Effect of mechanical strain on the pluripotency of murine embryonic stem cells seeded in a collagen‐I scaffold

Abstract

The use of embryonic stem cells (ESC) in regenerative medicine is restricted due to the possibility of tumorigenicity after inefficient or incomplete differentiation. Studies from our group, and others, suggest that mechanical stimuli may have a suppressive effect on the pluripotency/tumorigenesis of murine ESC (mESC). Furthermore, we have demonstrated that mESC seeded in a type I collagen scaffold, and transplanted into a murine bone fracture model, demonstrated repair without tumor formation. However, it remains unknown if mechanical factors were involved in blocking tumorigenicity of the mESC. Therefore, the aims of the current study were: (i) to characterize the mechanical environment within the transplanted construct (mESC-Col I) in an in vivo murine fracture model using computational analyses; and (ii) to reproduce this mechanical environment in vitro to elucidate the role of these mechanical factors on mESC pluripotent gene expression. It was predicted that the mESC-Col I construct was subjected to an average octahedral shear strain of ∼3.8% and a compressive strain of ∼3.1% within the fracture in vivo when the murine tibia was subjected to an axial compression load of 4 N (1 Hz). When a similar strain environment was replicated experimentally in vitro, the expression patterns of marker genes for pluripotency (Oct 4, Sox 2, Nanog, Rex 1, and oncogene ERas) were significantly down-regulated. This suggests that the local micro-mechanical environment within the fracture site in vivo may be involved in regulating stem cell fate after transplantation, and that these physical factors should be considered when developing regenerative medicine strategies. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:799-807, 2018.

Integrating physicomechanical and biological strategies for BTE: biomaterials-induced osteogenic differentiation of MSCs

“…This mechanical stimulation acts on the cells in the bone tissue and plays an important role in bone remodeling, such as early bone healing when fractures or bone defects occur [2]. Therefore, in order to investigate the optimal compressive stress on osteogenic differentiation of MSCs in vitro, large numbers of studies have been conducted by using compression bioreactors [158,159]. Compared with 2D environment, MSCs loaded on 3D scaffolds are studied more extensively in recent years, which is more closely to the physiological conditions in vivo [2].…”

A high throughput screening system for studying the effects of applied mechanical forces on reprogramming factor expression

“…In addition, mechanical force can lead to chromatin remodeling and altered binding of transcription factors 17 , 18 . Recent studies have also shown that application of mechanical strain can reduce the expression of pluripotency in mouse embryonic stem cells 19 , 20 . In human pluripotent stem cells (hPSCs), mechanical strain helped to maintain pluripotency through increased expression Nodal, transforming growth factor-β (TGF-β), and Activin 21 , 22 .…”

High Throughput Mechanobiological Screens Enable Mechanical Priming of Pluripotency in Mouse Fibroblasts

“…In addition, mechanical force can lead to chromatin remodeling and altered binding of transcription factors (Iyer et al, 2012;Tajik et al, 2016). Recent studies have also shown that application of mechanical strain can reduce the expression of pluripotency in mouse embryonic stem cells (Hazenbiller et al, 2017;Hazenbiller et al, 2018). In hPSCs, mechanical strain helped to maintain pluripotency through increased expression Nodal, TGF-β, and Activin (Saha et al, 2006(Saha et al, , 2008.…”