Hierarchy of cellular decisions in collective behavior: Implications for wound healing.
Hierarchy of cellular decisions in collective behavior: Implications for wound healing.
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DOI：
10.1038/srep20139
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发表时间：
2016-02-02
影响因子：
4.6
通讯作者：
Kreeger PK
中科院分区：
文献类型：
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作者：
Wickert LE;Pomerenke S;Mitchell I;Masters KS;Kreeger PK
集体过程，如伤口再上皮化，是个体细胞决定的整合结果。为了确定哪些个体细胞行为代表最有前途的目标工程再上皮化，我们检查了集体和个人的反应HaCaT角质形成细胞接种在聚丙烯酰胺凝胶的三个刚度（1，30，和100千帕）和治疗的范围内的表皮生长因子（EGF）剂量。伤口闭合被认为是增加与基板刚度，但EGF治疗仅高于刚度阈值。使用单个细胞行为来创建偏最小二乘回归模型，以预测驱动伤口闭合的因素的层次结构。出乎意料的是，发现细胞面积和持久性与观察到的伤口闭合差异具有最强的相关性。同时，该模型预测伤口闭合与增殖之间的相关性相对较弱，并且通过aphidicolin的抑制成功地测试了来自增殖的意外的微小输入。综合起来，这些结果表明，基于生长因子的慢性伤口治疗的临床结果不佳可能是由于这些方法中靶向的个体细胞行为与所产生的集体反应之间的脱节。此外，EGF敏感性的硬度依赖性表明，与微环境特征相匹配的疗法将更有效。
Collective processes such as wound re-epithelialization result from the integration of individual cellular decisions. To determine which individual cell behaviors represent the most promising targets to engineer re-epithelialization, we examined collective and individual responses of HaCaT keratinocytes seeded upon polyacrylamide gels of three stiffnesses (1, 30, and 100 kPa) and treated with a range of epidermal growth factor (EGF) doses. Wound closure was found to increase with substrate stiffness, but was responsive to EGF treatment only above a stiffness threshold. Individual cell behaviors were used to create a partial least squares regression model to predict the hierarchy of factors driving wound closure. Unexpectedly, cell area and persistence were found to have the strongest correlation to the observed differences in wound closure. Meanwhile, the model predicted a relatively weak correlation between wound closure with proliferation, and the unexpectedly minor input from proliferation was successfully tested with inhibition by aphidicolin. Combined, these results suggest that the poor clinical results for growth factor-based therapies for chronic wounds may result from a disconnect between the individual cellular behaviors targeted in these approaches and the resulting collective response. Additionally, the stiffness-dependency of EGF sensitivity suggests that therapies matched to microenvironmental characteristics will be more efficacious.