通过移植骨髓单核细胞,将基因工程血液系统的抗癌和延长寿命的能力进行长期的造血转移。

Long-term hematopoietic transfer of the anti-cancer and lifespan-extending capabilities of a genetically engineered blood system by transplantation of bone marrow mononuclear cells.

机构信息

The Ph.D. Program in Medicine Neuroscience, Taipei Medical University, Taipei, Taiwan.

Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.

出版信息

Elife. 2024 May 16;12:RP88275. doi: 10.7554/eLife.88275.

Abstract

A causal relationship exists among the aging process, organ decay and disfunction, and the occurrence of various diseases including cancer. A genetically engineered mouse model, termed or (K74R), carrying mutation on the well-conserved sumoylation site of the hematopoietic transcription factor KLF1/EKLF has been generated that possesses extended lifespan and healthy characteristics, including cancer resistance. We show that the healthy longevity characteristics of the (K74R) mice, as exemplified by their higher anti-cancer capability, are likely gender-, age-, and genetic background-independent. Significantly, the anti-cancer capability, in particular that against melanoma as well as hepatocellular carcinoma, and lifespan-extending property of (K74R) mice, could be transferred to wild-type mice via transplantation of their bone marrow mononuclear cells at a young age of the latter. Furthermore, NK(K74R) cells carry higher in vitro cancer cell-killing ability than wild-type NK cells. Targeted/global gene expression profiling analysis has identified changes in the expression of specific proteins, including the immune checkpoint factors PDCD and CD274, and cellular pathways in the leukocytes of the (K74R) that are in the directions of anti-cancer and/or anti-aging. This study demonstrates the feasibility of developing a transferable hematopoietic/blood system for long-term anti-cancer and, potentially, for anti-aging.

摘要

衰老过程、器官衰退和功能障碍以及包括癌症在内的各种疾病的发生之间存在因果关系。已经产生了一种称为或 (K74R) 的基因工程小鼠模型,该模型在造血转录因子 KLF1/EKLF 的高度保守的 sumoylation 位点携带突变,具有延长的寿命和健康特征,包括抗癌能力。我们表明,(K74R)小鼠的健康长寿特征,例如它们更高的抗癌能力,可能与性别、年龄和遗传背景无关。重要的是,(K74R)小鼠的抗癌能力,特别是对黑色素瘤和肝细胞癌的抗癌能力,以及延长寿命的特性,可以通过在后者年轻时移植其骨髓单核细胞转移到野生型小鼠中。此外,NK(K74R)细胞比野生型 NK 细胞具有更高的体外癌细胞杀伤能力。靶向/全局基因表达谱分析已经确定了(K74R)白细胞中特定蛋白质表达的变化,包括免疫检查点因子 PDCD 和 CD274,以及细胞途径,这些变化都朝着抗癌和/或抗衰老的方向发展。这项研究证明了开发可转移的造血/血液系统用于长期抗癌,并且可能用于抗衰老的可行性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa30/11098557/37403ac0960a/elife-88275-fig1.jpg

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