Lysyl hydroxylase 2 deficiency promotes filopodia formation and fibroblast migration.
Lysyl hydroxylase 2 deficiency promotes filopodia formation and fibroblast migration.
复制标题
DOI：
10.1016/j.bbrc.2021.11.100
复制
发表时间：
2022-01-08
影响因子：
3.1
通讯作者：
Uzawa, Katsuhiro
中科院分区：
文献类型：
--
作者：
Nozaki, Ryunosuke;Kasamatsu, Atsushi;Moss, Joel;Uzawa, Katsuhiro
赖氨酰羟基酶2(LH2)调节胶原分子间的交联性。LH2修饰的胶原蛋白的堆积是纤维化的原因之一，这种胶原蛋白高度稳定，不易胶原酶切割。我们之前证明了传统的LH2基因敲除小鼠表现出胚胎致死性。在这里，我们使用他莫昔芬诱导的Cre系统建立了LH2条件基因敲除小鼠。显微镜下对缺乏LH2的成纤维细胞的形态分析显示，丝状足的数量急剧增加，丝状细胞表面的突起使细胞能够移动。这些丝状孔的尖端和前沿显示肌球蛋白-X(Myo10)的表达上调，肌球蛋白-X(Myo10)是丝状孔完整性的调节因子。伤口愈合实验表明，LH2缺陷细胞的迁移速度明显快于对照细胞。基因表达谱数据也支持这种表型。综上所述，这些发现表明，LH2缺乏可能通过减少LH2-交联型胶原的积累来防止纤维化，而迁移速度更快的成纤维细胞有助于提高伤口愈合活性。总之，我们的细胞模型提供了证据，证明LH2缺乏在通过丝状足形成介导的细胞迁移中起关键作用。了解这种表型在LH2缺陷细胞中的确切作用可能有助于确定纤维化的发病机制。因此，需要使用LH2缺乏的小鼠模型对纤维化和伤口愈合进行详细的分析。
Lysyl hydroxylase 2 (LH2) regulates intermolecular cross-linking of collagen molecules. Accumulation of LH2-modified collagen, which is highly stable and resistant to collagenase cleavage, is one cause of fibrosis. We previously demonstrated that conventional LH2 knockout mice showed embryonic lethality. Here we established LH2 conditional knockout mice using a tamoxifen-inducible Cre system. Morphological analysis of LH2-deficient fibroblasts by microscopy showed a dramatic increase in the number of filopodia, the finger-like cell surface projections that enable cell movement. The tips and leading edges of these filopodia exhibited up-regulated expression of Myosin-X (Myo10), a regulator of filopodial integrity. Wound healing assays demonstrated that migration of LH2-deficient cells was significantly faster than that of control cells. Gene expression profiling data also supported this phenotype. Together these findings indicate that LH2 deficiency may prevent fibrosis through decreased accumulation of LH2-cross-linked collagen, and that fibroblasts with faster migration contribute to enhanced wound healing activity. In conclusion, our cellular models provide evidence that LH2 deficiency plays a critical role in cell migration mediated through filopodia formation. Understanding the precise role of this phenotype in LH2-deficient cells may be helpful to define the pathogenesis of fibrosis. As such, detailed analyses of fibrosis and wound healing using LH2-deficient mouse models are needed.
登录
查看更多内容
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
DOI：
10.1016/j.bbrc.2004.04.167
发表时间：
2004-06-18
影响因子：
3.1
作者：
Tokuo, H;Ikebe, M
通讯作者：
Ikebe, M
影响因子：
4.6
作者：
He K;Sakai T;Tsukasaki Y;Watanabe TM;Ikebe M
通讯作者：
Ikebe M
DOI：
10.1016/s0006-291x(03)01262-2
发表时间：
2003-08-08
影响因子：
3.1
作者：
Mercer, DK;Nicol, PF;Robins, SP
通讯作者：
Robins, SP
DOI：
10.1073/pnas.0602443103
发表时间：
2006-08-15
影响因子：
11.1
作者：
Bohil, Aparna B.;Robertson, Brian W.;Cheney, Richard E.
通讯作者：
Cheney, Richard E.