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Impaired neural differentiation potency by retinoic acid receptor-? pathway defect in induced pluripotent stem cells.

ABSTRACT: Induced pluripotent stem cells (iPSCs) are reprogrammed from somatic cells via ectopic gene expression and, similarly to embryonic stem cells (ESCs), possess powerful abilities to self-renew and differentiate into cells of various lineages. However, the neural differentiation potency of iPSCs remains unknown. In this study, we demonstrated the neural differentiation ability of iPSCs compared with ESCs using an retinoic acid (RA) induction system. The neural differentiation efficiency of iPSCs was obviously lower than that of ESCs. Retinoic acid receptor-? (RAR?) was critical in the RA-induced neural differentiation of iPSCs, and the effect of RAR? was confirmed by applying a specific RAR? antagonist ER50891 to ESCs. These findings indicate that iPSCs do not possess the complete properties that ESCs have.

SUBMITTER: Hou PS

PROVIDER: S-EPMC4245853 | biostudies-other | 2014 Dec

REPOSITORIES: biostudies-other

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Impaired neural differentiation potency by retinoic acid receptor-α pathway defect in induced pluripotent stem cells.

Hou Pei-Shan PS Huang Wen-Chin WC Chiang Wei W Lin Wei-Che WC Chien Chung-Liang CL

Cellular reprogramming 20141103 6

Induced pluripotent stem cells (iPSCs) are reprogrammed from somatic cells via ectopic gene expression and, similarly to embryonic stem cells (ESCs), possess powerful abilities to self-renew and differentiate into cells of various lineages. However, the neural differentiation potency of iPSCs remains unknown. In this study, we demonstrated the neural differentiation ability of iPSCs compared with ESCs using an retinoic acid (RA) induction system. The neural differentiation efficiency of iPSCs wa ...[more]

PMID: 25364979

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Project description: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.

Dataset Information

Impaired neural differentiation potency by retinoic acid receptor-? pathway defect in induced pluripotent stem cells.

Publications

Impaired neural differentiation potency by retinoic acid receptor-α pathway defect in induced pluripotent stem cells.

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