The adult brain and spinal cord do not regenerate after major injury or disease but there are stem cells present in the brain that are capable of repairing damaged neural networks. One region of the brain where new neurons are continuously produced is called the hippocampus. Unique signals within the hippocampus promote neurogenesis (i.e., the production of new nerve cells) and our hope is to identify and use these signals to promote neurogenesis following injury or disease. In addition, our laboratory has also shown that the tissue inflammation that accompanies injury or disease strongly inhibits neurogenesis and our ongoing research has two goals: First, to identify factors that naturally promote neurogenesis and apply these factors to enhance natural repair and/or improve stem cell transplant outcome. Second, we hope to identify inhibitory factors produced by the immune system during tissue inflammation and develop better interventions to block these signals and promote neural circuit repair when an injury or disease process is present.
Activities in year 3 have focused primarily on identifying immune mechanisms that impair neurogenesis when stem cell transplants are not perfectly matched to the recipient. Under normal circumstances, tissue transplants are rejected by the immune system if they do not closely match the recipient. This limits the clinical use of donor organs such as heart, liver, lung. However, transplants of cells to the brain are not rejected, even if they are poorly matched. However, we have found that immune signaling is not absent in the brain but simply different than in other areas of the body. While graft rejection does not occur, neurogenesis is strongly inhibited. We have found that there are two immune processes that are relevant to neurogenesis: 1) immune activation/inflammation that stimulates the production of immune signaling molecules impairs neurogenesis and 2) the elimination of transplanted cells that are “not exactly like me” by natural killer cells may selectively eliminate the newly forming neurons. In year 3 we have explored the interactions of NPCs with a variety of immune cell types, including T cells and NK cells. We have found that NPCs are recognized by both cell types and are now exploring methods to attenuate the effects of immune cell response following stem cell transplantation in cell transplant models. These include studies to restore neural stem cell function following therapy for brain cancer, studies to enhance regeneration and repair following spinal injury, and studies to improve stem cell therapy for Parkinson’s disease.