Dataset Information

Pretreatment with a ?-Secretase Inhibitor Prevents Tumor-like Overgrowth in Human iPSC-Derived Transplants for Spinal Cord Injury.

ABSTRACT: Neural stem/progenitor cells (NS/PCs) derived from human induced pluripotent stem cells (hiPSCs) are considered to be a promising cell source for cell-based interventions that target CNS disorders. We previously reported that transplanting certain hiPSC-NS/PCs in the spinal cord results in tumor-like overgrowth of hiPSC-NS/PCs and subsequent deterioration of motor function. Remnant immature cells should be removed or induced into more mature cell types to avoid adverse effects of hiPSC-NS/PC transplantation. Because Notch signaling plays a role in maintaining NS/PCs, we evaluated the effects of ?-secretase inhibitor (GSI) and found that pretreating hiPSC-NS/PCs with GSI promoted neuronal differentiation and maturation in vitro, and GSI pretreatment also reduced the overgrowth of transplanted hiPSC-NS/PCs and inhibited the deterioration of motor function in vivo. These results indicate that pretreatment with hiPSC-NS/PCs decreases the proliferative capacity of transplanted hiPSC-NS/PCs, triggers neuronal commitment, and improves the safety of hiPSC-based approaches in regenerative medicine.

SUBMITTER: Okubo T

PROVIDER: S-EPMC5063571 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Publications

Pretreatment with a γ-Secretase Inhibitor Prevents Tumor-like Overgrowth in Human iPSC-Derived Transplants for Spinal Cord Injury.

Okubo Toshiki T Iwanami Akio A Kohyama Jun J Itakura Go G Kawabata Soya S Nishiyama Yuichiro Y Sugai Keiko K Ozaki Masahiro M Iida Tsuyoshi T Matsubayashi Kohei K Matsumoto Morio M Nakamura Masaya M Okano Hideyuki H

Stem cell reports 20160922 4

Neural stem/progenitor cells (NS/PCs) derived from human induced pluripotent stem cells (hiPSCs) are considered to be a promising cell source for cell-based interventions that target CNS disorders. We previously reported that transplanting certain hiPSC-NS/PCs in the spinal cord results in tumor-like overgrowth of hiPSC-NS/PCs and subsequent deterioration of motor function. Remnant immature cells should be removed or induced into more mature cell types to avoid adverse effects of hiPSC-NS/PC tra ...[more]

PMID: 27666789

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Project description:Spinal cord injury (SCI) results in rapid and extensive sublesional bone loss. Sclerostin, an osteocyte-derived glycoprotein that negatively regulates intraskeletal Wnt signaling, is elevated after SCI and may represent a mechanism underlying this excessive bone loss. However, it remains unknown whether pharmacologic sclerostin inhibition ameliorates bone loss subsequent to SCI. Our primary purposes were to determine whether a sclerostin antibody (Scl-Ab) prevents hindlimb cancellous bone loss in a rodent SCI model and to compare the effects of a Scl-Ab to that of testosterone-enanthate (TE), an agent that we have previously shown prevents SCI-induced bone loss. Fifty-five (n = 11-19/group) skeletally mature male Sprague-Dawley rats were randomized to receive: (A) SHAM surgery (T8 laminectomy), (B) moderate-severe (250 kilodyne) SCI, (C) 250 kilodyne SCI + TE (7.0 mg/wk, im), or (D) 250 kilodyne SCI + Scl-Ab (25 mg/kg, twice weekly, sc) for 3 weeks. Twenty-one days post-injury, SCI animals exhibited reduced hindlimb cancellous bone volume at the proximal tibia (via μCT and histomorphometry) and distal femur (via μCT), characterized by reduced trabecular number and thickness. SCI also reduced trabecular connectivity and platelike trabecular structures, indicating diminished structural integrity of the remaining cancellous network, and produced deficits in cortical bone (femoral diaphysis) strength. Scl-Ab and TE both prevented SCI-induced cancellous bone loss, albeit via differing mechanisms. Specifically, Scl-Ab increased osteoblast surface and bone formation, indicating direct bone anabolic effects, whereas TE reduced osteoclast surface with minimal effect on bone formation, indicating antiresorptive effects. The deleterious microarchitectural alterations in the trabecular network were also prevented in SCI + Scl-Ab and SCI + TE animals, whereas only Scl-Ab completely prevented the reduction in cortical bone strength. Our findings provide the first evidence indicating that sclerostin inhibition represents a viable treatment to prevent SCI-induced cancellous and cortical bone deficits and provides preliminary rationale for future clinical trials focused on evaluating whether Scl-Ab prevents osteoporosis in the SCI population.

Project description:BackgroundSpinal cord ischemia/reperfusion injury (SCII) is one of the most serious spinal cord complications that stem from varied spine injuries or thoracoabdominal aortic surgery. Nevertheless, the molecular mechanisms underlying the SCII remain unclear.MethodsMale Sprague-Dawley (SD) rats were randomly divided into 5 groups of sham, SCII 24 h, SCII 72 h, sevoflurane preconditioning SCII 24 h (SCII 24 h+sevo), and sevoflurane preconditioning SCII 72 h (SCII 72 h+sevo) group. We then analyzed the expression of differentially expressed micro RNAs (DEmiRNAs) in these groups and their target genes. Functional enrichment analysis of their target genes was further performed using Metascape software. The microRNA-messenger RNA-pathway (miRNA-mRNA-pathway) network and the sevoflurane-miRNA-mRNA-pathway integrative network were further constructed to explore the molecular mechanisms underlying SCII and neuroprotective effects of sevoflurane against SCII. Molecular docking was also performed to evaluate the interactions between hub targets and sevoflurane. Finally, the expression levels of miR-21-5p and its target genes [mitogen-activated protein kinase kinase 3 and protein phosphatase 1 regulatory subunit 3B (MAP2K3 and PPP1R3B)] were measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analyses.ResultsWe found that sevoflurane alters several miRNA expression following SCII at 24 and 72 h after reperfusion. It was shown that miR-221-3p, miR-181a-1-3p, and miR-21-5p were upregulated both at 24 and 72 h in the sevoflurane pre-treatment reperfusion groups. Functional enrichment analysis revealed that target genes for the above co-DEmiRNAs at 24 and 72 h in the SCII group with sevoflurane pretreatment participated in the mitogen-activated protein kinase (MAPK), ErbB, apoptosis, and transforming growth factor-beta (TGF-beta) signaling pathways. Both MAP2K3 and PPP1R3B were found to be common targets for sevoflurane and miRNA-mRNA-pathway (rno-miR-21-5p). It was shown that MAP2K3 regulates the MAPK signaling and the T cell receptor signaling pathways, whereas PPP1R3B regulates the ErbB signaling pathway. Molecular docking further revealed that sevoflurane strongly binds the MAP2K3 and PPP1R3B proteins. Compared to the sham group, SCII induced significant under-expression of miR-21-5p but upregulated PPP1R3B and MAP2K3 proteins; sevoflurane pretreatment increased the expression of miR-21-5p but decreased those of PPP1R3B and MAP2K3 proteins.ConclusionsIn general, sevoflurane regulates the expression of several miRNAs following SCII. In particular, sevoflurane might protect against SCII via regulating the expression of miR-21-5p, its target genes (MAP2K3 and PPP1R3B), and related signaling pathways.

Dataset Information

Pretreatment with a ?-Secretase Inhibitor Prevents Tumor-like Overgrowth in Human iPSC-Derived Transplants for Spinal Cord Injury.

Publications

Pretreatment with a γ-Secretase Inhibitor Prevents Tumor-like Overgrowth in Human iPSC-Derived Transplants for Spinal Cord Injury.

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