The engineering of a native-like articular cartilage (AC) is a long-standing objective that could serve the clinical needs of millions of patients suffering from osteoarthritis and cartilage injury. An incomplete understanding of the developmental stages of AC has contributed to limited success in this endeavor. Using next generation RNA sequencing, we have transcriptionally characterized two critical stages of AC development in humans-that is, immature neonatal and mature adult, as well as tissue-engineered cartilage derived from culture expanded human mesenchymal stem cells. We identified key transcription factors (TFs) and long noncoding RNAs (lncRNAs) as candidate drivers of the distinct phenotypes of these tissues. AGTR2, SCGB3A1, TFCP2L1, RORC, and TBX4 stand out as key TFs, whose expression may be capable of reprogramming engineered cartilage into a more expandable and neonatal-like cartilage primed for maturation into biomechanically competent cartilage. We also identified that the transcriptional profiles of many annotated but poorly studied lncRNAs were dramatically different between these cartilages, indicating that lncRNAs may also be playing significant roles in cartilage biology. Key neonatal-specific lncRNAs identified include AC092818.1, AC099560.1, and KC877982. Collectively, our results suggest that tissue-engineered cartilage can be optimized for future clinical applications by the specific expression of TFs and lncRNAs.

中文翻译：

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较长的非编码RNA和转录因子的转录组动力学描述了人类新生儿，成人和人类间充质干细胞衍生的工程软骨的分界。

像天然关节软骨（AC）的工程设计是一个长期目标，可以满足数百万患有骨关节炎和软骨损伤的患者的临床需求。对AC的发展阶段的不完全了解导致这项工作的成功有限。使用下一代RNA测序，我们已经在人类AC发育的两个关键阶段进行了转录表征-即未成熟的新生儿和成熟的成年人，以及从培养的人间充质干细胞中衍生的组织工程软骨。我们确定关键转录因子（TFs）和长非编码RNA（lncRNAs）作为这些组织的不同表型的候选驱动程序。AGTR2，SCGB3A1，TFCP2L1，RORC和TBX4作为关键TF脱颖而出，其表达可能能够将工程软骨重编程为更易扩展的新生儿样软骨，以使其成熟成为具有生物力学能力的软骨。我们还确定，在这些软骨之间，许多带注释但研究不足的lncRNA的转录谱差异显着，这表明lncRNA在软骨生物学中也可能起着重要作用。确定的关键新生儿特异性lncRNAs包括AC092818.1，AC099560.1和KC877982。总体而言，我们的结果表明，组织工程化的软骨可以通过TF和lncRNA的特异性表达而针对未来的临床应用进行优化。我们还确定，在这些软骨之间，许多带注释但研究不足的lncRNA的转录谱差异显着，这表明lncRNA在软骨生物学中也可能起着重要作用。确定的关键新生儿特异性lncRNAs包括AC092818.1，AC099560.1和KC877982。总体而言，我们的结果表明，组织工程化的软骨可以通过TF和lncRNA的特异性表达而针对未来的临床应用进行优化。我们还确定，在这些软骨之间，许多带注释但研究不足的lncRNA的转录谱差异显着，这表明lncRNA在软骨生物学中也可能起着重要作用。确定的关键新生儿特异性lncRNAs包括AC092818.1，AC099560.1和KC877982。总的来说，我们的研究结果表明，组织工程化的软骨可以通过TF和lncRNA的特异性表达进行优化，以用于未来的临床应用。