Mucopolysaccharidosis enzyme production by bone marrow and dental pulp derived human mesenchymal stem cells

Jackson, Matilda R.; Derrick-Roberts, Ainslie L.K.; Martin, Ellenore; Rout-Pitt, Nathan; Gronthos, Stan; Byers, Sharon

doi:10.1016/j.ymgme.2015.02.001

Cited by 12 publications

(10 citation statements)

References 78 publications

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“…Exon-exon boundary gene specific primers were designed for all neural genes. Primers for OCT-4 , NANOG and SOX-2 were as previously described [37] and βIII-TUBULIN as per [46] . All other primer sequences are shown in Table 1 , with cyclophilin A included as the housekeeping gene.…”

Section: Methodsmentioning

confidence: 99%

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

Lehmann

Jolly

Johnson

et al. 2021

Molecular Genetics and Metabolism Reports

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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.

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Section: Methodsmentioning

confidence: 99%

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

Lehmann

Jolly

Johnson

et al. 2021

Molecular Genetics and Metabolism Reports

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“…1,3 This results in their accumulation in a range of cell types inducing tissue and organ degeneration. 4 Dental features are also dependent on the distinct type of MPS (Table 1). Identification of dental abnormalities can be of clinical significance.…”

Section: Discussionmentioning

confidence: 99%

“…The intellectual disability and neurological symptoms that present in several types of MPS often necessitates dental intervention under general anesthetic. 1,4 This can produce significant challenges for the anesthetist and varying levels of risk. Airway management may be compromised in MPS patients due to the susceptibility for glycosaminoglycan accumulation in the head and neck region.…”

Section: Discussionmentioning

confidence: 99%

“…Mucopolysaccharidoses are rare lysosomal storage disorders (LSD), representing a heterogenous group of diseases arising from a deficiency in one of the eleven enzymes responsible for the breakdown of glycosaminoglycans (GAGs) 1,3 . This results in their accumulation in a range of cell types inducing tissue and organ degeneration 4 …”

Section: Discussionmentioning

confidence: 99%

“…The management of MPS patients with gross caries therefore presents an additional challenge for clinicians. The intellectual disability and neurological symptoms that present in several types of MPS often necessitates dental intervention under general anesthetic 1,4 . This can produce significant challenges for the anesthetist and varying levels of risk.…”

Section: Discussionmentioning

confidence: 99%

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Mucopolysaccharidosis (MPS): Review of the literature and case series of five pediatric dental patients

Hirst

Mubeen

Abou-Ameira

et al. 2021

Clinical Case Reports

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Stem Cell Applications in Lysosomal Storage Disorders: Progress and Ongoing Challenges

Köse

Aerts‐Kaya

Çetinkaya

et al. 2021

Advances in Experimental Medicine and Biology

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Mucopolysaccharidosis enzyme production by bone marrow and dental pulp derived human mesenchymal stem cells

Cited by 12 publications

References 78 publications

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

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

Mucopolysaccharidosis (MPS): Review of the literature and case series of five pediatric dental patients

Stem Cell Applications in Lysosomal Storage Disorders: Progress and Ongoing Challenges

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