Pressureless mechanical induction of stem cell differentiation is dose and frequency dependent.

Robert Dettman,Roland Fuhrer,Jolanda R Vetsch,Nora Hild,Robert N Grass,Wendelin J Stark,Sandra Hofmann,Inge K Herrmann

doi:10.1371/journal.pone.0081362

Abstract

Movement is a key characteristic of higher organisms. During mammalian embryogenesis fetal movements have been found critical to normal tissue development. On the single cell level, however, our current understanding of stem cell differentiation concentrates on inducing factors through cytokine mediated biochemical signaling. In this study, human mesenchymal stem cells and chondrogenesis were investigated as representative examples. We show that pressureless, soft mechanical stimulation precipitated by the cyclic deformation of soft, magnetic hydrogel scaffolds with an external magnetic field, can induce chondrogenesis in mesenchymal stem cells without any additional chondrogenesis transcription factors (TGF-β1 and dexamethasone). A systematic study on the role of movement frequency revealed a classical dose-response relationship for human mesenchymal stem cells differentiation towards cartilage using mere mechanical stimulation. This effect could even be synergistically amplified when exogenous chondrogenic factors and movement were combined.

Highlights

Chemical signaling organizes the structure of biological tissues[1] and stem cell differentiation during growth or repair
The role of movement has probably been best studied in tissue engineering for the growth of articular cartilage in vitro[4,5,6,7,8] using mechanical top load[9,10,11]
We demonstrate that purely mechanical stimulation provokes correct differentiation even in vitro and in the complete absence of any exogenous biochemical differentiation factors

Summary

Introduction

Chemical signaling organizes the structure of biological tissues[1] and stem cell differentiation during growth or repair. Clinical evidence provides a clear argument for the necessity of movement in function-guided, local cell differentiation[19,20]: Mammalian embryogenesis is characterized by an early start of intense movement (for humans, typically in the first third of gestation), a prerequisite to normal organ development[21] and takes place in a pressurefree environment. Without adequate traumatic surgery or fixation, pseudoarthrosis may occur at non-fixed bone fracture sites[22]. Continued movement of such non-fixed primary callus promotes local stem cell differentiation into cartilage and ligament tissue instead of bone tissue. A fourth argument is counter-intuitive: Mechanical stress on ligaments regeneration has recently been shown by Altmann et al [24] to improve the healing process

Methods

Results

Conclusion