续临床应用提供重要参考。