在非生物源电纺支架中长期培养源自患者的乳腺器官组织,以确定衰老和衰老过程中金属蛋白和运动蛋白的活性。

3区 生物学 Q1 Biochemistry, Genetics and Molecular Biology
Eleonora Piscitelli, Iriczalli Cruz Maya, Cinzia Cocola, Valentina Martino, Edoardo Abeni, Paride Pelucchi, Elena Angeli, Patrizia Guida, Arianna Consiglio, Giorgio Grillo, Theodoros Karnavas, Angelos Gritzapis, Mira Palizban, Ioannis Missitzis, Martin Götte, Sabino Luini, James Kehler, Cristiana Balbino, Vincenzo Guarino, Luciano Milanesi, Ileana Zucchi, Alberto Diaspro, Rolland Reinbold
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引用次数: 0

摘要

我们最近发现 TMEM230 是细胞内膜系统的主调节器。TMEM230 的表达对于促进线粒体中用于细胞能量生产的金属蛋白的依赖性细胞内转运是必要的。TMEM230 也需要金属蛋白酶的运输和分泌,以进行自噬和吞噬体依赖性清除折叠错误的蛋白质、有缺陷的 RNA 和受损细胞,这些活动会随着衰老而减少。这表明,TMEM230 的异常水平可能会导致衰老,而恢复其正常水平可能具有治疗用途。内膜系统的组成部分包括高尔基复合体、其他膜结合细胞器以及分泌囊泡和因子。分泌的细胞成分可调节衰老过程中的免疫反应和组织再生。内质体成分的细胞内包装、贩运和分泌的上调虽然是组织稳态和正常伤口愈合所必需的,但也会促进促炎症和促衰老因子的分泌。我们最近发现,TMEM230 与内膜系统的转运货物(包括 RNASET2 等溶酶体因子)共同调控。正常的组织再生(衰老)、修复(损伤后)和异常的破坏性组织重塑(癌症或自身免疫)很可能受 TMEM230 内膜系统、线粒体和自噬体活动的调控。TMEM230 能够调节高龄和慢性病患者组织细胞中的促炎症分泌组和衰老相关分泌表型,这支持了 TMEM230 在衰老中的作用。在年轻患者和高龄患者中确定受 TMEM230 调节的分泌因子,将有助于确定与衰老相关的异常促进、抑制或逆转衰老的靶点。对患者衍生细胞进行原位培养,以确定组织再生和衰老过程中的分泌因子,为开发治疗和个性化医疗策略提供了机会。鉴定和验证组织再生中的人类分泌因子需要长期稳定的支架培养条件,这与之前报道的用作衰老细胞模型的细胞系的培养条件不同。我们介绍了一种三维(3D)平台,该平台利用非生物源性和非易损性聚ε-己内酯支架,支持长期连续培养人类干细胞、体外生成的三维有机体和患者衍生组织。结合不含动物成分的培养基,非生物源支架适用于蛋白质组学和糖生物学分析,以确定衰老的人为因素。在三维细胞培养中应用电纺纳米纤维技术,可以进行原位筛选,开发患者个性化治疗策略,并预测其在缓解或促进衰老方面的效果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Long-term culture of patient-derived mammary organoids in non-biogenic electrospun scaffolds for identifying metalloprotein and motor protein activities in aging and senescence.

We recently identified TMEM230 as a master regulator of the endomembrane system of cells. TMEM230 expression is necessary for promoting motor protein dependent intracellular trafficking of metalloproteins for cellular energy production in mitochondria. TMEM230 is also required for transport and secretion of metalloproteinases for autophagy and phagosome dependent clearance of misfolded proteins, defective RNAs and damaged cells, activities that decline with aging. This suggests that aberrant levels of TMEM230 may contribute to aging and regain of proper levels may have therapeutic applications. The components of the endomembrane system include the Golgi complex, other membrane bound organelles, and secreted vesicles and factors. Secreted cellular components modulate immune response and tissue regeneration in aging. Upregulation of intracellular packaging, trafficking and secretion of endosome components while necessary for tissue homeostasis and normal wound healing, also promote secretion of pro-inflammatory and pro-senescence factors. We recently determined that TMEM230 is co-regulated with trafficked cargo of the endomembrane system, including lysosome factors such as RNASET2. Normal tissue regeneration (in aging), repair (following injury) and aberrant destructive tissue remodeling (in cancer or autoimmunity) likely are regulated by TMEM230 activities of the endomembrane system, mitochondria and autophagosomes. The role of TMEM230 in aging is supported by its ability to regulate the pro-inflammatory secretome and senescence-associated secretory phenotype in tissue cells of patients with advanced age and chronic disease. Identifying secreted factors regulated by TMEM230 in young patients and patients of advanced age will facilitate identification of aging associated targets that aberrantly promote, inhibit or reverse aging. Ex situ culture of patient derived cells for identifying secreted factors in tissue regeneration and aging provides opportunities in developing therapeutic and personalized medicine strategies. Identification and validation of human secreted factors in tissue regeneration requires long-term stabile scaffold culture conditions that are different from those previously reported for cell lines used as cell models for aging. We describe a 3 dimensional (3D) platform utilizing non-biogenic and non-labile poly ε-caprolactone scaffolds that supports maintenance of long-term continuous cultures of human stem cells, in vitro generated 3D organoids and patient derived tissue. Combined with animal component free culture media, non-biogenic scaffolds are suitable for proteomic and glycobiological analyses to identify human factors in aging. Applications of electrospun nanofiber technologies in 3D cell culture allow for ex situ screening and the development of patient personalized therapeutic strategies and predicting their effectiveness in mitigating or promoting aging.

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来源期刊
Advances in protein chemistry and structural biology
Advances in protein chemistry and structural biology BIOCHEMISTRY & MOLECULAR BIOLOGY-
CiteScore
7.40
自引率
0.00%
发文量
66
审稿时长
>12 weeks
期刊介绍: Published continuously since 1944, The Advances in Protein Chemistry and Structural Biology series has been the essential resource for protein chemists. Each volume brings forth new information about protocols and analysis of proteins. Each thematically organized volume is guest edited by leading experts in a broad range of protein-related topics.
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