Stem cell therapy holds promise for the almost million Americans yearly who suffer a stroke. Preclinical data have shown that human neural stem cells (hNSCs) aid recovery after stroke, resulting in a major effort to advance stem cell therapy to the clinic, and we are currently transitioning our hNSC product to the clinic for stroke therapy. In this proposal we will explore how these cells improve lost function. We have already shown that injected hNSCs secrete factors that promote the gross rewiring of the brain, a major component of the spontaneous recovery observed after stroke. We now intend to focus on the connections between neurons, the synapses, which are a critical part of this rewiring process. We aim to quantify the effect of hNSCs on synapse density and function, and explore whether the stem cells secrete restorative synaptogenic factors or form functional synapses with pre-existing neurons. Our pursuit is made possible by our combination of state-of-the-art imaging techniques enabling us to visualize, characterize, and quantify these tiny synaptic structures and their interaction with the hNSCs. Furthermore, by engineering the hNSCs we can identify the factors they secrete in the brain and identify those which modulate synaptic connections. Our proposed studies will provide important insight into how transplanted stem cells induce recovery after stroke, with potential applicability to other brain diseases.
Cerebrovascular stroke is the fourth leading cause of mortality in the United States and a significant source of long-term physical and cognitive disability that has devastating consequences to patients and their families. In California alone, over 9% of adults 65 years or older have had a stroke according to a 2005 study. In the next 20 years the societal toll is projected to amount to millions of patients and 18.8 billion dollars per year in direct medical costs. To date, there is no approved therapeutic agent for the recovery phase after stroke, making the long-term care of stroke patients a tremendous socioeconomic burden that will continue to rise as our aging population increases. Our laboratory and others have demonstrated the promise of stem cell transplantation to treat stroke. We are dedicated to developing human neural stem cells (hNSCs) as a novel neuro-restorative treatment for lost motor function after stroke. The goal of our proposed work is to further understand how transplanted hNSCs improve stroke recovery, as dissecting the mechanism of action of stem cells in the stroke brain will ultimately improve the chance of clinical success. This could potentially provide significant cost savings to California, but more importantly benefit the thousands of Californians and their families who struggle with the aftermath of stroke.
Stem cell transplantation is known to produce therapeutic benefit in both experimental animal models of stroke and in patients, though there is limited understanding of the mechanisms involved. This fundamental track proposal aims to investigate the mechanisms by which transplanted stem cells can potentially enhance brain plasticity that is crucial for the recovery after stroke. The effect of human neural stem cells (hNSCs) on the formation and function of synapses will be investigated and will explore whether the stem cells secrete restorative synaptogenic factors or form functional synapses with pre-existing neurons. The experiments will involve a line of stem cells being prepared by the investigative team for clinical translation. This cell line will be investigated in a series of in vitro and rat transplant experiments aimed at (i) studying the paracrine secretion by this line of NSCs and identifying the secreted factors; (ii) assessing the levels of certain neurotransmitters in the brains of stroke model animals; (iii) evaluating the function of secreted factors in an animal model.
Significance and Innovation
- The goal of this proposal is to improve the understanding of the mechanisms by which transplanted hNSCs produce benefit in both experimental animal models of stroke and in patients. This understanding is crucially important for further progress to be made, and for safety issues to be addressed.
- The experimental design is focused on a rational hypothesis, is novel and exciting, and employs very challenging technology using unique tools.
- The applicants incorporate very elegant approaches using electrophysiological, molecular and pharmacological studies to answer key questions.
Feasibility and Experimental Design
- The feasibility of the selected approach is strongly supported by substantial preliminary data, including the successful use of the very complex experimental techniques proposed. Experimental difficulties are well-anticipated and alternative approaches are in place.
- The feasibility is further enhanced by successful identification of one of the NSC-secreted factors that modulate synaptogenesis.
- One of the Aims attempts to relate the secreted factors with the level of the functional recovery is especially challenging, but is likely to be achieved, given the success of this approach with rodent NSCs.
Principal Investigator (PI) and Research Team
- The PI is an experienced, highly renowned investigator of stroke and its therapy.
- Very strong team, which includes world-class experts who complement the considerable technological expertise of the PI.
- The time commitments and budget are appropriate for the proposal.
Responsiveness to the RFA
- The proposal is highly responsive to the RFA as it tackles a set of problems crucial to the successful use of stem cells in the treatment of stroke. It will provide important information on the mechanisms by which hNSCs provide benefit in an important class of central nervous system injury.