Fractal heterogeneity in minimal matrix models of scars modulates stiff-niche stem-cell responses via nuclear exit of a mechanorepressor.
Fractal heterogeneity in minimal matrix models of scars modulates stiff-niche stem-cell responses via nuclear exit of a mechanorepressor.
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DOI：
10.1038/nmat4350
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发表时间：
2015-09
期刊：
影响因子：
41.2
通讯作者：
Discher DE
中科院分区：
文献类型：
--
作者：
Dingal PC;Bradshaw AM;Cho S;Raab M;Buxboim A;Swift J;Discher DE
在高等动物中，瘢痕形成是一个长期存在的问题，简化主义的方法可以帮助开发治疗方法。在这里，我们展示了胶原- 1与聚丙烯酰胺的共聚合产生了最小基质疤痕模型（MMMS），其中分形纤维束在水凝胶表面下不均匀地分离。基质局部硬化-如疤痕-同时允许单独控制黏合剂配体密度。MMMS从间充质干细胞（MSCs）中诱导出疤痕样表型：细胞迅速扩散和极化，增加核骨骼纤层蛋白a，但表达“疤痕标志物”平滑肌肌动蛋白（SMA）的速度较慢。令人惊讶的是，对MMMS的表达反应比均匀的硬凝胶表现出更少的细胞间噪声。这种与体积平均反应的差异是因为一种强SMA抑制因子NKX2.5在刚性基质上缓慢地离开细胞核。NKX2.5过表达覆盖刚性表型，抑制SMA和细胞扩散，而细胞质定位的NKX2.5突变体在扩散良好的细胞中降解。因此，MSCs通过逐渐抑制NKX2.5形成刚性的“机械记忆”，从而在疤痕样状态下提高SMA。
Scarring is a long-lasting problem in higher animals, and reductionist approaches could aid in developing treatments. Here, we show that co-polymerization of collagen-I with polyacrylamide produces minimal matrix models of scars (MMMS), in which fractal-fiber bundles segregate heterogeneously to the hydrogel subsurface. Matrix stiffens locally – as in scars – while allowing separate control over adhesive-ligand density. The MMMS elicits scar-like phenotypes from mesenchymal stem cells (MSCs): cells spread and polarize quickly, increasing nucleoskeletal lamin-A yet expressing the ‘scar marker’, smooth muscle actin (SMA) more slowly. Surprisingly, expression responses to MMMS exhibit less cell-to-cell noise than homogeneously stiff gels. Such differences from bulk-average responses arise because a strong SMA repressor, NKX2.5, slowly exits the nucleus on rigid matrices. NKX2.5 overexpression overrides rigid phenotypes, inhibiting SMA and cell spreading, while cytoplasm-localized NKX2.5 mutants degrade in well-spread cells. MSCs thus form a ‘mechanical memory’ of rigidity by progressively suppressing NKX2.5, thereby elevating SMA in a scar-like state.