Fidgetin-Like 2: A Microtubule-Based Regulator of Wound Healing.
Fidgetin-Like 2: A Microtubule-Based Regulator of Wound Healing.
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DOI：
10.1038/jid.2015.94
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发表时间：
2015-09
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影响因子：
--
通讯作者：
Sharp DJ
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文献类型：
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作者：
Charafeddine RA;Makdisi J;Schairer D;O'Rourke BP;Diaz-Valencia JD;Chouake J;Kutner A;Krausz A;Adler B;Nacharaju P;Liang H;Mukherjee S;Friedman JM;Friedman A;Nosanchuk JD;Sharp DJ
伤口愈合是一个复杂的过程，主要是由多种不同类型的细胞从伤口边缘迁移到伤口区域驱动的。在这项研究中，我们确定了以前未表征的微管切断酶 Fidgetin-like 2 (FL2)，作为细胞迁移的基本调节因子，可以使用纳米颗粒封装的 siRNA 在体内靶向该酶，以促进伤口闭合和再生。在体外，哺乳动物组织培养细胞中 FL2 的消耗导致细胞运动速率增加两倍以上，部分原因是定向运动显着增加。免疫荧光分析表明，FL2 通常定位于细胞边缘，重要的是定位于极化细胞的前缘，在那里它调节微管细胞骨架的组织和动态。为了将这些发现应用于临床，我们利用基于纳米颗粒的 siRNA 递送平台来局部消除小鼠全层切除伤口和烧伤伤口中的 FL2。相对于对照，将 FL2 siRNA 纳米颗粒局部应用于任一伤口类型都会导致临床和组织学上伤口闭合的速度和质量显着提高。综上所述，这些结果表明 FL2 是促进皮肤伤口再生和修复的有前景的治疗靶点。
Wound healing is a complex process driven largely by the migration of a variety of distinct cell types from the wound margin into the wound zone. In this study, we identify the previously uncharacterized microtubule-severing enzyme, Fidgetin-like 2 (FL2), as a fundamental regulator of cell migration that can be targeted in vivo using nanoparticle-encapsulated siRNA to promote wound closure and regeneration. In vitro, depletion of FL2 from mammalian tissue culture cells results in a more than two-fold increase in the rate of cell movement, due in part to a significant increase in directional motility. Immunofluorescence analyses indicate that FL2 normally localizes to the cell edge, importantly to the leading edge of polarized cells, where it regulates the organization and dynamics of the microtubule cytoskeleton. To clinically translate these findings, we utilized a nanoparticle-based siRNA delivery platform to locally deplete FL2 in both murine full-thickness excisional and burn wounds. Topical application of FL2 siRNA nanoparticles to either wound type results in a significant enhancement in the rate and quality of wound closure both clinically and histologically relative to controls. Taken together, these results identify FL2 as a promising therapeutic target to promote the regeneration and repair of cutaneous wounds.