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

Abstract

Oligodendrocytes are extensively coupled to astrocytes, a phenomenon ensuring glial homeostasis and maintenance of central nervous system myelin. Molecular disruption of this communication occurs in demyelinating diseases such as multiple sclerosis. Less is known about the vulnerability and reconstruction of the panglial network during adult demyelination‐remyelination. Here, we took advantage of lysolcithin‐induced demyelination to investigate the expression dynamics of the oligodendrocyte specific connexin 47 (Cx47) and to some extent that of astrocyte Cx43, and whether this dynamic could be modulated by grafted induced pluripotent stem cell (iPSC)‐neural progeny. Our data show that disruption of Cx43‐Cx47 mediated hetero‐cellular gap‐junction intercellular communication following demyelination is larger in size than demyelination. Loss of Cx47 expression is timely rescued during remyelination and accelerated by the grafted neural precursors. Moreover, mouse and human iPSC‐derived oligodendrocytes express Cx47, which co‐labels with astrocyte Cx43, indicating their integration into the panglial network. These data suggest that in rodents, full lesion repair following transplantation occurs by panglial reconstruction in addition to remyelination. Targeting panglial elements by cell therapy or pharmacological compounds may help accelerating or stabilizing re/myelination in myelin disorders.

Validating a minipig model of reversible cerebral demyelination using human diagnostic modalities and electron microscopy

“…Also, LPC and ethidium bromide-induced demyelination have been proven to lead to signs compatible with demyelination in the cerebral WM of large, domestic landrace pigs 15 and demonstrated demyelination in the rabbit cerebral WM 16 and the non-human primate (macaque) optic nerve. 17 However, there is considerable heterogeneity in the reported timelines of myelin-related events across species, ranging from reports of relatively quick demyelination (i.e., ensuing within 30 min and reaching full extent within four days 18 and complete remyelination without evidence of substantial axonal damage within 5–6 weeks in the case of rodent models), 19 , 20 , 21 to persistent demyelination conducive of axonal degeneration even eight weeks after LPC injection in the macaque optic nerve. 17 Interspecies differences such as the degree of collateral inflammation, the efficiency of lesion repopulation by oligodendrocyte progenitor cells (OPC), lesion volume, and reduction in oligodendroglial support to axons have all been postulated to contribute to the wide range of myelination and neurodegeneration responses.…”

Multimodally trackable and clinically translatable platform for modelling human demyelinating brain diseases by temporally dispersed chemically induced lesions in the pig brain

“…Also, LPC and ethidium bromide-induced demyelination have been proven to lead to signs compatible with demyelination in the cerebral WM of larger, domestic landrace pigs (14) and to reliable demyelination of the rabbit cerebral WM (15) and of the non-human primate (macaque) optic nerve (16). However, there is considerable heterogeneity in the reported timelines of myelin-related events across species, ranging from initial reports of relatively quick demyelination (i.e., ensuing within 30 min and reaching full extent within 4 days(17)) and complete remyelination without evidence of substantial axonal damage within 5-6 weeks in the case of rodent models (18)(19)(20), to persistent demyelination conducive of axonal degeneration even 8 weeks after LPC injection in the macaque optic nerve. Interspecies differences such as the degree of collateral inflammation, the efficiency of lesion repopulation by oligodendrocyte progenitor cells (OPC), lesion volume, and reduction in oligodendroglial support to axons have all been postulated to contribute to the wide range of myelination and neurodegeneration responses (16).…”