Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA.
Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, New York, USA.
J Orthop Res. 2023 Oct;41(10):2273-2286. doi: 10.1002/jor.25562. Epub 2023 Apr 11.
Clinical and animal studies have reported the influence of sex on the incidence and progression of tendinopathy, which results in disparate structural and biomechanical outcomes. However, there remains a paucity in our understanding of the sex-specific biological mechanisms underlying effective tendon healing. To overcome this hurdle, our group has investigated the impact of sex on tendon regeneration using the super-healer Murphy Roths Large (MRL/MpJ) mouse strain. We have previously shown that the scarless healing capacity of MRL/MpJ patellar tendons is associated with sexually dimorphic regulation of gene expression for pathways involved in fibrosis, cell migration, adhesion, and extracellular matrix (ECM) remodeling following an acute mid-substance injury. Thus, we hypothesized that MRL/MpJ scarless tendon healing is mediated by sex-specific and temporally distinct orchestration of cell-ECM interactions. Accordingly, the present study comparatively evaluated MRL/MpJ tendon cells on two-dimensional (2D; glass) and scaffold platforms to examine cell behavior under biochemical and topographical cues associated with tendon homeostasis and healing. Female MRL/MpJ cells showed reduced 2D migration and spreading area accompanied by enhanced mechanosensing, ECM alignment, and fibronectin-mediated cell proliferation compared to male MRL/MpJ cells. Interestingly, female MRL/MpJ cells cultured on isotropic scaffolds showed diminished cell-ECM organization compared to male MRL/MpJ cells. Lastly, MRL/MpJ cells elicited enhanced cytoskeletal elongation and alignment, ECM deposition and organization, and connexin 43-mediated intercellular communication compared to male B6 cells, regardless of culture condition or sex. These results provide insight into the cellular features conserved within the MRL/MpJ phenotype and potential sex-specific targets for the development of more equitable therapeutics.
临床和动物研究报告了性别对腱病发病率和进展的影响，这导致了不同的结构和生物力学结果。然而，我们对有效腱愈合的性别特异性生物学机制仍知之甚少。为了克服这一障碍，我们的研究小组使用超强愈合的 Murphy Roths Large（MRL/MpJ）小鼠品系研究了性别对腱再生的影响。我们之前已经表明，MRL/MpJ 髌腱无瘢痕愈合能力与纤维化、细胞迁移、黏附和细胞外基质（ECM）重塑途径相关基因表达的性别二态性调节有关，在急性中段损伤后。因此，我们假设 MRL/MpJ 无瘢痕腱愈合是由性别特异性和时间上不同的细胞-ECM 相互作用的协调介导的。因此，本研究比较了二维（2D；玻璃）和支架平台上的 MRL/MpJ 腱细胞，以研究在与腱稳态和愈合相关的生化和拓扑线索下细胞行为。与雄性 MRL/MpJ 细胞相比，雌性 MRL/MpJ 细胞在 2D 迁移和扩展面积上减少，同时表现出增强的机械感知、ECM 对齐和纤连蛋白介导的细胞增殖。有趣的是，与雄性 MRL/MpJ 细胞相比，在各向同性支架上培养的雌性 MRL/MpJ 细胞表现出细胞-ECM 组织减少。最后，与雄性 B6 细胞相比，无论培养条件或性别如何，MRL/MpJ 细胞都表现出增强的细胞骨架伸长和对齐、ECM 沉积和组织以及缝隙连接蛋白 43 介导的细胞间通讯。这些结果提供了对 MRL/MpJ 表型中保守的细胞特征的深入了解，并为开发更公平的治疗方法提供了潜在的性别特异性靶点。
