open access

https://doi.org/10.14943/doctoral.k16533

https://hdl.handle.net/2115/97869

ハイドロゲル誘導性筋芽細胞分化とカルシウム駆動性神経膠芽腫幹細胞性におけるメカノケミストリーとイオン性微小環境の役割に関する研究

英語

2025-06-30

Hokkaido University

105p

Glioblastoma has a poor prognosis and a markedly low five-year survival rate. Glioma stemcells(GSCs) are regarded as a critical factor in recurrence, but the molecular mechanisms of GSCs generation in tumor microenvironment remain unclear. It has been reported that glioblastomatissueis rich in positive charges due to the influence of the extracellular matrix and hypoxia. In this study, we developed adjustable, fully synthetic hydrogels to elucidate the effect of different charges onstemness induction. By varying the concentration of polymer-associated ionizable monomers, wesynthesized hydrogels with surface charges ranging from negative to positive, and found that cationichydrogels induced stem cell characteristics to the greatest extent. RNA sequencing revealedthat cationic hydrogels enhance the expression of genes related to epithelial-to-mesenchymal transition, improve cell tolerance to temozolomide, and increase the expression of calciumchannel proteins. Mechanistically, chromatin immunoprecipitation assays demonstrated that the cationic hydrogel activates the calcium ion-NFAT pathway, allowing NFATc1 and NFATc2 to translocate intothenucleus and act as transcription factors, thereby inducing c-Myc expression to promote glioblastomastemness. The knockdown of NFATc1 and c-Myc significantly reduced cationic hydrogel-inducedstemness, indicating that NFAT and c-Myc are crucial for this process. Spatial transcriptomeanalysisdemonstrated that c-Myc is expressed surrounding palisading necrosis areas in addition toperivascular regions in human glioblastoma tissues. These results suggest that positively chargedtumor microenvironment promote malignant phenotypes through calcium-NFAT-c-Myc-drivenglioma reprogramming, providing a new strategy for glioma treatment.

2025-06-30

甲第16533号

博士(ソフトマター科学)

(主査) 准教授 津田 真寿美, 教授 芳賀 永, 教授 黒川 孝幸, 教授 田中 伸哉 （医学研究院）, 准教授 中島 祐

生命科学院（ソフトマター専攻）

博士論文

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