ABSTRACT
Self-renewing, totipotent embryonic stem (ES) cells may provide a virtually unlimited donor source for transplantation. A protocol that permits the in vitro generation of precursors for oligodendrocytes and astrocytes from ES cells was devised. Transplantation in a rat model of a human myelin disease shows that these ES cell-derived precursors interact with host neurons and efficiently myelinate axons in brain and spinal cord. Thus, ES cells can serve as a valuable source of cell type-specific somatic precursors for neural transplantation.
Subject(s)
Astrocytes/cytology , Diffuse Cerebral Sclerosis of Schilder/therapy , Myelin Sheath/physiology , Oligodendroglia/cytology , Oligodendroglia/transplantation , Stem Cells/cytology , Animals , Brain/embryology , Brain/metabolism , Cell Differentiation , Cell Line , Cell Movement , Cerebral Ventricles/embryology , Cerebral Ventricles/surgery , Diffuse Cerebral Sclerosis of Schilder/genetics , Embryo, Mammalian/cytology , Growth Substances/pharmacology , Humans , Male , Mice , Myelin Basic Protein/biosynthesis , Myelin Proteolipid Protein/biosynthesis , Myelin Proteolipid Protein/genetics , Oligodendroglia/metabolism , Oligodendroglia/ultrastructure , Rats , Spinal Cord , Stem Cell TransplantationABSTRACT
Limited experimental access to the central nervous system (CNS) is a key problem in the study of human neural development, disease, and regeneration. We have addressed this problem by generating neural chimeras composed of human and rodent cells. Fetal human brain cells implanted into the cerebral ventricles of embryonic rats incorporate individually into all major compartments of the brain, generating widespread CNS chimerism. The human cells differentiate into neurons, astrocytes, and oligodendrocytes, which populate the host fore-, mid-, and hindbrain. These chimeras provide a unique model to study human neural cell migration and differentiation in a functional nervous system.
Subject(s)
Brain Tissue Transplantation , Brain/embryology , Fetal Tissue Transplantation , Animals , Biotechnology , Brain/cytology , Cell Differentiation , Cerebral Ventricles/cytology , Cerebral Ventricles/embryology , Chimera , Female , Humans , Models, Neurological , Neurons/cytology , Pregnancy , Rats , Rats, Sprague-Dawley , Stem Cells/cytologyABSTRACT
During embryogenesis, pluripotent stem cells segregate into daughter lineages of progressively restricted developmental potential. In vitro, this process has been mimicked by the controlled differentiation of embryonic stem cells into neural precursors. To explore the developmental potential of these cell-culture-derived precursors in vivo, we have implanted them into the ventricles of embryonic rats. The transplanted cells formed intraventricular neuroepithelial structures and migrated in large numbers into the brain tissue. Embryonic-stem-cell-derived neurons, astrocytes, and oligodendrocytes incorporated into telencephalic, diencephalic, and mesencephalic regions and assumed phenotypes indistinguishable from neighboring host cells. These observations indicate that entirely in vitro-generated neural precursors are able to respond to environmental signals guiding cell migration and differentiation and have the potential to reconstitute neuronal and glial lineages in the central nervous system.