California's Stem Cell Agency

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 generating new brain tissues. In some regions of the brain, these brain-specific stem cells are continuously producing new nerve cells or “neurons”, the type of cell that forms the brain’s internal circuitry. The process of generating new neurons is called neurogenesis and our goal in this grant is to learn how neurogenesis is naturally maintained and controlled. Using the information we gain, our ultimate goal is to stimulate neurogenesis and repair in other areas of the brain, either by activating resident stem cells or by improving the effectiveness of stem cell transplants. One region of the brain where neurogenesis naturally occurs is called the hippocampus. This small brain structure is important for short term learning and memory. It is one of the brain regions affected in Alzheimer’s disease. Our laboratory was one of the first groups to show that brain tissue inflammation that accompanies injury or disease strongly inhibits neurogenesis in this area. We have gone on to show that the production of neurons by stem cell transplants is also strongly inhibited by tissue inflammation. Tissue inflammation is caused by the natural activation of the immune system when cells or tissues are damaged. One focus of our research in this grant is to identify factors produced by the immune system that inhibit neurogenesis and to determine if blocking these factors will enhance endogenous neurogenesis or neurogenesis from stem cell transplants. The concepts are summarized in a recent publication from our group (Carpentier and Palmer, Neuron 2009) We are also using genetically mutant mice to determine if the absence of specific inflammatory molecules can promotes neurogenesis and have found that the absence of one immune molecule does indeed improve neurogenesis. There are experimental drugs that block the activity of this molecule and we hope to test these drugs in the coming year for their ability to promote neurogenesis. A second focus of this project is to identify signals that promote neurogenesis. The stem cells in the hippocampus provide several intriguing leads. Our research has uncovered two important neurogenesis-promoting signals present in the hippocampus. The first is a specialized matrix of proteins that are produced in the hippocampus. This matrix acts like a “gate keeper” to define where stem cells should (or should not) generate new neurons. It is also known that stem cells in a petri dish will generate more neurons if one treats them with drugs that mimic brain circuit activity. However, no one had directly confirmed this in animals. To test this, we have produced a genetically modified mouse in which we can control activity in the hippocampal neural circuitry (Haditsch et al Molecular and Cellular Neuroscience 2009). Using this mouse, our ongoing research has identified proteins released from active neurons that promote neurogenesis. Again, we have found experimental drugs used for other purposes that appear to mimic the neurogenesis-promoting aspects of circuit activity and our hope is that these can be used to promote neurogenesis for therapy. Of course, the ultimate goal of our work is to translate our findings into treatments for brain injury or disease and the final aim of our project is use these combined observations to determine if stem cell transplants can be effectively harnessed for repair. The first step for transplantation strategies is to determine if stem cell derived transplants can work to produce new circuitry. We have just completed studies showing that the methods used to prepare embryonic stem cells for transplant have a large effect on the ability of the transplanted cells to form neurons that make correct connections within the brain. Stem cells must be programmed correctly before transplant if they are to function as desired. We are also performing experiments to understand the immunology of stem cell transplantation itself. At present, stem cells being used in clinical trials come from either human embryonic stem cells isolated from a human blastocyst or from neural stem cells isolated from human fetal brain. Neither of these sources would be perfectly matched to the recipient but recent discoveries have shown that stem cells can be generated from the skin fibroblasts of a patient. These “induced pluripotent stem cells” or iPSC are perfectly matched but the technology and clinical applications are lagging far behind. Even as fetal or embryonic stem cells are entering clinical trials, the impact of transplant matching and immunology remains an unanswered question and our ongoing work may uncover methods that can improve transplant outcome even if the cells are poorly matched to the recipient.

Research supported by this CIRM grant focused on understanding the immune signaling that influences neural stem cells in the brain and spinal cord. Stem cells are important for the natural replacement of brain cells that may be lost due to age, disease, or injury. Stem cells may also be useful in repairing the brain. Our research has shown that immune signaling and the tissue inflammation that accompanies injury or disease strongly inhibits “neurogenesis” or the production of new neurons from stem cells. Our goals in this work are to identify factors that naturally promote neurogenesis and apply these factors to enhance natural repair and/or improve the utility of stem cell transplants for therapy. One of our strategies is 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. As a result of the research supported by CIRM we have identified three novel uses for drugs that have already been used in clinical settings. These drugs increase the number of new neurons produced by stem cells in the brain by either blocking negative immune signals or by directly stimulating neurogenesis. Experiments started in the final year of this grant will now continue in studies of stem cell transplants that are not perfectly matched to the recipient. Many cell transplant therapies for neurological disease or injury have utilized cells from another individual rather than a patient’s own cells. Tissue transplants are normally rejected by the immune system if they do not closely match the recipient and we have found that classical methods to protect grafted cells may not work as well as anticipated. Using the drugs identified in our CIRM funded research, we will next test whether controlling immune system effects can further improve the efficacy of stem cell therapies that have been engineered to treat stroke, spinal injury or Parkinson’s disease.