Following traumatic spinal cord injury (SCI), three major cellular deficits need to be addressed to attempt therapeutic repair: regeneration of severed axons, myelination of demyelinated and regeneration axons, and replacement of lost neurons. Both the fetal and adult CNS contain pluripotent stem cells that can be expanded in vitro and will differentiate into astrocytes oligodendrocytes and/or neurons. We hypothesize that transplantation of CNS stem cells, whose phenotyping fate can be precisely controlled in vitro, into the injured spinal cord may foster endogenous axonal regeneration and remyelination and enable functional neuronal replacement and circuit restoration.
Aim 1 will establish cellular and molecular approaches that direct cell-specific differentiation of stem cells into astrocytes, neurons, and oligodendrocytes.
Aim 2 will determine the lineage restriction of CNS stem cells in the lesioned spinal cord. The lesioned CNS has distinctive white and gray matter environments rostral to, caudal to, or at the injury epicenter and the epigenetic signals in these diverse cellular terrains will direct very different neural precursor cell differentiation. We hypothesize that the constitutive differentiated phenotypes in vivo will be different from those in vitro, and variables for cell-specific differentiation in vivo will have to be empirically determined in vitro before grafting.
Aim 3 will determine the physiological potential of CNS stem cells to engender repair in SCI. Stem cells with defined phenotypes in vivo will be used to address three specific deficits in adult rat SCI: a) remyelinate axons after transplantation into the demyelinated spinal cord, and b) integrate into host circuitry and receive afferent input after transplantation into the contused spinal cord. We hypothesize that judicious choice of differentiated cell typed and neurotrophic factor delivery for particular lesions will enable improved anatomical and potentially behavioral recovery subsequent to stem cell transplantation.
Showing the most recent 10 out of 53 publications
