Chi Ani, Yang Chao, Liu Jie, Zhai Zhichen, Shi Xuetao
National Engineering Research Centre for Tissue Restoration and Reconstruction, Key Laboratory of Biomedical Engineering of Guangdong Province, South China University of Technology, Guangzhou, 510640, P. R. China.
Key Laboratory of Biomedical Engineering of Guangdong Province, South China University of Technology, Guangzhou, 510006, P. R. China.
Adv Sci (Weinh). 2025 Jan;12(2):e2410808. doi: 10.1002/advs.202410808. Epub 2024 Nov 18.
Therapies involving the use of stem Leydig cells (SLCs), as testicular mesenchymal stromal cells, have shown great promise in the treatment of Leydig cell (LC) dysfunction in aging males. However, the outcomes of these therapies are not satisfactory. In this study, it is demonstrated that the aging microenvironment of the testicular interstitium impairs the function of SLCs, leading to poor regeneration of LCs and, consequently, inefficient functional restoration. The study develops a decellularized testicular extracellular matrix (dTECM) hydrogel from young pigs and evaluates its safety and feasibility as a supportive niche for the expansion and differentiation of SLCs. dTECM hydrogel facilitates the steroidogenic differentiation of SLCs into LCs, the primary producers of testosterone. The combination of SLCs with a dTECM hydrogel leads to a significant and sustained increase in testosterone levels, which promotes the restoration of spermatogenesis and fertility in an LC-deficient and aged mouse model. Mechanistically, collagen 1 within the dTECM is identified as a key factor contributing to these effects. Notably, symptoms associated with testosterone deficiency syndrome are significantly alleviated in aged mice. These findings may aid the design of therapeutic interventions for patients with testosterone deficiency in the clinic.
将睾丸间质干细胞（SLCs）作为睾丸间充质基质细胞的治疗方法，在治疗老年男性睾丸间质细胞（LC）功能障碍方面显示出巨大潜力。然而，这些治疗的效果并不理想。在本研究中，证明了睾丸间质的衰老微环境会损害SLCs的功能，导致LCs再生不良，进而导致功能恢复效率低下。该研究从幼猪身上制备了去细胞化睾丸细胞外基质（dTECM）水凝胶，并评估了其作为SLCs扩增和分化支持性微环境的安全性和可行性。dTECM水凝胶促进SLCs向睾酮主要产生者LCs的类固醇生成分化。SLCs与dTECM水凝胶的组合导致睾酮水平显著且持续升高，这促进了LC缺陷和老年小鼠模型中精子发生和生育能力的恢复。从机制上讲，dTECM中的胶原蛋白1被确定为促成这些效应的关键因素。值得注意的是，老年小鼠中与睾酮缺乏综合征相关的症状得到显著缓解。这些发现可能有助于临床设计针对睾酮缺乏患者的治疗干预措施。
