Maturation State and Matrix Microstructure Regulate Interstitial Cell Migration in Dense Connective Tissues

Feini Qu,Miltiadis H. Zgonis,Xiao Wang,Vivek B. Shenoy,Xuan Cao,Lin Han,John L. Esterhai,Qing Li,Robert L. Mauck

doi:10.1038/s41598-018-21212-4

Feini Qu, Miltiadis H. Zgonis + Show 7 more

Open Access

https://doi.org/10.1038/s41598-018-21212-4

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Abstract

Few regenerative approaches exist for the treatment of injuries to adult dense connective tissues. Compared to fetal tissues, adult connective tissues are hypocellular and show limited healing after injury. We hypothesized that robust repair can occur in fetal tissues with an immature extracellular matrix (ECM) that is conducive to cell migration, and that this process fails in adults due to the biophysical barriers imposed by the mature ECM. Using the knee meniscus as a platform, we evaluated the evolving micromechanics and microstructure of fetal and adult tissues, and interrogated the interstitial migratory capacity of adult meniscal cells through fetal and adult tissue microenvironments with or without partial enzymatic digestion. To integrate our findings, a computational model was implemented to determine how changing biophysical parameters impact cell migration through these dense networks. Our results show that the micromechanics and microstructure of the adult meniscus ECM sterically hinder cell mobility, and that modulation of these ECM attributes via an exogenous matrix-degrading enzyme permits migration through this otherwise impenetrable network. By addressing the inherent limitations to repair imposed by the mature ECM, these studies may define new clinical strategies to promote repair of damaged dense connective tissues in adults.

Highlights

Resulting in increased bulk mechanical properties[1]
We demonstrated that modulating extracellular matrix (ECM) properties, via the application of exogenous matrix-degrading enzymes, enhanced interstitial mobility, and that this acted synergistically with cell-produced matrix metalloproteinase (MMP) to promote cell migration through the dense ECM
To directly query the impediments to cell migration in dense connective tissues, and how they might be affected by tissue maturation, we first inspected the microenvironment of the knee meniscus at two developmental states

Summary

Introduction

Resulting in increased bulk mechanical properties[1]. Unlike migration in 2D (where increasing substrate stiffness generally increases migration speeds), adult cells in a 3D environment must overcome the increased biophysical resistance of their surrounding environment. Observations in isotropic, non-native environments likely do not recapitulate the impediments to migration experienced in dense connective tissues, and so there is a pressing need to develop new systems to study 3D cell migration in a more physiologic context. We demonstrated that modulating ECM properties, via the application of exogenous matrix-degrading enzymes, enhanced interstitial mobility, and that this acted synergistically with cell-produced MMPs to promote cell migration through the dense ECM. These studies provide evidence of the role of native ECM properties on cell migration and establish new clinical strategies to promote endogenous repair of the meniscus and other dense connective tissues of the musculoskeletal system

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Results

Conclusion