Transplantation of Oligodendrocyte Progenitors and CG4 Cells into the Dveloping Rat Brain: Differences and Similarities

Unlike most organs, the Central Nervous System (CNS) is very complex, containing a variety of cell types which form not a homogenous organ but rather a group of diverse components acting in concert to perform CNS functions. Once the CNS has developed during the early postnatal life of the organism, a function of each cell type is the maintenance of the newly formed structures such as synapses, myelin, and blood brain barrier. Neurons, astrocytes, and oligodendrocytes, form this well organized system and favorable extracellular milieu. The cell-cell interactions and biochemical exchanges between the various cell types contribute to the function and health of the CNS. The CNS can lose its functionality as a consequence of injury or disease. When CNS is damaged, neurons and glial cells respond in different ways and generally the result is poor regeneration. In the case of trauma, axonal regrowth is limited and restricted to a small area around the wound. Synaptic sprouting is observed, undamaged neurons form new branches and synapses in order to replace some of the lost ones. However, oligodendrocytes (the myelin producing cells in CNS) unlike Schwann cells (PNS) do not promote regrowth of the damaged axons. Furthermore, it has been recently shown that oligodendrocytes can block regeneration ( 24). The astrocyte, the second major glial cell type, responds to injury by forming a scar at the site of the wound and blocks axonal regrowth as well. The enormous difference between PNS and CNS regeneration capacities has led to the conclusion that the CNS and in particular glial cells respond to injury by actively blocking “repair”. Besides injury, disease can also alter or impair CNS function. Many diseases affect neuronal population in a direct manner while others affect glial cells, astrocytes or oligodendrocytes, directly and consequently alter neuronal function. A condition proper to oligodendroglial cells is myelin deficiency. Myelin deficiency can result either from failure to produce the normal amount of myelin during development or from demyelination. The lack of myelin or abnormal myelin formation during CNS development is known as dysmyelination (For Review see 21). Myelin deficient mutants belong to this category (Review:20). The neurological dysmyelinating disorder Pelizaeus-Merzbacher (26) is the result of a mutation in the PLP/DM20 gene (19). The rodent PLP mutants Jimpy, Jimpy msd mice, myelin-deficient (md) rat present dysmyelination similar to the human condition and the disease is lethal in all cases (18,1). In the past it has been assumed that CNS dysfunction due to either injury or disease was irreversible. However, during the last two decades it has become clear that the CNS with the proper stimuli has the capacity to regenerate. In the case of remyelination it is still unclear if new myelinforming cells can be regenerated in sufficient numbers to rescue the myelin deficient CNS. For this reason many researchers have chosen transplantation of myelin forming cells from either PNS or CNS (11,17 and many others) as the alternative of providing healthy cells to the host in order to myelinate impaired CNS (27). Recently various studies on oligodendroglial transplants into dysmyelinating mutants have been described (14,3). In our own laboratory different kind of transplant experiments have been designed with the final goal of their therapeutic application. Nevertheless the optimization of the system to achieve this goal involves extensive characterization on the behavior of the graft in the in vivo environment (10). By grafting young oligodendrocytes (5), or their progenitors (6) into the developing rat brain within the first week of postnatal life we have learned that they survive, migrate (7) and integrate within the host parenchyma upon transplantation. In the present report we summarize previous findings on the transplantation of young oligodendrocytes (5). We studied and compared after transplantation the behavior of wild type oligodendroglial progenitors (OLP) and, CG4 (central glial four) cells at a progenitor stage (16). Either one of the cell types as grafted into myelin deficient (md) and unaffected litter mates rat pups. We also used wild type rat pups for long-term transplantation experiments up to 6 months. Two implant sites were chosen, the hippocampus and the dorsal subarachnoidal space of the cerebellum.