Multi-omic analysis reveals divergent molecular events in scarring and regenerative wound healing.
Multi-omic analysis reveals divergent molecular events in scarring and regenerative wound healing.
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DOI：
10.1016/j.stem.2021.12.011
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发表时间：
2022-02-03
期刊：
影响因子：
23.9
通讯作者：
Longaker MT
中科院分区：
文献类型：
--
作者：
Mascharak S;Talbott HE;Januszyk M;Griffin M;Chen K;Davitt MF;Demeter J;Henn D;Bonham CA;Foster DS;Mooney N;Cheng R;Jackson PK;Wan DC;Gurtner GC;Longaker MT
再生是组织修复的圣杯，但皮肤损伤通常会产生纤维化、无功能性疤痕。开发促再生疗法需要严格了解从损伤到纤维化或再生的分子进展。在这里，我们报告了驱动皮肤伤口细胞形成疤痕或再生命运的不同分子事件。我们在转录（单细胞 RNA 测序）、蛋白质（timsTOF 蛋白质组学）和组织（细胞外基质超微结构分析）水平上分析了疤痕形成与 YAP 抑制诱导的伤口再生。使用细胞表面条形码，我们整合这些数据来揭示纤维化和再生的愈合“分子轨迹”。我们发现，破坏 YAP 机械转导可通过激活 Trps1 和 Wnt 信号传导的成纤维细胞产生再生修复。最后，通过体内基因敲低和伤口中的过度表达，我们将Trps1确定为伤口再生所必需且部分充分的关键调控基因。我们的研究结果作为伤口再生的多组学图谱，可能对病理性纤维化具有治疗意义。 Mascharak、Talbott、Januszyk 等人利用单细胞转录组、蛋白质组和组织超微结构数据的综合分析。在 YAP 抑制的背景下，定义了疤痕形成与伤口再生的不同分子轨迹。他们揭示了 Trps1 在驱动伤口再生中的关键作用，并表明激活的 Wnt 和 Trps1 信号传导是再生愈合的标志。
Regeneration is the holy grail of tissue repair, but skin injury typically yields fibrotic, non-functional scars. Developing pro-regenerative therapies requires rigorous understanding of the molecular progression from injury to fibrosis or regeneration. Here, we report the divergent molecular events driving skin wound cells toward scarring or regenerative fates. We profile scarring versus YAP-inhibition-induced wound regeneration at the transcriptional (single-cell RNA sequencing), protein (timsTOF proteomics), and tissue (extracellular matrix ultrastructural analysis) levels. Using cell-surface barcoding, we integrate these data to reveal fibrotic and regenerative “molecular trajectories” of healing. We show that disrupting YAP mechanotransduction yields regenerative repair by fibroblasts with activated Trps1 and Wnt signaling. Finally, via in vivo gene knockdown and overexpression in wounds, we identify Trps1 as a key regulatory gene that is necessary and partially sufficient for wound regeneration. Our findings serve as a multi-omic map of wound regeneration and could have therapeutic implications for pathologic fibroses. Using integrated analysis of single-cell transcriptomic, proteomic, and tissue ultrastructural data, Mascharak, Talbott, Januszyk, et al. define divergent molecular trajectories of scarring versus wound regeneration in the context of YAP inhibition. They reveal a key role for Trps1 in driving wound regeneration and show that activated Wnt and Trps1 signaling are hallmarks of regenerative healing.
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影响因子：
4.8
作者：
Aarabi, Shahram;Bhatt, Kirit A.;Gurtner, Geoffrey C.
通讯作者：
Gurtner, Geoffrey C.
影响因子：
48
作者：
Aibar, Sara;Gonzalez-Blas, Carmen Bravo;Aerts, Stein
通讯作者：
Aerts, Stein
DOI：
10.1126/science.aba2374
发表时间：
2021-04-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
通讯作者：
--
影响因子：
6.5
作者：
Myung, Peggy S.;Takeo, Makoto;Ito, Mayumi;Atit, Radhika P.
通讯作者：
Atit, Radhika P.
影响因子：
3.6
作者：
Phan QM;Sinha S;Biernaskie J;Driskell RR
通讯作者：
Driskell RR