Rejuvenation of mesenchymal stromal cells via partial reprogramming enables scalable generation of transcriptionally diverse MSC libraries.

IF 7.3 2区医学 Q1 CELL & TISSUE ENGINEERING Stem Cell Research & Therapy Pub Date : 2026-03-20 DOI:10.1186/s13287-026-04977-8

Haochen Tu, Aoi Hosaka, Genki Hichiwa, Yayan Wang, Kanako Kazuki, Toshiaki Tabata, Mitsuhiko Osaki, Yuji Nakayama, Iori Kanazawa, Kazuhisa Honma, Makoto T Kimura, Xu Gao, Norichika Ogata, Satoshi Abe, Mitsuo Oshimura, Yasuhiro Kazuki

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Abstract

Background: Mesenchymal stromal cells (MSCs) are widely used in regenerative medicine, but their clinical utility is limited by replicative senescence. Strategies that reverse aging while maintaining MSC identity are urgently needed.

Methods: We developed a non-integrating, temperature-sensitive Sendai virus (SeV)-mediated rejuvenation protocol transiently expressing hTERT, BMI1, and SV40T in human MSCs. Following SeV removal, we evaluated proliferation, telomere length, karyotype stability, transcriptomic reset, producing heterogeneity, and differentiation potential.

Results: Rejuvenated MSCs (rej-MSCs) demonstrated extended proliferation beyond 100 days, telomere elongation, and normal karyotypes after SeV clearance. Transcriptomic profiling showed a reset of senescence-associated programs while retaining mesenchymal identity. Functional analyses revealed clone-specific heterogeneity, including HGF-driven angiogenic activity. Multilineage differentiation capacity was preserved across rej-MSCs.

Conclusions: This transient, non-integrating rejuvenation strategy establishes an operational definition of rej-MSCs and provides a transcriptionally diverse and scalable platform for MSC manufacturing and precision therapy design.

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通过部分重编程实现间充质间质细胞的返老还童，使转录多样化的间充质间质文库能够规模化生成。

背景：间充质间质细胞（MSCs）广泛应用于再生医学，但其临床应用受到复制性衰老的限制。迫切需要在保持MSC身份的同时逆转衰老的策略。方法：我们开发了一种在人间充质干细胞中瞬时表达hTERT、BMI1和SV40T的非整合、温度敏感的仙台病毒（SeV）介导的返老方案。去除SeV后，我们评估了增殖、端粒长度、核型稳定性、转录组重置、产生异质性和分化潜力。结果：在SeV清除后，再生的MSCs （rej-MSCs）增殖超过100天，端粒延长，核型正常。转录组学分析显示，在保留间质特性的同时，衰老相关程序的重置。功能分析揭示了克隆特异性异质性，包括hgf驱动的血管生成活性。多系分化能力在jj - mscs中得以保留。结论：这种短暂的、非整合的再生策略建立了rej-MSCs的可操作定义，并为MSC制造和精确治疗设计提供了转录多样化和可扩展的平台。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Stem Cell Research & Therapy CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL

CiteScore

13.20

自引率

8.00%

发文量

525

审稿时长

1 months

期刊介绍： Stem Cell Research & Therapy serves as a leading platform for translational research in stem cell therapies. This international, peer-reviewed journal publishes high-quality open-access research articles, with a focus on basic, translational, and clinical research in stem cell therapeutics and regenerative therapies. Coverage includes animal models and clinical trials. Additionally, the journal offers reviews, viewpoints, commentaries, and reports.