Yu Chieh, Griffiths Lyn R, Haupt Larisa M
Genomics Research Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
Front Integr Neurosci. 2017 Oct 17;11:28. doi: 10.3389/fnint.2017.00028. eCollection 2017.
Unspecialized, self-renewing stem cells have extraordinary application to regenerative medicine due to their multilineage differentiation potential. Stem cell therapies through replenishing damaged or lost cells in the injured area is an attractive treatment of brain trauma and neurodegenerative neurological disorders. Several stem cell types have neurogenic potential including neural stem cells (NSCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and mesenchymal stem cells (MSCs). Currently, effective use of these cells is limited by our lack of understanding and ability to direct lineage commitment and differentiation of neural lineages. Heparan sulfate proteoglycans (HSPGs) are ubiquitous proteins within the stem cell microenvironment or niche and are found localized on the cell surface and in the extracellular matrix (ECM), where they interact with numerous signaling molecules. The glycosaminoglycan (GAG) chains carried by HSPGs are heterogeneous carbohydrates comprised of repeating disaccharides with specific sulfation patterns that govern ligand interactions to numerous factors including the fibroblast growth factors (FGFs) and wingless-type MMTV integration site family (Wnts). As such, HSPGs are plausible targets for guiding and controlling neural stem cell lineage fate. In this review, we provide an overview of HSPG family members syndecans and glypicans, and perlecan and their role in neurogenesis. We summarize the structural changes and subsequent functional implications of heparan sulfate as cells undergo neural lineage differentiation as well as outline the role of HSPG core protein expression throughout mammalian neural development and their function as cell receptors and co-receptors. Finally, we highlight suitable biomimetic approaches for exploiting the role of HSPGs in mammalian neurogenesis to control and tailor cell differentiation into specific lineages. An improved ability to control stem cell specific neural lineage fate and produce abundant cells of lineage specificity will further advance stem cell therapy for the development of improved repair of neurological disorders. We propose a deeper understanding of HSPG-mediated neurogenesis can potentially provide novel therapeutic targets of neurogenesis.
未分化的自我更新干细胞因其多谱系分化潜能在再生医学中具有非凡的应用价值。通过补充损伤区域受损或丢失的细胞进行干细胞治疗，是治疗脑外伤和神经退行性神经疾病的一种有吸引力的方法。几种干细胞类型具有神经发生潜能，包括神经干细胞（NSCs）、胚胎干细胞（ESCs）、诱导多能干细胞（iPSCs）和间充质干细胞（MSCs）。目前，由于我们对神经谱系定向分化的理解不足以及缺乏相关能力，这些细胞的有效利用受到限制。硫酸乙酰肝素蛋白聚糖（HSPGs）是干细胞微环境或生态位中普遍存在的蛋白质，定位于细胞表面和细胞外基质（ECM），在那里它们与众多信号分子相互作用。HSPGs携带的糖胺聚糖（GAG）链是由具有特定硫酸化模式的重复二糖组成的异质碳水化合物，这些模式决定了与包括成纤维细胞生长因子（FGFs）和无翅型MMTV整合位点家族（Wnts）在内的众多因子的配体相互作用。因此，HSPGs是指导和控制神经干细胞谱系命运的合理靶点。在本综述中，我们概述了HSPG家族成员syndecans、glypicans和perlecan及其在神经发生中的作用。我们总结了随着细胞进行神经谱系分化硫酸乙酰肝素的结构变化及其后续功能影响，以及概述了HSPG核心蛋白在整个哺乳动物神经发育过程中的表达作用及其作为细胞受体和共受体的功能。最后，我们强调了利用HSPGs在哺乳动物神经发生中的作用来控制和调整细胞分化为特定谱系的合适仿生方法。提高控制干细胞特定神经谱系命运以及产生大量谱系特异性细胞的能力，将进一步推动干细胞治疗在改善神经疾病修复方面的发展。我们提出，对HSPG介导的神经发生有更深入的理解可能会潜在地提供神经发生的新治疗靶点。
