Mechanosensitivity of Human Oligodendrocytes.

Daniela Espinosa-Hoyos,Suzanne R Burstein,Valentina Fossati,Krystyn J Van Vliet,Tanya Jain,Jaaram Cha,Madhura Nijsure,Anna Jagielska

doi:10.3389/fncel.2020.00222

Abstract

Oligodendrocytes produce and repair myelin, which is critical for the integrity and function of the central nervous system (CNS). Oligodendrocyte and oligodendrocyte progenitor cell (OPC) biology is modulated in vitro by mechanical cues within the magnitudes observed in vivo. In some cases, these cues are sufficient to accelerate or inhibit terminal differentiation of murine oligodendrocyte progenitors. However, our understanding of oligodendrocyte lineage mechanobiology has been restricted primarily to animal models to date, due to the inaccessibility and challenges of human oligodendrocyte cell culture. Here, we probe the mechanosensitivity of human oligodendrocyte lineage cells derived from human induced pluripotent stem cells. We target phenotypically distinct stages of the human oligodendrocyte lineage and quantify the effect of substratum stiffness on cell migration and differentiation, within the range documented in vivo. We find that human oligodendrocyte lineage cells exhibit mechanosensitive migration and differentiation. Further, we identify two patterns of human donor line-dependent mechanosensitive differentiation. Our findings illustrate the variation among human oligodendrocyte responses, otherwise not captured by animal models, that are important for translational research. Moreover, these findings highlight the importance of studying glia under conditions that better approximate in vivo mechanical cues. Despite significant progress in human oligodendrocyte derivation methodology, the extended duration, low yield, and low selectivity of human-induced pluripotent stem cell-derived oligodendrocyte protocols significantly limit the scale-up and implementation of these cells and protocols for in vivo and in vitro applications. We propose that mechanical modulation, in combination with traditional soluble and insoluble factors, provides a key avenue to address these challenges in cell production and in vitro analysis.

Highlights

Glial cells play fundamental roles in homeostasis, pathology, and repair of the central nervous system (CNS)
We adapted the directed differentiation of human oligodendrocytes from Human-induced pluripotent stem cells (hiPSCs) that we previously developed (Douvaras et al, 2014; Douvaras and Fossati, 2015) to a well-established system of polyacrylamide (PAAm) hydrogels (Tse and Engler, 2010; Pelham and Wang, 1997; Moshayedi et al, 2010; Jagielska et al, 2012) functionalized to facilitate cell adhesion to their surface (Figure 1A)
Tissue culture polystyrene (TCP) was used as the state-of-the-art control culture substratum, representing current typical in vitro culture conditions of oligodendrocytes and of adherent cells generally

Summary

Introduction

Glial cells play fundamental roles in homeostasis, pathology, and repair of the central nervous system (CNS). Oligodendrocytes primarily produce, maintain, and repair the myelin sheaths surrounding neuronal axons, which enable cognitive and motor abilities in vertebrate animals (Bunge, 1968; Baumann and Pham-Dinh, 2001; Zalc et al, 2008). The physical properties and forces in this ‘‘niche’’ provide cues that can regulate behavior and cell fate (Makhija et al, 2020) Changes in this mechanical landscape are characteristic of developmental (Franze, 2013; Budday et al, 2015) and aging (Morawski et al, 2014) processes, as well as various CNS disorders that include multiple sclerosis (MS; Streitberger et al, 2012; Urbanski et al, 2019), Alzheimer’s (Murphy et al, 2011, 2016) and Parkinson’s (Lipp et al, 2013). Given the direct role of oligodendrocytes in myelination and neuronal health, we and others seek improved understanding of how these glial cells may respond to mechanical and other cues that limit or promote repair in demyelinating diseases such as MS

Methods

Results

Conclusion