PNIPAAm-co-Jeffamine(®) (PNJ) scaffolds as in vitro models for niche enrichment of glioblastoma stem-like cells.
PNIPAAm-co-Jeffamine(®) (PNJ) scaffolds as in vitro models for niche enrichment of glioblastoma stem-like cells.
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DOI：
10.1016/j.biomaterials.2017.05.007
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发表时间：
2017-10
期刊：
影响因子：
14
通讯作者：
Sirianni RW
中科院分区：
文献类型：
--
作者：
Heffernan JM;McNamara JB;Borwege S;Vernon BL;Sanai N;Mehta S;Sirianni RW
胶质母细胞瘤（GBM）是最常见的成人原发性脑肿瘤，5年生存率低于5%。GBM恶性肿瘤部分由GBM干细胞样细胞（GSC）群体驱动，所述GBM干细胞样细胞（GSC）群体表现出无限的自我更新能力、多能分化、神经干细胞标志物的表达和对常规治疗的抗性。GSC富集在调节干细胞表型和支持GSC辐射抗性的专门的微环境中。因此，鉴定调节干细胞表型的GSC-生态位相互作用可能是破坏这种治疗抗性群体的维持和持久性的独特靶标。在这项工作中，我们从温度响应性聚（N-异丙基丙烯酰胺-co-Jeffamine M-1000®丙烯酰胺）或PNJ共聚物中设计了3D支架，作为在两种分子上不同的人类患者来源的GSC细胞系中富集干细胞特异性表型的平台。值得注意的是，我们观察到，与传统的神经球培养物相比，PNJ培养的GSC保持了多能性，并表现出增强的自我更新能力。已知调节GSC自我更新、侵袭和干细胞维持的蛋白质（NESTIN、EGFR、CD 44）表达的同时增加表明PNJ支架有效地富集了GSC群体。我们进一步观察到，与在标准神经球条件下培养的GSC相比，PNJ培养的GSC表现出对辐射处理的抗性增加。GSC辐射抗性在体内由小生境微环境支持，这仍然是有效治疗这些高度致瘤性细胞的重要障碍。总之，这些数据表明，由合成PNJ支架创建的微环境模拟了GSC在患者来源的GBM细胞系中的生态位富集，并为研究临床重要行为如体外辐射抗性提供了组织工程机会。
Glioblastoma (GBM) is the most common adult primary brain tumor, and the 5-year survival rate is less than 5%. GBM malignancy is driven in part by a population of GBM stem-like cells (GSCs) that exhibit indefinite self-renewal capacity, multipotent differentiation, expression of neural stem cell markers, and resistance to conventional treatments. GSCs are enriched in specialized niche microenvironments that regulate stem phenotypes and support GSC radioresistance. Therefore, identifying GSC-niche interactions that regulate stem phenotypes may present a unique target for disrupting the maintenance and persistence of this treatment resistant population. In this work, we engineered 3D scaffolds from temperature responsive poly(N-isopropylacrylamide-co-Jeffamine M-1000® acrylamide), or PNJ copolymers, as a platform for enriching stem-specific phenotypes in two molecularly distinct human patient-derived GSC cell lines. Notably, we observed that, compared to conventional neurosphere cultures, PNJ cultured GSCs maintained multipotency and exhibited enhanced self-renewal capacity. Concurrent increases in expression of proteins known to regulate self-renewal, invasion, and stem maintenance in GSCs (NESTIN, EGFR, CD44) suggest that PNJ scaffolds effectively enrich the GSC population. We further observed that PNJ cultured GSCs exhibited increased resistance to radiation treatment compared to GSCs cultured in standard neurosphere conditions. GSC radioresistance is supported in vivo by niche microenvironments, and this remains a significant barrier to effectively treating these highly tumorigenic cells. Taken in sum, these data indicate that the microenvironment created by synthetic PNJ scaffolds models niche enrichment of GSCs in patient-derived GBM cell lines, and presents tissue engineering opportunities for studying clinically important behaviors such as radioresistance in vitro.
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