SummaryLoss of spiral ganglion neurons (SGNs) significantly contributes to hearing loss. Otic progenitor cell transplantation is a potential strategy to replace lost SGNs. Understanding how key transcription factors promote SGN differentiation in otic progenitors accelerates efforts for replacement therapies. A pro-neural transcription factor, Neurogenin1 (Neurog1), is essential for SGN development. Using an immortalized multipotent otic progenitor (iMOP) cell line that can self-renew and differentiate into otic neurons, NEUROG1 was enriched at the promoter of cyclin-dependent kinase 2 (Cdk2) and neurogenic differentiation 1 (NeuroD1) genes. Changes in H3K9ac and H3K9me3 deposition at the Cdk2 and NeuroD1 promoters suggested epigenetic regulation during iMOP proliferation and differentiation. In self-renewing iMOP cells, overexpression of NEUROG1 increased CDK2 to drive proliferation, while knockdown of NEUROG1 decreased CDK2 and reduced proliferation. In iMOP-derived neurons, overexpression of NEUROG1 accelerated acquisition of neuronal morphology, while knockdown of NEUROG1 prevented differentiation. Our findings suggest that NEUROG1 can promote proliferation or neuronal differentiation.
Even though gene repression is a powerful approach to exogenously regulate cellular behavior, developing a platform to effectively repress targeted genes, especially for stem cell applications, remains elusive. Herein, we introduce a nanomaterial-based platform that is capable of mimicking the function of transcription repressor proteins to downregulate gene expression at the transcriptional level for enhancing stem cell differentiation. We developed the NanoScript platform by integrating multiple gene repression molecules with a nanoparticle. First, we show a proof-of-concept demonstration using a GFP-specific NanoScript to knockdown GFP expression in neural stem cells (NSCs-GFP). Then, we show that a Sox9-specific NanoScript can repress Sox9 expression to initiate enhanced differentiation of NSCs into functional neurons. Overall, the tunable properties and gene knockdown capabilities of NanoScript enables its utilization for gene-repression applications in stem cell biology.
Use of human induced pluripotent stem cells (iPSC) or embryonic stem cells (ESC) for cell replacement therapies holds great promise. Several limitations including low yields and heterogeneous populations of differentiated cells hinder the progress of stem cell therapies. A fate restricted immortalized multipotent otic progenitor (iMOP) cell line was generated to facilitate efficient differentiation of large numbers of functional hair cells and spiral ganglion neurons (SGN) for inner ear cell replacement therapies. Starting from dissociated cultures of single iMOP cells, protocols that promote cell cycle exit and differentiation by growth factor (bFGF) withdrawal were described. A significant decrease in proliferating cells after bFGF withdrawal was confirmed using an EdU cell proliferation assay. Concomitant with a decrease in proliferation, successful differentiation resulted in expression of molecular markers and morphological changes. Immunostaining of Cdkn1b (p27KIP) and Cdh1 (E-cadherin) in iMOP-derived otospheres was used as an indicator for differentiation into inner ear sensory epithelia while immunostaining of Cdkn1b and Tubb3 (neuronal β-tubulin) was used to identify iMOP-derived neurons. Use of iMOP cells provides an important tool for understanding cell fate decisions made by inner ear neurosensory progenitors and will help develop protocols for generating large numbers of iPSC or ESC-derived hair cells and SGNs. These methods will accelerate efforts for generating otic cells for replacement therapies.
Background: We obtained conflicting results regarding the relationship between the genetic role of the rs1138272 C/T polymorphism of the GSTP1 (Glutathione S-Transferase pi) gene and the risk of various cancers.Methods: Using the presently available data, a meta-analysis was conducted to comprehensively evaluate the genetic relationship between the GSTP1 rs1138272 polymorphism and cancer susceptibility.Results: A total of 43 studies including 15,688 cases and 17,143 controls were recruited into our quantitative synthesis. In the overall population, we observed an increased risk of overall cancer cases, compared with unrelated controls, in the genetic models of allele T vs. allele C (P-association = 0.007, OR = 1.17), carrier T vs. carrier C (P-association = 0.035, OR = 1.11), TT vs. CC (P-association = 0.002, OR = 1.45), TT vs. CC+CT (P-association = 0.009, OR = 1.42), and CT+TT vs. CC (P-association = 0.027, OR = 1.13). We detected similar positive results within the Asian population. Additionally, there was a significant increase in the incidence of cancer for Africans under all genetic models (all P-association < 0.05, OR > 1). When targeting the Caucasian population, we detected a positive association with the TT vs. CC and TT vs. CC+CT models in the “Colorectal cancer” (P-association < 0.05, OR < 1) and “Head and neck cancer” (P-association < 0.05, OR > 1) subgroups. For the “Lung cancer” subgroup, we observed a slightly increased risk in Caucasians under the models of allele T vs. allele C, carrier T vs. carrier C, CT vs. CC, and CT+TT vs. CC (P-association < 0.05, OR > 1).Conclusion: The TT genotype of the GSTP1 rs1138272 polymorphism is likely related to the susceptibility to overall cancer in the Asian and African populations and, specifically, “Colorectal” and “Head and neck” cancers in the Caucasian population. In addition, the CT genotype of the GSTP1 rs1138272 polymorphism may be linked to the risk of lung cancer in Caucasians. Additional evidence is required to confirm this conclusion.
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