IPSC-derived myelinoids to study myelin biology of humans.

Owen G James,Dario Magnani,David A Lyons,David Story,Karen Burr,David W Hampton,Robert Smigiel,Navneet A Vasistha,Samantha K Barton,Siddharthan Chandran,Peter J Brophy,Rafal Ploski,Peter Connick,Charles Ffrench-Constant,Bhuvaneish T Selvaraj

doi:10.1016/j.devcel.2021.04.006

Abstract

SummaryMyelination is essential for central nervous system (CNS) formation, health, and function. Emerging evidence of oligodendrocyte heterogeneity in health and disease and divergent CNS gene expression profiles between mice and humans supports the development of experimentally tractable human myelination systems. Here, we developed human iPSC-derived myelinating organoids (“myelinoids”) and quantitative tools to study myelination from oligodendrogenesis through to compact myelin formation and myelinated axon organization. Using patient-derived cells, we modeled a monogenetic disease of myelinated axons (Nfasc155 deficiency), recapitulating impaired paranodal axo-glial junction formation. We also validated the use of myelinoids for pharmacological assessment of myelination—both at the level of individual oligodendrocytes and globally across whole myelinoids—and demonstrated reduced myelination in response to suppressed synaptic vesicle release. Our study provides a platform to investigate human myelin development, disease, and adaptive myelination.

Highlights

The formation and maintenance of myelin in the central nervous system (CNS) of humans is a dynamic life-long process (Westlye et al, 2010; Williamson and Lyons, 2018)
Embryoid bodies generated from dual-SMAD inhibition were exposed to retinoic acid (RA) and smoothened agonist (SAG) to promote caudalization and ventralization, respectively, before being treated with PDGF-AA, IGF-1, and T3 to induce oligodendrogenesis (Livesey et al, 2016)
Resulting spheroids contained an abundance of OLIG2+ cells, demonstrating acquisition of pMN domain-derived cells as well as NESTIN+ neural precursor cells, PDGFRa+ oligodendrocyte progenitor cells (OPCs), CNP+ oligodendrocytes, NF-H+ neurons, and GFAP+ astrocytes (Figures 1B and S1A)

Summary

Introduction

The formation and maintenance of myelin in the central nervous system (CNS) of humans is a dynamic life-long process (Westlye et al, 2010; Williamson and Lyons, 2018). Recent studies have revealed previously unappreciated heterogeneity in human oligodendrocytes in health and disease as well as differences in gene expression profiles compared with mammalian model organisms, including mouse (Castelijns et al, 2020; Hodge et al, 2019; Ja€kel et al, 2019; Xu et al, 2018). Together, this indicates that development of human models of myelination that could recapitulate structural and physiological features of myelin would serve as important experimental platforms to both better understand human myelin biology and complement existing models.

Objectives

Methods

Results

Discussion

Conclusion