RESUMEN
During development, boundary cap cells (BC) and neural crest cell (NCC) derivatives generate Schwann cells (SC) of the spinal roots and a subpopulation of neurons and satellite cells in the dorsal root ganglia. Despite their stem-like properties, their therapeutic potential in the diseased central nervous system (CNS) was never explored. The aim of this work was to explore BC therapeutic potential for CNS remyelination. We derived BC from Krox20(Cre) x R26R(Yfp) embryos at E12.5, when Krox20 is exclusively expressed by BC. Combining microdissection and cell fate mapping, we show that acutely isolated BC are a unique population closely related but distinct from NCC and SC precursors. Moreover, when grafted in the demyelinated spinal cord, BC progeny expands in the lesion through a combination of time-regulated processes including proliferation and differentiation. Furthermore, when grafted away from the lesion, BC progeny, in contrast to committed SC, show a high migratory potential mediated through enhanced interactions with astrocytes and white matter, and possibly with polysialylated neural cell adhesion molecule expression. In response to demyelinated axons of the CNS, BC progeny generates essentially myelin-forming SC. However, in contact with axons and astrocytes, some of them generate also myelin-forming oligodendrocytes. There are two primary outcomes of this study. First, the high motility of BC and their progeny, in addition to their capacity to remyelinate CNS axons, supports the view that BC are a reservoir of interest to promote CNS remyelination. Second, from a developmental point of view, BC behavior in the demyelinated CNS raises the question of the boundary between central and peripheral myelinating cells.
Asunto(s)
Células Madre Embrionarias/fisiología , Vaina de Mielina/fisiología , Regeneración Nerviosa/fisiología , Cresta Neural/fisiología , Células de Schwann/fisiología , Trasplante de Células Madre/métodos , Animales , Diferenciación Celular/fisiología , Linaje de la Célula/fisiología , Movimiento Celular/fisiología , Células Cultivadas , Enfermedades Desmielinizantes/cirugía , Modelos Animales de Enfermedad , Células Madre Embrionarias/citología , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Fibras Nerviosas Mielínicas/fisiología , Cresta Neural/citología , Oligodendroglía/citología , Oligodendroglía/fisiología , Células de Schwann/citología , Médula Espinal/citología , Médula Espinal/fisiopatología , Médula Espinal/cirugía , Factores de Tiempo , Resultado del TratamientoRESUMEN
CNS/PNS interfaces constitute cell boundaries, since they delimit territories with different neuronal and glial contents. Despite their potential interest in regenerative medicine, the mechanisms restricting oligodendrocytes and astrocytes to the CNS, and Schwann cells to the PNS in mammals are not known. To investigate the involvement of peripheral glia and myelin in the maintenance of the CNS/PNS boundary, we have first made use of different mouse mutants. We show that inactivation of Krox20/Egr2, a master regulatory gene for myelination in Schwann cells, results in transgression of the CNS/PNS boundary by astrocytes and oligodendrocytes and in myelination of nerve root axons by oligodendrocytes. In contrast, such migration does not occur with the Trembler(J) mutation, which prevents PNS myelination without affecting Krox20 expression. Altogether these data suggest that maintenance of the CNS/PNS boundary requires a new Krox20 function separable from myelination control. Finally, we have analyzed a human patient affected by a congenital amyelinating neuropathy, associated with the absence of the KROX20 protein in Schwann cells. In this case, the nerve roots were also invaded by oligodendrocytes and astrocytes. This indicates that transgression of the CNS/PNS boundary by central glia can occur in pathological situations in humans and suggests that the underlying mechanisms are common with the mouse.