Year 5 NCE

A central goal in stem cell therapy for neurological disease or injury is to understand how to optimize the survival and functional integration of stem cell-derived neurons. Neurons are the nervous system cells that form the interconnected networks that control cognition and behavior. Neurons are also the most sensitive cell type in the brain and the loss of function that accompanies disease or injury is due, in large part, to the inability of the brain to replace neurons that die. We have found that the inflammation that accompanies tissue damage selectively impairs the survival of newly generated neurons and research supported by this CIRM grant focused on understanding why immune signaling has such a detrimental effect in the brain and spinal cord.

The process of generating new neurons is termed neurogenesis. Neurogenesis is mediated by tissue-specific stem cells or “neural stem cells”. Neural stem cells mediate the formation of the brain and spinal cord during development. Neural stem cells are also important for the natural replacement of many types of brain cells that may be lost due to age, disease, or injury. Neural stem cells also continuously generate new neurons in select regions of the adult brain and our research focus has been to understand this natural process in order to improve the survival and functional benefit of new neurons that are transplanted to the damaged nervous system.

Research supported under this CIRM Comprehensive Grant has shown that immune signaling and the tissue inflammation that accompanies injury or disease strongly inhibits neurogenesis and 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.

Our earlier studies have led to several specific predictions about the cells and/or molecular signals that inhibit young neuron survival in the damaged brain. Experiments that that continued into a 6 month extension of this research tested whether genetically eliminating the implicated immune cell type or signaling molecule improves transplant outcome. Several drugs were also identified for their ability to protect newly generated neurons and enhance their survival and integration. Using genetic tools, we have confirmed that a specific type of immune cell selectively targets young transplanted neurons. Future studies will test drugs that selectively target this cell type with hopes of improving stem cell-based therapies.

We have also confirmed that two clinically approved drugs which modulate tissue inflammation are beneficial in two transplant models. The first involves a model of childhood brain injury caused by cancer treatments. The young brain is particularly sensitive radiation and chemotherapy. Young cancer survivors often have permanent neurological problems. Stem cell grafts may be useful to replace neural stem cells that have been killed by the cancer treatment. We are also testing transplants of stem cell-derived neurons in a model of Parkinson’s disease. In both model systems, the drug-based interventions protected the transplanted cells and future studies will test these interventions in several additional stem cell therapy models, including stroke and spinal cord injury.