Frontiers in Molecular Biosciences ( IF 5 ) Pub Date : 2020-08-10 , DOI: 10.3389/fmolb.2020.00224 Marco Luciani , Angela Gritti , Vasco Meneghini
Lysosomal storage diseases (LSDs) are a group of rare genetic conditions. The absence or deficiency of lysosomal proteins leads to excessive storage of undigested materials and drives secondary pathological mechanisms including autophagy, calcium homeostasis, ER stress, and mitochondrial abnormalities. A large number of LSDs display mild to severe central nervous system (CNS) involvement. Animal disease models and post-mortem tissues partially recapitulate the disease or represent the final stage of CNS pathology, respectively. In the last decades, human models based on induced pluripotent stem cells (hiPSCs) have been extensively applied to investigate LSD pathology in several tissues and organs, including the CNS. Neural stem/progenitor cells (NSCs) derived from patient-specific hiPSCs (hiPS-NSCs) are a promising tool to define the effects of the pathological storage on neurodevelopment, survival and function of neurons and glial cells in neurodegenerative LSDs. Additionally, the development of novel 2D co-culture systems and 3D hiPSC-based models is fostering the investigation of neuron-glia functional and dysfunctional interactions, also contributing to define the role of neurodevelopment and neuroinflammation in the onset and progression of the disease, with important implications in terms of timing and efficacy of treatments. Here, we discuss the advantages and limits of the application of hiPS-NSC-based models in the study and treatment of CNS pathology in different LSDs. Additionally, we review the state-of-the-art and the prospective applications of NSC-based therapy, highlighting the potential exploitation of hiPS-NSCs for gene and cell therapy approaches in the treatment of neurodegenerative LSDs.
中文翻译:
基于人iPSC的神经退行性溶酶体贮积病治疗方法开发模型
溶酶体贮积病(LSD)是一组罕见的遗传病。溶酶体蛋白的缺乏或缺乏会导致未消化物质的过多存储,并驱动继发性病理机制,包括自噬,钙稳态,内质网应激和线粒体异常。大量的LSD表现出轻度到重度的中枢神经系统(CNS)受累。动物疾病模型和验尸组织分别部分概括了疾病或代表了CNS病理的最后阶段。在过去的几十年中,基于诱导多能干细胞(hiPSC)的人体模型已广泛应用于研究包括CNS在内的多个组织和器官的LSD病理。源自患者特异性hiPSC(hiPS-NSC)的神经干/祖细胞(NSC)是一种有前途的工具,可用于定义病理性贮藏对神经退行性LSD中神经元和神经胶质细胞的神经发育,存活和功能的影响。此外,新型2D共培养系统和基于3D hiPSC的模型的开发正在促进对神经元神经胶质功能和功能障碍相互作用的研究,也有助于确定神经发育和神经炎症在疾病发作和发展中的作用,在时间安排和疗效方面具有重要意义。在这里,我们讨论了基于hiPS-NSC的模型在不同LSD中的CNS病理学研究和治疗中应用的优势和局限性。另外,