Cysteine-rich domain of type III collagen N-propeptide inhibits fibroblast activation by attenuating TGFβ signaling.
Cysteine-rich domain of type III collagen N-propeptide inhibits fibroblast activation by attenuating TGFβ signaling.
复制标题
DOI：
10.1016/j.matbio.2022.03.004
复制
发表时间：
2022-05
期刊：
影响因子：
6.9
通讯作者：
Volk, Susan W.
中科院分区：
文献类型：
--
作者：
Brisson, Becky K.;Stewart, Daniel C.;Burgwin, Chelsea;Chenoweth, David;Wells, Rebecca G.;Adams, Sherrill L.;Volk, Susan W.
关键词：
TGFβ是细胞与细胞外基质之间动态相互作用的关键调节因子，其驱动组织修复和肿瘤微环境中的生理和病理反应。我们的研究将III型胶原（Col 3）定义为通过其对肌成纤维细胞的部分作用而抑制瘢痕形成和结缔组织增生的抑制剂。TGFβ刺激肌成纤维细胞的活化，在这里，我们证明了培养的Col 3缺陷型成纤维细胞与野生型成纤维细胞相比具有增加的TGFβ信号传导。此外，动力学结合研究表明，在其N-前肽中发现的含有Col 3富含半胱氨酸（CR）结构域的合成肽以剂量依赖性方式与TGFβ1结合，而具有突变半胱氨酸的CR对照肽不与TGFβ1结合，这表明Col 3部分地通过N-前肽CR结构域减弱TGFβ信号传导。与该假设一致，CR肽减弱成纤维细胞和4 T1乳腺癌细胞中的TGFβ信号传导，并抑制成纤维细胞活化和收缩，如通过α-平滑肌肌动蛋白染色、可变形硅胶的细胞粘附和应激成纤维细胞填充的胶原晶格收缩试验所评估的。最后，与CR对照相比，原位注射的乳腺癌细胞（4 T1）的CR肽处理抑制肿瘤内成纤维细胞活化并抑制原发性肿瘤生长。用CR肽治疗降低了肿瘤内典型和非典型下游TGFβ信号传导靶标，与其与TGFβ的细胞外结合一致。综上所述，我们的结果表明，Col 3 N-前肽CR结构域结合TGFβ1并减弱（但重要的是不消除）成纤维细胞和癌细胞中的TGFβ信号传导。扩展我们以前的工作，这项研究证明了Col 3在损伤后和肿瘤微环境中调节细胞行为的另一种机制，并表明新的Col 3靶向策略可以有效地控制体内生物反应，改善抗瘢痕/纤维化和肿瘤治疗。
TGFβ is a key regulator of the dynamic reciprocity between cells and the extracellular matrix that drives physiologic and pathologic responses in both tissue repair and tumor microenvironments. Our studies define type III Collagen (Col3) as a suppressor of scar formation and desmoplasia through its effects, in part, on myofibroblasts. TGFβ stimulates activation of myofibroblasts, and here, we demonstrate that cultured Col3-deficient fibroblasts have increased TGFβ signaling compared to wild-type fibroblasts. Moreover, kinetic binding studies show that a synthetic peptide containing a Col3 cysteine-rich (CR) domain found within its N-propeptide binds in a dose-dependent manner to TGFβ1, while a CR control peptide with mutated cysteines does not, suggesting that Col3 attenuates TGFβ signaling in part through the N-propeptide CR domain. Consistent with this hypothesis, the CR peptide attenuates TGFβ signaling in fibroblasts and 4T1 breast cancer cells and suppresses fibroblast activation and contraction, as assessed by α-smooth-muscle actin staining, cell wrinkling of deformable silicone, and stressed-fibroblast populated collagen lattice contraction assays. Finally, CR peptide treatment of orthotopically injected breast cancer cells (4T1) suppresses intratumoral fibroblast activation and inhibits primary tumor growth compared to CR control. Treatment with the CR peptide decreases both intratumoral canonical and non-canonical downstream TGFβ signaling targets, consistent with its extracellular binding to TGFβ. Taken together, our results suggest that the Col3 N-propeptide CR domain binds TGFβ1 and attenuates (but importantly does not eliminate) TGFβ signaling in fibroblasts and cancer cells. Expanding on our previous work, this study demonstrates an additional mechanism by which Col3 regulates cell behaviors in post-injury and tumor microenvironments and suggests that novel Col3-targeted strategies could effectively control biologic responses in vivo and improve anti-scarring/fibrosis and oncologic therapies.
登录
查看更多内容
DOI：
10.1083/jcb.201704053
发表时间：
2017-11-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Erdogan B;Ao M;White LM;Means AL;Brewer BM;Yang L;Washington MK;Shi C;Franco OE;Weaver AM;Hayward SW;Li D;Webb DJ
通讯作者：
Webb DJ
影响因子：
2.9
作者：
Lichtman, Michael K.;Otero-Vinas, Marta;Falanga, Vincent
通讯作者：
Falanga, Vincent
影响因子：
6
作者：
Brisson, Becky K.;Mauldin, Elizabeth A.;Volk, Susan W.
通讯作者：
Volk, Susan W.
影响因子：
4.8
作者：
Kach, Jacob;Sandbo, Nathan;Dulin, Nickolai O.
通讯作者：
Dulin, Nickolai O.
影响因子：
5.6
作者：
Exposito JY;Valcourt U;Cluzel C;Lethias C
通讯作者：
Lethias C