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Atena Zahedi, PhD Stem Cell Research Center Mentor: Aileen Anderson, PhD |
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Project Title: Mitochondrial Innovations for the Enhancement and Tracking of Stem Cell Transplantation in Spinal Cord Injury |
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Stem cell activity and function are critical in development, aging, disease, and injury. Transplantation of human neural stem cells (hNSC) to replace damaged tissues in traumatic injuries and neurodegenerative diseases has shown great promise in pre-clinical studies and early clinical trials. hNSC transplantation can contribute to repair by generating new CNS cells, as well as secreting neuroprotective factors. However, the heterogeneity in the efficacy and survival of different human NSC lines after transplantation is vast, and there is an unmet need for corresponding data in different clinical models. Spinal cord injury (SCI) causes nerve fiber degeneration and loss of motor and sensory functions, and globally affects over 27 million people. Individual costs of cervical SCI can exceed $1M/year, in addition to the economic costs due to loss of work for SCI individuals and primary caregivers. Combined with the lack of SCI therapeutics, these data highlight significant unmet medical and quality of life needs. SCI is marked by a secondary injury phase, characterized by stress due to elevated levels of reactive oxygen species (ROS), secreted inflammatory factors, and mitochondria dysfunction. These factors are shown to impair NSC repair potential (efficacy) by affecting functions such as cell division and differentiation. Mitochondria are also vital for providing the energy demands (bioenergetics) of cells during times of high energy demand such as during stem cell differentiation and migration. However, mitochondria are sensitive to stress, where overproduction of ROS can lead to mitochondrial dysfunction, degradation, and eventual exhaustion. We propose a model where key mitochondria fitness traits (MFTs) can determine: 1) the efficacy of hNSC line after transplantation into a SCI model, and 2) the outcome of potential mitochondrial drug candidates (Figs. 2). To test this hypothesis, I will use human NSC UCI lines developed in the Anderson laboratory where one set of lines exhibits efficacy after transplantation into SCI models, while a second fails this test. I will also develop a novel mitochondria DNA (mtDNA)-targeted CRISPR/Cas reporter system for stable tracking of mitochondria transfer (MT) from transplanted NSCs in vivo and studying the effect of mitochondria uptake on host cells. Not many studies have investigated the mechanisms of how stem cell line intrinsic mitochondria characteristics are related to functional recovery from injury and neuroinflammation. This lack identifies a critical gap in knowledge in the stem cell transplantation field. We ultimately aim to elucidate the role mitochondria fitness and transfer in the efficacy of stem cell lines and develop new mitochondria-based therapeutic approaches to advance clinical trials for traumatic injuries and neurodegenerative diseases. |
