Functional roles of microglia in neural tissue transplantation / by Nathan Adam Pennell.

Abstract

Transplantation of fetal neural tissue is being evaluated as a treatment for neuropathological disorders ranging from Parkinson's disease to spinal cord injury. This dissertation addresses some fundamental aspects of fetal transplant development with a primary focus on microglial cells. First, fluorescently prelabeled microglia were traced for two weeks after injection into the adult rat brain. The labeled cells survived in vivo and differentiated into ramified microglia. This study showed that, unlike perivascular cells, resting endogenous microglia are not actively pinoor phagocytic. This finding sheds some doubt upon previous ideas of microglial immunocompetence.Second, to test the hypothesis that donor microglia induce alio-and xenograft rejection, fetal rat and mouse suspensions were depleted of microglia prior to transplantation into the either the injured spinal cord or the intact striatum. This treatment did not alter the pattern or time course of xenograft rejection. Both depleted and nondepleted allografts, however, survived ftDr three weeks without signs of rejection.Between three and four weeks post-transplantation (pt) rejection started and proceeded rapidly with destruction of all grafts by 45 days. Rejection did not correlate with graft major histocompatability complex (MHC) antigen expression, suggesting that minor histocompatability antigens were involved. The ineffectiveness of microglial depletion in preventing rejection, along with in vitro results showing that allogeneic microglia are not functional antigen presenting cells, indicates that microglia do not initiate allograft rejection.Finally, the development of microglia, astrocytes, and vasculature within fetal intrastriatal and intraspinal transplants was followed for the first month pt, as was the expression of angiogenic cytokines within the grafts. Microglia, of primarily host origin, invaded the grafts prior to the onset of neovascularization and were often associated with developing vessels. Astrocytes and blood vessels were intimately associated with each other during the early time points p/. The grafts expressed high levels of vascular endothelial growth factor (VEGF) throughout the first month pt, while basic fibroblast growth factor (bPGF) and transforming growth factor-beta (TGF-P) were primarily expressed after 2 1 days pt. These cytokines were not primarily expressed by glial cells, however, indicating that the relationship between glia and angiogenesis may be indirect. CHAPTER 1 BACKGROUND Neural Tissue TransplantationAlthough it was once thought that damage to the central nervous system was irreversible and irreparable, it is now understood that the CNS's lack of regenerative ability is surmountable (Richardson et al., 1980; Savio and Schwab, 1990; Davies et al., 1997). The use of fetal neural transplants is currently under investigation as a possible treatment for a wide range of neuropathies, ranging from neurodegenerative disorders such as Parkinson's Disease to traumatic disorders such as spinal cord injury (Bjorklund,...