Mechanical memory stored through epigenetic remodeling reduces cell therapeutic potential.
Mechanical memory stored through epigenetic remodeling reduces cell therapeutic potential.
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通过表观遗传重塑存储的机械记忆降低了细胞的治疗潜力。
DOI：
10.1016/j.bpj.2023.03.004
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发表时间：
2023
影响因子：
3.4
通讯作者：
Neu,CoreyP
中科院分区：
文献类型：
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作者：
Scott,AdrienneK;Casas,Eduard;Schneider,StephanieE;Swearingen,AlisonR;VanDenElzen,CourtneyL;Seelbinder,Benjamin;Barthold,JeanneE;Kugel,JenniferF;Stern,JoshLewis;Foster,KylaJ;Emery,NancyC;Brumbaugh,Justin;Neu,CoreyP
了解细胞如何记住先前的机械环境来影响它们的命运，或机械记忆，可以为生物材料的设计和医学治疗提供信息。目前的再生疗法，如软骨再生手术，需要二维细胞扩增过程来获得对修复受损组织至关重要的大细胞群。然而，在扩展过程中诱导长期机械记忆之前，软骨再生过程的机械启动的限制是未知的，并且确定物理环境如何影响细胞治疗潜力的机制仍然知之甚少。在这里，我们确定了一个阈值，机械启动分离可逆和不可逆的机械记忆效应。在二维培养16倍群体后，原代软骨细胞（软骨细胞）中组织识别基因的表达水平在转移到三维水凝胶时没有恢复，而这些基因的表达水平仅在扩增8倍群体的细胞中恢复。此外，我们发现软骨细胞表型的丧失和恢复与染色质结构的变化相关，如H3K9三甲基化的结构重塑所示。通过抑制或增加H3K9me3水平来破坏染色质结构的努力表明，只有随着H3K9me3水平的增加，天然软骨细胞表型的染色质结构才会部分恢复，同时软骨基因表达水平也会增加。这些结果进一步支持了软骨细胞表型和染色质结构之间的联系，也揭示了表观遗传修饰因子抑制剂作为机械记忆破坏者的治疗潜力，当大量表型合适的细胞需要用于再生过程时。
Understanding how cells remember previous mechanical environments to influence their fate, or mechanical memory, informs the design of biomaterials and therapies in medicine. Current regeneration therapies, such as cartilage regeneration procedures, require 2D cell expansion processes to achieve large cell populations critical for the repair of damaged tissues. However, the limit of mechanical priming for cartilage regeneration procedures before inducing long-term mechanical memory following expansion processes is unknown, and mechanisms defining how physical environments influence the therapeutic potential of cells remain poorly understood. Here, we identify a threshold to mechanical priming separating reversible and irreversible effects of mechanical memory. After 16 population doublings in 2D culture, expression levels of tissue-identifying genes in primary cartilage cells (chondrocytes) are not recovered when transferred to 3D hydrogels, while expression levels of these genes were recovered for cells only expanded for eight population doublings. Additionally, we show that the loss and recovery of the chondrocyte phenotype correlates with a change in chromatin architecture, as shown by structural remodeling of the trimethylation of H3K9. Efforts to disrupt the chromatin architecture by suppressing or increasing levels of H3K9me3 reveal that only with increased levels of H3K9me3 did the chromatin architecture of the native chondrocyte phenotype partially return, along with increased levels of chondrogenic gene expression. These results further support the connection between the chondrocyte phenotype and chromatin architecture, and also reveal the therapeutic potential of inhibitors of epigenetic modifiers as disruptors of mechanical memory when large numbers of phenotypically suitable cells are required for regeneration procedures.