老年成纖維細胞異質性影響重編程與傷口癒合
作者：
小柯機器人發布時間：2019/10/24 16:24:33
美國史丹福大學Anne Brunet研究組發現，老年成纖維細胞的異質性與重編程和傷口癒合的變異性有關。相關論文發表於2019年10月24日的《自然》雜誌。
研究人員發現成年小鼠的成纖維細胞培養物會分泌炎性細胞因子，並在小鼠之間的誘導多能幹（iPS）細胞重編程效率中顯示出增加的變異性。個體之間的變異性正在逐漸成為老年的一個特徵，但是其潛在機制仍然未知。
為了確定這種可變性的驅動因素，研究人員對具有不同重編程效率的年輕和成年小鼠的成纖維細胞培養物進行了多組學分析。這種方法表明，來自老年小鼠的成纖維細胞培養物中含有分泌炎症細胞因子的「活化成纖維細胞」，並且在培養物中活化成纖維細胞的比例與該培養物的重編程效率相關。在不同培養液之間交換條件培養基的實驗表明，活化成纖維細胞分泌的外在因素是小鼠之間重編程效率變異的部分原因，並且研究人員已經確定了包括TNF在內的炎症細胞因子是關鍵因素。
值得注意的是，老小鼠體內的傷口癒合速度也表現出差異。單細胞RNA測序分析確定了成年老小鼠傷口中成纖維細胞的不同亞群，它們具有不同的細胞因子表達和信號傳導，具有慢速癒合速度和快速癒合速度。因此，成纖維細胞組成的變化以及它們分泌的炎性細胞因子的比率可能會驅動小鼠在體外重編程時的變異性，並影響體內傷口的癒合速度。這種變異性可能反映了個體之間不同的隨機衰老軌跡，並可能有助於開發個性化策略以改善老年個體的iPS細胞生成和傷口癒合。
據了解，與年齡相關的慢性炎症是衰老的主要特徵，但其對特定細胞的影響仍然未知。成纖維細胞存在於大多數組織中，並有助於傷口癒合。它們也是用於重編程為iPS細胞的最廣泛使用的細胞類型，這一過程對再生醫學具有重要意義。
附：英文原文
Title:Heterogeneity in old fibroblasts is linked to variability in reprogramming and wound healing
Author:Salah Mahmoudi, Elena Mancini, Lucy Xu, Alessandra Moore, Fereshteh Jahanbani, Katja Hebestreit, Rajini Srinivasan, Xiyan Li, Keerthana Devarajan, Laurie Prélot, Cheen Euong Ang, Yohei Shibuya, Bérénice A. Benayoun, Anne Lynn S. Chang, Marius Wernig, Joanna Wysocka, Michael T. Longaker, Michael P. Snyder & Anne Brunet
Issue&Volume:Volume 574 Issue 7779
Abstract: Age-associated chronic inflammation (inflammageing) is a central hallmark of ageing1, but its influence on specific cells remains largely unknown. Fibroblasts are present in most tissues and contribute to wound healing2,3. 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 strategies4. 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 age5,6,7,8, 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.
DOI:10.1038/s41586-019-1658-5