Molecular and functional heterogeneity of meniscal fibrochondrocytes in bioengineering avascular meniscus repair: is Rap1 signaling vital?

Grimes, Kiarra1; Ma, Zhiyao2; Adesida, Adetola B.1,2,*

1Department of Biomedical Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB, Canada

2Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada

*Correspondence to: Adetola B. Adesida, PhD, adesida@ualberta.ca.

Abstract

Knee menisci are intra-articular fibrocartilaginous structures critical to the biomechanics of the knee joint. To relieve the symptoms of meniscal injuries, partial or total meniscectomy has been widely used despite predisposing the joint toward developing osteoarthritis, a painful and debilitating condition. Because of this major drawback, cell-based approaches are being investigated to restore the inner avascular portion of the knee meniscus with improved longevity and integrity. Current techniques for isolating meniscal fibrochondrocytes (MFCs), the optimal cell type for repair, include collagenase digestion (d), outgrowth (og), and a recently introduced digestion-after-outgrowth (dog) method. Heterogeneity regarding the transcriptomic profiles and biomechanical properties of these MFC isolation methods has recently been documented; owing to their demonstrated enhanced migratory capacity and production of microtissue models with higher expression of alpha-smooth muscle actin (ACTA2) and transgelin (TAGLN), we propose that og-MFC populations facilitate superior wound closure. This narrative review delineates the molecular underpinnings conferring various advantages of MFC populations isolated using these three methods and suggests how such differences may be strategically leveraged in either tissue repair or tissue engineering contexts. Specifically, we identify the significance of using og-MFCs for avascular meniscus tissue repair, considering the role of Ras-associated protein 1 (Rap1) signaling and ACTA2/TAGLN in coordinating cell migration and contractility, respectively. We discuss how the use of dog-MFCs may be optimal in tissue-engineered meniscus given its high chondrogenic capacity. Ultimately, we highlight the importance of further examination concerning the transcriptomic and functional diversity of MFCs to optimize the outcomes of cell-based avascular meniscus repair.

生物工程化血管性半月板修复中半月板纤维软骨细胞的分子和功能异质性：Rap1 信号是否至关重要？

摘要

膝关节半月板是关节内纤维软骨结构，对膝关节的生物力学至关重要。为了缓解半月板损伤的症状，半月板部分或全部切除已被广泛使用，尽管这种手术容易导致关节患上骨关节炎。由于这一主要缺陷，目前正在研究基于细胞的方法，以恢复膝关节半月板的内部无血管部分，提高其寿命和完整性。目前分离半月板纤维软骨细胞--修复的最佳细胞类型--的技术包括胶原酶消化法、外生法和最近推出的消化后外生法。这些半月板纤维软骨细胞分离方法的转录组特征和生物力学特性的异质性最近已有报道；由于它们的迁移能力被证明更强，并能产生α-平滑肌肌动蛋白（ACTA2）和转髓鞘蛋白（TAGLN）表达量更高的微组织模型，被认为消化后外生-半月板纤维软骨细胞群体能促进伤口的良好闭合。此叙述性综述描述了使用这三种方法分离出的半月板纤维软骨细胞群体所具有的各种优势的分子基础，并提出了如何在组织修复或组织工程中战略性地利用这些差异。具体来说，考虑到 Ras-association proximate 1 (Rap1) 信号和 ACTA2/TAGLN 分别在协调细胞迁移和收缩性方面的作用，确定了使用外生法-半月板纤维软骨细胞进行血管性半月板组织修复的意义。文章讨论了在组织工程半月板中如何使用狗-半月板纤维软骨细胞，因为它具有很高的软骨生成能力。最后，强调了进一步研究半月板纤维软骨细胞转录组和功能多样性以优化基于细胞的血管性半月板修复结果的重要性。