我们最近确定 TMEM230 是细胞内膜系统的主要调节因子。 TMEM230 表达对于促进运动蛋白依赖性金属蛋白的细胞内运输以在线粒体中产生细胞能量是必需的。 TMEM230 还需要金属蛋白酶的运输和分泌，以实现自噬和吞噬体依赖性清除错误折叠的蛋白质、缺陷 RNA 和受损细胞，以及随衰老而下降的活性。这表明 TMEM230 的异常水平可能会导致衰老，而恢复正常水平可能具有治疗应用。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。分泌的细胞成分在衰老过程中调节免疫反应和组织再生。细胞内包装、内体成分的运输和分泌的上调虽然是组织稳态和正常伤口愈合所必需的，但也促进促炎和促衰老因子的分泌。我们最近确定 TMEM230 与内膜系统的运输货物共同调节，包括溶酶体因子，例如 RNASET2。正常组织再生（衰老）、修复（损伤后）和异常破坏性组织重塑（癌症或自身免疫）可能受内膜系统、线粒体和自噬体的 TMEM230 活性调节。 TMEM230 在衰老中的作用得到了其调节高龄和慢性病患者组织细胞中促炎分泌组和衰老相关分泌表型的能力的支持。识别年轻患者和高龄患者中受 TMEM230 调节的分泌因子将有助于识别异常促进、抑制或逆转衰老的衰老相关靶标。用于识别组织再生和衰老中的分泌因子的患者来源细胞的异位培养为开发治疗和个性化医学策略提供了机会。组织再生中人类分泌因子的鉴定和验证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条件不同。我们描述了一个 3 维 (3D) 平台，利用非生物源和不稳定的聚 ε-己内酯支架，支持维持人类干细胞、体外生成的 3D 类器官和患者来源组织的长期连续培养。与不含动物成分的培养基相结合，非生物支架适用于蛋白质组学和糖生物学分析，以识别衰老中的人为因素。电纺纳米纤维技术在 3D 细胞培养中的应用可实现异位筛选、制定患者个性化治疗策略并预测其减轻或促进衰老的有效性。版权所有 © 2024。由 Elsevier Inc. 出版。

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.Copyright © 2024. Published by Elsevier Inc.