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Heterogeneity in old fibroblasts is linked to variability in reprogramming and wound healing

机译：旧成纤维细胞的异质性与重编程和伤口愈合的变异性有关

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摘要

Age-associated chronic inflammation (inflammageing) is a central hallmark of ageing(1), but its influence on specific cells remains largely unknown. Fibroblasts are present in most tissues and contribute to wound healing(2,3). They are also the most widely used cell type for reprogramming to induced pluripotent stem (iPS) cells, a process that has implications for regenerative medicine and rejuvenation strategies(4). Here we show that fibroblast cultures from old mice secrete inflammatory cytokines and exhibit increased variability in the efficiency of iPS cell reprogramming between mice. Variability between individuals is emerging as a feature of old age(5-8), but the underlying mechanisms remain unknown. To identify drivers of this variability, we performed multi-omics profiling of fibroblast cultures from young and old mice that have different reprogramming efficiencies. This approach revealed that fibroblast cultures from old mice contain 'activated fibroblasts' that secrete inflammatory cytokines, and that the proportion of activated fibroblasts in a culture correlates with the reprogramming efficiency of that culture. Experiments in which conditioned medium was swapped between cultures showed that extrinsic factors secreted by activated fibroblasts underlie part of the variability between mice in reprogramming efficiency, and we have identified inflammatory cytokines, including TNF, as key contributors. Notably, old mice also exhibited variability in wound healing rate in vivo. Single-cell RNA-sequencing analysis identified distinct subpopulations of fibroblasts with different cytokine expression and signalling in the wounds of old mice with slow versus fast healing rates. Hence, a shift in fibroblast composition, and the ratio of inflammatory cytokines that they secrete, may drive the variability between mice in reprogramming in vitro and influence wound healing rate in vivo. This variability may reflect distinct stochastic ageing trajectories between individuals, and could help in developing personalized strategies to improve iPS cell generation and wound healing in elderly individuals.
机译：与年龄相关的慢性炎症（发炎）是衰老的主要特征（1），但其对特定细胞的影响仍未知。成纤维细胞存在于大多数组织中，有助于伤口愈合（2,3）。它们也是用于重编程为诱导多能干（iPS）细胞的最广泛使用的细胞类型，这一过程对再生医学和复兴策略具有重要意义（4）。在这里，我们显示了成年小鼠的成纤维细胞培养物会分泌炎性细胞因子，并在小鼠之间的iPS细胞重编程效率中显示出增加的可变性。个体之间的差异正在逐渐成为老年人的特征（5-8岁），但其潜在机制仍然未知。为了确定这种可变性的驱动因素，我们对具有不同重编程效率的年轻和成年小鼠的成纤维细胞培养物进行了多组学分析。这种方法表明，来自老年小鼠的成纤维细胞培养物含有分泌炎症细胞因子的“活化成纤维细胞”，并且在培养物中活化成纤维细胞的比例与该培养物的重编程效率相关。在不同培养物之间交换条件培养基的实验表明，活化成纤维细胞分泌的外在因素是小鼠之间重编程效率差异的部分原因，并且我们已确定包括TNF在内的炎症细胞因子是关键因素。值得注意的是，老小鼠体内的伤口愈合速度也表现出差异。单细胞RNA测序分析确定了成年老小鼠伤口中成纤维细胞的不同亚群，它们具有不同的细胞因子表达和信号传导，具有慢速愈合速度和快速愈合速度。因此，成纤维细胞组成的变化以及它们分泌的炎性细胞因子的比率可能会驱动小鼠在体外重编程时的变异性，并影响体内伤口的愈合速度。这种变异性可能反映了个体之间不同的随机衰老轨迹，并可能有助于开发个性化策略以改善老年个体的iPS细胞生成和伤口愈合。

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  • 来源
    《Nature》 |2019年第7779期|553-558|共6页
  • 作者

    Mahmoudi Salah; Mancini Elena; Xu Lucy; Moore Alessandra; Jahanbani Fereshteh; Hebestreit Katja; Srinivasan Rajini; Li Xiyan; Devarajan Keerthana; Prelot Laurie; Ang Cheen Euong; Shibuya Yohei; Benayoun Berenice A.; Chang Anne Lynn S.; Wernig Marius; Wysocka Joanna; Longaker Michael T.; Snyder Michael P.; Brunet Anne;

  • 作者单位

    Stanford Univ Dept Genet Stanford CA 94305 USA;

    Stanford Univ Dept Genet Stanford CA 94305 USA|Stanford Univ Dept Biol Stanford CA 94305 USA;

    Stanford Univ Dept Surg Div Plast & Reconstruct Surg Stanford CA 94305 USA|Stanford Univ Inst Stem Cell Biol & Regenerat Med Stanford CA 94305 USA;

    Stanford Univ Inst Stem Cell Biol & Regenerat Med Stanford CA 94305 USA|Stanford Univ Dept Chem & Syst Biol Stanford CA 94305 USA;

    Stanford Univ Inst Stem Cell Biol & Regenerat Med Stanford CA 94305 USA|Stanford Univ Dept Bioengn Stanford CA 94305 USA|Stanford Univ Dept Pathol Stanford CA 94305 USA;

    Stanford Univ Inst Stem Cell Biol & Regenerat Med Stanford CA 94305 USA|Stanford Univ Dept Pathol Stanford CA 94305 USA;

    Stanford Univ Dept Genet Stanford CA 94305 USA|Univ Southern Calif Leonard Davis Sch Gerontol Los Angeles CA USA;

    Stanford Univ Dept Dermatol Stanford CA 94305 USA;

    Stanford Univ Dept Genet Stanford CA 94305 USA|Stanford Univ Glenn Labs Biol Aging Stanford CA 94305 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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