PDF(Pubmed)
Abstract：
The human auricle has a complex structure, and microtia is a congenital malformation characterized by decreased size and loss of elaborate structure in the affected ear with a high incidence. Our previous studies suggest that inadequate cell migration is the primary cytological basis for the pathogenesis of microtia, however, the underlying mechanism is unclear. Here, we further demonstrate that microtia chondrocytes show a decreased directional persistence during cell migration. Directional persistence can define a leading edge associated with oriented movement, and any mistakes would affect cell function and tissue morphology. By the screening of motility-related genes and subsequent confirmations, active Rac1 (Rac1-GTP) is identified to be critical for the impaired directional persistence of microtia chondrocytes migration. Moreover, Rho guanine nucleotide exchange factors (GEFs) and Rho GTPase-activating proteins (GAPs) are detected, and overexpression of Tiam1 significantly upregulates the level of Rac1-GTP and improves directional migration in microtia chondrocytes. Consistently, decreased expression patterns of Tiam1 and active Rac1 are found in microtia mouse models, Bmp5se/J and Prkralear-3J/GrsrJ. Collectively, our results provide new insights into microtia development and therapeutic strategies of tissue engineering for microtia patients.
摘要：
人的耳廓有着复杂的结构,小耳畸形是一种先天性畸形，其特征是受影响的耳朵中尺寸减小和复杂结构的丢失，发病率很高。我们以前的研究表明，细胞迁移不足是小视体发病的主要细胞学基础，然而,潜在机制尚不清楚.这里,我们进一步证明了小耳软骨细胞在细胞迁移过程中显示出降低的定向持久性。定向持久性可以定义与定向运动相关的前沿，任何错误都会影响细胞功能和组织形态。通过对运动性相关基因的筛选和后续的确认,活性Rac1（Rac1-GTP）被确定为对于微耳软骨细胞迁移的定向持久性受损至关重要。此外，检测到Rho鸟嘌呤核苷酸交换因子（GEF）和RhoGTPase激活蛋白（GAP），Tiam1的过表达显着上调Rac1-GTP的水平并改善小耳软骨细胞的定向迁移。始终如一，Tiam1和活性Rac1的表达模式在小耳小鼠模型中发现，Bmp5se/J和Prkralear-3J/GrsrJ。总的来说，我们的研究结果为小耳畸形患者的小耳发育和组织工程治疗策略提供了新的见解。
