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Calreticulin exploits TGF‐β for extracellular matrix induction engineering a tissue regenerative process
The FASEB Journal ( IF 4.4 ) Pub Date : 2020-10-05 , DOI: 10.1096/fj.202001161r
Unnati M. Pandya 1 , Miguel A. Manzanares 1 , Ana Tellechea 1 , Chinaza Egbuta 1 , Julien Daubriac 1 , Couger Jimenez‐Jaramillo 1 , Fares Samra 1 , Alexa Fredston‐Hermann 1 , Khalil Saadipour 1 , Leslie I. Gold 1, 2
Affiliation  

Topical application of extracellular calreticulin (eCRT), an ER chaperone protein, in animal models enhances wound healing and induces tissue regeneration evidenced by epidermal appendage neogenesis and lack of scarring. In addition to chemoattraction of cells critical to the wound healing process, eCRT induces abundant neo‐dermal extracellular matrix (ECM) formation by 3 days post‐wounding. The purpose of this study was to determine the mechanisms involved in eCRT induction of ECM. In vitro, eCRT strongly induces collagen I, fibronectin, elastin, α‐smooth muscle actin in human adult dermal (HDFs) and neonatal fibroblasts (HFFs) mainly via TGF‐β canonical signaling and Smad2/3 activation; RAP, an inhibitor of LRP1 blocked eCRT ECM induction. Conversely, eCRT induction of α5 and β1 integrins was not mediated by TGF‐β signaling nor inhibited by RAP. Whereas eCRT strongly induces ECM and integrin α5 proteins in K41 wild‐type mouse embryo fibroblasts (MEFs), CRT null MEFs were unresponsive. The data show that eCRT induces the synthesis and release of TGF‐β3 first via LRP1 or other receptor signaling and later induces ECM proteins via LRP1 signaling subsequently initiating TGF‐β receptor signaling for intracellular CRT (iCRT)‐dependent induction of TGF‐β1 and ECM proteins. In addition, TGF‐β1 induces 2‐3‐fold higher level of ECM proteins than eCRT. Whereas eCRT and iCRT converge for ECM induction, we propose that eCRT attenuates TGF‐β‐mediated fibrosis/scarring to achieve tissue regeneration.

中文翻译:

钙网蛋白利用 TGF-β 进行细胞外基质诱导工程组织再生过程

细胞外钙网蛋白 (eCRT)(一种 ER 伴侣蛋白)在动物模型中的局部应用可增强伤口愈合并诱导组织再生,这一点由表皮附属物新生和无疤痕证明。除了对伤口愈合过程至关重要的细胞的化学吸引外,eCRT 在伤口后 3 天诱导大量新真皮细胞外基质 (ECM) 形成。本研究的目的是确定 eCRT 诱导 ECM 所涉及的机制。在体外,eCRT 主要通过 TGF-β 经典信号传导和 Smad2/3 激活强烈诱导成人真皮 (HDF) 和新生儿成纤维细胞 (HFF) 中的胶原 I、纤连蛋白、弹性蛋白、α-平滑肌肌动蛋白;RAP 是一种 LRP1 抑制剂,可阻断 eCRT ECM 诱导。相反,eCRT 对 α5 和 β1 整联蛋白的诱导不受 TGF-β 信号的介导,也不受 RAP 的抑制。eCRT 在 K41 野生型小鼠胚胎成纤维细胞 (MEF) 中强烈诱导 ECM 和整合素α5 蛋白,而 CRT 无效 MEF 没有反应。数据显示,eCRT 首先通过 LRP1 或其他受体信号传导诱导 TGF-β3 的合成和释放,然后通过 LRP1 信号传导诱导 ECM 蛋白,随后启动 TGF-β 受体信号传导,用于细胞内 CRT (iCRT) 依赖的 TGF-β1 诱导和ECM 蛋白。此外,TGF-β1 诱导的 ECM 蛋白水平比 eCRT 高 2-3 倍。eCRT 和 iCRT 会聚用于 ECM 诱导,我们建议 eCRT 减弱 TGF-β 介导的纤维化/瘢痕形成以实现组织再生。数据显示,eCRT 首先通过 LRP1 或其他受体信号传导诱导 TGF-β3 的合成和释放,然后通过 LRP1 信号传导诱导 ECM 蛋白,随后启动 TGF-β 受体信号传导,用于细胞内 CRT (iCRT) 依赖的 TGF-β1 诱导和ECM 蛋白。此外,TGF-β1 诱导的 ECM 蛋白水平比 eCRT 高 2-3 倍。eCRT 和 iCRT 会聚用于 ECM 诱导,我们建议 eCRT 减弱 TGF-β 介导的纤维化/瘢痕形成以实现组织再生。数据显示,eCRT 首先通过 LRP1 或其他受体信号传导诱导 TGF-β3 的合成和释放,然后通过 LRP1 信号传导诱导 ECM 蛋白,随后启动 TGF-β 受体信号传导,用于细胞内 CRT (iCRT) 依赖的 TGF-β1 诱导和ECM 蛋白。此外,TGF-β1 诱导的 ECM 蛋白水平比 eCRT 高 2-3 倍。eCRT 和 iCRT 会聚用于 ECM 诱导,我们建议 eCRT 减弱 TGF-β 介导的纤维化/瘢痕形成以实现组织再生。
更新日期:2020-10-05
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