Impaired neural differentiation of MPS IIIA patient induced pluripotent stem cell-derived neural progenitor cells

Simple item page
dc.contributor.authorLehmann, R.J.
dc.contributor.authorJolly, L.A.
dc.contributor.authorJohnson, B.V.
dc.contributor.authorLord, M.S.
dc.contributor.authorKim, H.N.
dc.contributor.authorSaville, J.T.
dc.contributor.authorFuller, M.
dc.contributor.authorByers, S.
dc.contributor.authorDerrick-Roberts, A.L.K.
dc.date.issued2021
dc.description.abstractMucopolysaccharidosis 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.
dc.description.statementofresponsibilityRebecca J. Lehmann, Lachlan A. Jolly, Brett V. Johnson, Megan S. Lord, Ha Na Kim, Jennifer T. Saville, Maria Fuller, Sharon Byers, Ainslie L.K. Derrick-Roberts
dc.identifier.citationMolecular Genetics and Metabolism Reports, 2021; 29:100811-1-100811-11
dc.identifier.doi10.1016/j.ymgmr.2021.100811
dc.identifier.issn2214-4269
dc.identifier.issn2214-4269
dc.identifier.orcidLehmann, R.J. [0000-0001-6145-5971]
dc.identifier.orcidJolly, L.A. [0000-0003-4538-2658]
dc.identifier.orcidJohnson, B.V. [0000-0003-3883-3158]
dc.identifier.orcidSaville, J.T. [0000-0002-1401-314X]
dc.identifier.orcidFuller, M. [0000-0001-9092-8942]
dc.identifier.orcidByers, S. [0000-0001-5576-3636]
dc.identifier.urihttps://hdl.handle.net/2440/133814
dc.language.isoen
dc.publisherElsevier
dc.relation.granthttp://purl.org/au-research/grants/arc/DE160100620
dc.rights© 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
dc.source.urihttps://doi.org/10.1016/j.ymgmr.2021.100811
dc.subjectInduced pluripotent stem cells; MPS IIIA; neurogenesis; heparan sulphate glycosaminoglycan; fibroblast growth factor 2
dc.titleImpaired neural differentiation of MPS IIIA patient induced pluripotent stem cell-derived neural progenitor cells
dc.typeJournal article
pubs.publication-statusPublished

Files

Original bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
hdl_133814.pdf
Size:
7.74 MB
Format:
Adobe Portable Document Format
Description:
Published version
Download

Collections

Medicine publications