RESUMEN
Murine- and human-induced pluripotent stem cell-derived neural stem/progenitor cells (iPSC-NS/PCs) promote functional recovery following transplantation into the injured spinal cord in rodents and primates. Although remyelination of spared demyelinated axons is a critical mechanism in the regeneration of the injured spinal cord, human iPSC-NS/PCs predominantly differentiate into neurons both in vitro and in vivo. We therefore took advantage of our recently developed protocol to obtain human-induced pluripotent stem cell-derived oligodendrocyte precursor cell-enriched neural stem/progenitor cells and report the benefits of transplanting these cells in a spinal cord injury (SCI) model. We describe how this approach contributes to the robust remyelination of demyelinated axons and facilitates functional recovery after SCI.
Asunto(s)
Axones/fisiología , Células Madre Pluripotentes Inducidas/trasplante , Vaina de Mielina/fisiología , Oligodendroglía/fisiología , Traumatismos de la Médula Espinal/terapia , Animales , Diferenciación Celular/fisiología , Células Cultivadas , Femenino , Miembro Posterior/fisiología , Humanos , Células Madre Pluripotentes Inducidas/citología , Ratones Endogámicos NOD , Ratones SCID , Regeneración Nerviosa/fisiología , Células-Madre Neurales/citología , Células-Madre Neurales/trasplante , Neuronas/citología , Neuronas/fisiología , Oligodendroglía/citología , Recuperación de la Función/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Trasplante de Células Madre/métodos , Trasplante HeterólogoRESUMEN
Pelizaeus-Merzbacher disease (PMD) is a form of X-linked leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene. Although PLP1 proteins with missense mutations have been shown to accumulate in the rough endoplasmic reticulum (ER) in disease model animals and cell lines transfected with mutant PLP1 genes, the exact pathogenetic mechanism of PMD has not previously been clarified. In this study, we established induced pluripotent stem cells (iPSCs) from two PMD patients carrying missense mutation and differentiated them into oligodendrocytes in vitro. In the PMD iPSC-derived oligodendrocytes, mislocalization of mutant PLP1 proteins to the ER and an association between increased susceptibility to ER stress and increased numbers of apoptotic oligodendrocytes were observed. Moreover, electron microscopic analysis demonstrated drastically reduced myelin formation accompanied by abnormal ER morphology. Thus, this study demonstrates the involvement of ER stress in pathogenic dysmyelination in the oligodendrocytes of PMD patients with the PLP1 missense mutation.