Multiple sclerosis iPSC-derived oligodendroglia conserve their intrinsic properties to functionally interact with axons and glia in vivo

Abstract

One Sentence Summary: Multiple Sclerosis oligodendroglia, regardless of major immune manipulators, are intrinsically capable of myelination and making functional axo-glia and glia-glia connections after engraftment in the murine CNS, reinforcing the view that the MS oligodendrocyte differentiation block is not due to major intrinsic oligodendroglial deficits but most likely to environmental conditions. 2 Abstract: The remyelination failure in multiple sclerosis (MS) is associated with a migration/differentiation block of oligodendroglia. The reason for this block is highly debated. It could result from disease-related extrinsic regulators of the oligodendroglial biology or reflect MS oligodendrocyte intrinsic properties . To avoid confounding immunemediated extrinsic effect, we used an immune-deficient, dysmyelinating mouse model, to compare side-by-side induced pluripotent stem-cell-derived O4+ oligodendroglia from MS and healthy donors following their engraftment in the developing CNS. We show that the MS-progeny survives, proliferates and differentiates into oligodendrocytes to the same extent as controls. Quantitative multi-parametric imaging indicates that MS and control oligodendrocytes generate equal amounts of myelin, with bona-fide nodes of Ranvier and promote equal restoration of their host slow conduction. Moreover, the MS-derived progeny expressed oligodendrocyte-and astrocyte-specific connexins and established functional connections with donor and host glial cells. Thus, MS pluripotent stem cell-derived progeny fully integrates into functional axo-glial and glial-glial components, reinforcing the view that the MS oligodendrocyte differentiation block is not due to intrinsic oligodendroglial deficits. These biological findings as well as the fully integrated human-murine chimeric model should facilitate the development of pharmacological or cell-based therapies to promote CNS remyelination.

Beneficial contribution of induced pluripotent stem cell‐progeny to Connexin 47 dynamics during demyelination‐remyelination

“…Thus, mouse and human skin‐derived remyelinating oligodendrocytes are capable of being integrated into the panglial network by establishing proper molecular connections with other glial cells to ensure their functionality. A recent dye‐coupling study of human iPSC‐derived oligodendrocytes grafted in the corpus callosum of newborn shiverer mice showed that the cells were capable of forming functional GJs with neighbor murine or human glial cells, indicating that exogenous cells could not only myelinate host axons, but also functionally integrate into the host pan‐glial network (Mozafari et al, 2020). Although not tested here, it is assumed that exogenous cells also proceed to functional integration into the host pan‐glial network during repair.…”

“…We reported previously that following lysolecithin (LPC)‐induced adult demyelination, grafted iPSC‐NPCs/OPCs timely differentiate into oligodendrocytes (but also ~20% to astrocytes), and extensively remyelinate the lesion 6 weeks (rodent cells) or 12 weeks (human cells) after engraftment (Ehrlich et al, 2017; Mozafari et al, 2015; Mozafari et al, 2020). However, the timing and dynamics of loss and gain of Cx47 expression during demyelination and remyelination, and the potential interaction of the iPSC‐derived oligodendrocytes (through the connexins) with astrocytes during this successful remyelination has not been addressed.…”

Oligodendrocyte Development and Regenerative Therapeutics in Multiple Sclerosis

“…Several promising ongoing research strategies for drug discovery of pharmacological compounds target OPC differentiation with the ultimate goal to find new treatments for progressive MS. Although, it is worth noting that human oligodendrocytes, derived from IPSCs of MS patients, have normal myelination properties and interact with axons when grafted in the shiverer:rag2 mouse brain [ 87 ], suggesting that the oligodendrocyte differentiation block is not related to an intrinsic defect of this cell type.…”

Study on the Safety of Human Oligodendrocyte Precursor Cell Transplantation in Young Animals and Its Efficacy on Myelination

“…Newborns are one of the most at-risk groups for developing demyelinating diseases [ 1 ], characterized by loss of or damage to the central nervous system's oligodendrocytes (OLs), the primary myelin sheath-forming cells in the brain and spinal cord. Recovery from this disease requires myelin replacement through normal proliferation and differentiation of OLs [ 2 ]. Over the past few decades, a series of studies have been conducted on treatment of demyelinating diseases with cell transplantation.…”