Rapid specialization and stiffening of the primitive matrix in developing articular cartilage and meniscus
Rapid specialization and stiffening of the primitive matrix in developing articular cartilage and meniscus
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DOI：
10.1016/j.actbio.2023.06.047
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发表时间：
2023-08-18
影响因子：
9.7
通讯作者：
Han，Lin
中科院分区：
文献类型：
--
作者：
Kwok，Bryan;Chandrasekaran，Prashant;Han，Lin
了解细胞外基质 (ECM) 形成中的早期模式事件可以为再生策略提供蓝图，以更好地重现天然组织的功能。目前，人们对关节软骨和半月板（膝关节的两个承重部分）最初的 ECM 知之甚少。这项研究通过研究小鼠从妊娠中期（胚胎第 15.5 天）到新生儿（出生后第 7 天）阶段这两种组织的组成和生物力学，阐明了其发育中的 ECM 的独特特征。我们表明，关节软骨起始于细胞周基质（PCM）样原始基质的形成，然后分离成不同的 PCM 和域/域间（T/IT）-ECM 域，然后，通过成熟进一步扩展 T/IT-ECM。在此过程中，原始矩阵经历快速的指数硬化，每日模量增加率为 35.7% [31.9 39.6]%（平均值 [95% CI]）。同时，基质的性能空间分布变得更加不均匀，微模量的标准偏差和局部微模量与距细胞表面距离的斜率同时指数增加。与关节软骨相比，半月板的原始基质也表现出指数硬化和异质性增加，尽管每日硬化率要慢得多，为 19.8% [14.9 24.9]%，并且 PCM 和 T/IT-ECM 的分离延迟。这些对比强调了透明软骨与纤维软骨的不同发育路径。总的来说，这些发现为膝关节组织如何形成提供了新的见解，以更好地指导基于细胞和生物材料的关节软骨、半月板和潜在的其他承重软骨组织的修复。 意义声明关节软骨和半月板的成功再生受到对驱动体内组织细胞外基质初始形成的早期事件的不完全了解的挑战。这项研究表明，在胚胎发育过程中，关节软骨始于细胞周基质（PCM）样原始基质。然后，该原始矩阵分成不同的 PCM 和域/域间域，每天经历约 36% 的指数硬化和微机械异质性的增加。在这个早期阶段，半月板原始基质显示出不同的分子特征，并表现出较慢的每日硬化约 20%，强调了这两种组织之间不同的基质发育。因此，我们的研究结果建立了一个新的蓝图来指导再生策略的设计，以概括体内的关键发育步骤。
Understanding early patterning events in the extracellular matrix (ECM) formation can provide a blueprint for regenerative strategies to better recapitulate the function of native tissues. Currently, there is little knowledge on the initial, incipient ECM of articular cartilage and meniscus, two load-bearing counterparts of the knee joint. This study elucidated distinctive traits of their developing ECMs by studying the composition and biomechanics of these two tissues in mice from mid-gestation (embryonic day 15.5) to neo-natal (post-natal day 7) stages. We show that articular cartilage initiates with the formation of a pericellular matrix (PCM)-like primitive matrix, followed by the separation into distinct PCM and territorial/interterritorial (T/IT)-ECM domains, and then, further expansion of the T/IT-ECM through maturity. In this process, the primitive matrix undergoes a rapid, exponential stiffening, with a daily modulus increase rate of 35.7% [31.9 39.6]% (mean [95% CI]). Meanwhile, the matrix becomes more heterogeneous in the spatial distribution of properties, with concurrent exponential increases in the standard deviation of micromodulus and the slope correlating local micromodulus with the distance from cell surface. In comparison to articular cartilage, the primitive matrix of meniscus also exhibits exponential stiffening and an increase in heterogeneity, albeit with a much slower daily stiffening rate of 19.8% [14.9 24.9]% and a delayed separation of PCM and T/IT-ECM. These contrasts underscore distinct development paths of hyaline versus fibrocartilage. Collectively, these findings provide new insights into how knee joint tissues form to better guide cell- and biomaterial-based repair of articular cartilage, meniscus and potentially other load-bearing cartilaginous tissues.Statement of significanceSuccessful regeneration of articular cartilage and meniscus is challenged by incomplete knowledge of early events that drive the initial formation of the tissues’ extracellular matrix in vivo. This study shows that articular cartilage initiates with a pericellular matrix (PCM)-like primitive matrix during embryonic development. This primitive matrix then separates into distinct PCM and territorial/interterritorial domains, undergoes an exponential daily stiffening of ≈36% and an increase in micromechanical heterogeneity. At this early stage, the meniscus primitive matrix shows differential molecular traits and exhibits a slower daily stiffening of ≈20%, underscoring distinct matrix development between these two tissues. Our findings thus establish a new blueprint to guide the design of regenerative strategies to recapitulate the key developmental steps in vivo.