Progenitor cell (PC) therapies are being developed as a therapeutic alternative after myocardial in- jury. However, changes in the post-ischemic myocardium may affect the functionality and survival of donor PCs and limit the benefit of this intervention. Thus, there is significant interest in better under- standing the mechanisms that regulate the phenotype and survival of PCs in the myocardium after in- jury;this will likely lead to more optimized therapies. The PI has previously shown that reporter gene bioluminescence imaging (BLI) can be used to ac- curately and longitudinally monitor cell viability noninvasively. Furthermore, we recently developed a novel reporter gene-based imaging sensor that can noninvasively monitor the biology of transplanted PCs, using a clinically applicable imaging strategy. Myocardial injury leads to increased oxidative stress, an imbalance between pro- and anti-oxidants, as well as, inflammation and apoptosis, creating a hostile microenvironment that will affect the fate of transplanted PCs. Furthermore, we have previously shown that antioxidant modulation of PCs leads to increased cell survival rates after transplantation. Thus, it appears that oxidant stress is a good and relevant candidate to test these novel monitoring strategies. The hypothesis of this proposal is that the interaction between the post-ischemic myocardium and PCs can be monitored non-invasively, and that such imaging strategies can be adapted for clinical use.
Aim 1 will test the hypothesis that the oxidant status of PCs can be monitored using reporter genes.
Aim 2 will test the hypothesis that a) the oxidant status of transplanted PCs can be monitored noninvasively directly in the living subject, and b) endogenous oxidant signals can be used to drive a therapeutic gene and optimize the survival and functionality of PCs.
Aim 3 will test the hypothesis that this novel strategy to monitor oxidant status in PCs can be adapted for use in large animals.

Public Health Relevance

Stem cell therapy is being developed for myocardial repair, but the retention and survival of transplanted cells has been very limited. The cardiac muscle (myocardium) after infarction undergoes many changes that can affect the fate of transplanted progenitor cells, which adversely impacts progenitor cells'regenerative potential. Thus, it becomes critical to better understand the interaction between transplanted stem cells with the post-ischemic myocardium. We have shown that non-invasive molecular imaging can be used to monitor the survival of transplanted cells. In this proposal, we will use reporter genes to non-invasively monitor the biology of transplanted stem cells in real-time and use the endogenous information to optimize cell therapies. Furthermore, we will translate these strategies to use in large animals. The knowledge obtained here will be invaluable for taking full advantage of stem cell therapies and make them more efficient as they become available for clinical use.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
High Priority, Short Term Project Award (R56)
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Special Emphasis Panel (ZRG1-SBIB-Q (03))
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Buxton, Denis B
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Mayo Clinic, Rochester
United States
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Franchi, Federico; Peterson, Karen M; Paulmurugan, Ramasamy et al. (2016) Noninvasive Monitoring of the Mitochondrial Function in Mesenchymal Stromal Cells. Mol Imaging Biol 18:510-8
Franchi, Federico; Peterson, Karen M; Xu, Rende et al. (2015) Mesenchymal Stromal Cells Improve Renovascular Function in Polycystic Kidney Disease. Cell Transplant 24:1687-98
Franchi, Federico; Ezenekwe, Adachukwu; Wellkamp, Lukas et al. (2014) Renin inhibition improves the survival of mesenchymal stromal cells in a mouse model of myocardial infarction. J Cardiovasc Transl Res 7:560-9