Impaired neural differentiation of MPS IIIA patient induced pluripotent stem cell-derived neural progenitor cells
| العنوان: | Impaired neural differentiation of MPS IIIA patient induced pluripotent stem cell-derived neural progenitor cells |
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| المؤلفون: | Jennifer T. Saville, Ainslie L. K. Derrick-Roberts, Brett V. Johnson, Megan S. Lord, Maria Fuller, Ha Na Kim, Lachlan A. Jolly, Rebecca J. Lehmann, Sharon Byers |
| المساهمون: | Lehmann, Rebecca J, Jolly, Lachlan A, Johnson, Brett, V, Lord, Megan S, Kim, Ha Na, Saville, Jennifer T, Fuller, Maria, Byers, Sharon, Derrick-Roberts, Ainslie LK |
| المصدر: | Molecular Genetics and Metabolism Reports, Vol 29, Iss, Pp 100811-(2021) Molecular Genetics and Metabolism Reports |
| بيانات النشر: | Elsevier, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | iPSC, induced pluripotent stem cell, congenital, hereditary, and neonatal diseases and abnormalities, Medicine (General), induced pluripotent stem cells, QH301-705.5, Neurogenesis, Cell, GAG, glycosaminoglycan, Fibroblast growth factor, CNS, central nervous system, Glycosaminoglycan, Endocrinology, R5-920, Genetics, medicine, NPC, neural progenitor cell, Biology (General), fibroblast growth factor 2, Induced pluripotent stem cell, Receptor, Molecular Biology, Mucopolysaccharidosis Type IIIA, Chemistry, MPS IIIA, mucopolysaccharidosis type IIIA, Heparan sulphate glycosaminoglycan, Fibroblast growth factor 2, MEF, mouse embryonic fibroblast, Neural stem cell, Cell biology, neurogenesis, Induced pluripotent stem cells, medicine.anatomical_structure, HS, heparan sulphate, MPS IIIA, FGF, Fibroblast growth factor, Research Paper |
| الوصف: | Mucopolysaccharidosis type IIIA (MPS IIIA) is characterised by a progressive neurological decline leading to early death. It is caused by bi-allelic loss-of-function mutations in SGSH encoding sulphamidase, a lysosomal enzyme required for heparan sulphate glycosaminoglycan (HS GAG) degradation, that results in the progressive build-up of HS GAGs in multiple tissues most notably the central nervous system (CNS). Skin fibroblasts from two MPS IIIA patients who presented with an intermediate and a severe clinical phenotype, respectively, were reprogrammed into induced pluripotent stem cells (iPSCs). The intermediate MPS IIIA iPSCs were then differentiated into neural progenitor cells (NPCs) and subsequently neurons. The patient derived fibroblasts, iPSCs, NPCs and neurons all displayed hallmark biochemical characteristics of MPS IIIA including reduced sulphamidase activity and increased accumulation of an MPS IIIA HS GAG biomarker. Proliferation of MPS IIIA iPSC-derived NPCs was reduced compared to control, but could be partially rescued by reintroducing functional sulphamidase enzyme, or by doubling the concentration of the mitogen fibroblast growth factor 2 (FGF2). Whilst both control heparin, and MPS IIIA HS GAGs had a similar binding affinity for FGF2, only the latter inhibited FGF signalling, suggesting accumulated MPS IIIA HS GAGs disrupt the FGF2:FGF2 receptor:HS signalling complex. Neuronal differentiation of MPS IIIA iPSC-derived NPCs was associated with a reduction in the expression of neuronal cell marker genes βIII-TUBULIN, NF-H and NSE, revealing reduced neurogenesis compared to control. A similar result was achieved by adding MPS IIIA HS GAGs to the culture medium during neuronal differentiation of control iPSC-derived NPCs. This study demonstrates the generation of MPS IIIA iPSCs, and NPCs, the latter of which display reduced proliferation and neurogenic capacity. Reduced NPC proliferation can be explained by a model in which soluble MPS IIIA HS GAGs compete with cell surface HS for FGF2 binding. The mechanism driving reduced neurogenesis remains to be determined but appears downstream of MPS IIIA HS GAG accumulation. Highlights • Induced pluripotent stem cells (iPSCs) were generated from MPS IIIA skin fibroblasts. • MPS IIIA iPSCs were successfully differentiated into neural progenitor cells (NPCs). • MPS IIIA NPC proliferation was reduced due to interference with FGF2 signalling. • Neurogenesis from MPS IIIA iPSC-derived NPCs is reduced via an unknown mechanism. |
| اللغة: | English |
| تدمد: | 2214-4269 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8319b125d94dfde1df85ea9122f3ab4d http://www.sciencedirect.com/science/article/pii/S2214426921001063 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....8319b125d94dfde1df85ea9122f3ab4d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22144269 |
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