We are a collaborative and tightly knit group of investigators who wish to contribute to the CCTRN our expertise in 1) small molecules and stem cells in peripheral arterial disease (John Cooke);2) clinical device development in stem cell delivery, coronary artery disease, and structural heart disease (William Fearon, Robert Robbins, and Alan Yeung);3) multimodality cellular, molecular, and physiologic imaging of stem cells and ischemic cardiovascular diseases (Sanjiv Gambhir, Dwight Nishimura, Joseph Wu, and Phillip Yang);4) bone marrow stem cell harvest and processing (Robert Negrin);and 5) stem cell characterization (Garry Nolan). We propose to contribute a novel multi-modality approach to assess stem cell engraftment employing manganese enhanced MRI (MEMRI) by Phillip Yang, and stem cell localization utilizing lndium-111 cell labeling by Joe Wu and Sam Gambhir. In addition, we will contribute innovative methodology to evaluate tissue perfusion and peri-infarct viability using magnetic resonance imaging (MRI) algorithms developed by Dwight Nishimura and Phillip Yang for peripheral and myocardial imaging, respectively. Finally, we will provide a comprehensive definition of the CD34+ mononuclear cells (MNCs) to be used in our human studies, using the paradigm-changing technology of single cell mass cytometry recently developed at Stanford (Bendall SC et al. Science 2011). This new technology provides a platform for massively multiplexed measurements of single-cell biological parameters that can finely delineate cellular subsets. We intend to correlate these subsets with clinical endpoints in our PAD and CAD research protocols, to determine what cell subsets may be most critical for any observed benefit.

Public Health Relevance

Adult stem cell trials in patients with CAD PAD have shown promise. However, the effect size for most endpoints has been modest. The mechanism(s) of benefit remain poorly understood. We suggest that a better definition and imaging ofthe therapeutic cell population could yield insights that might improve our selection and administration of adult stem cells, and potentially improve therapeutic benefit.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project with Complex Structure Cooperative Agreement (UM1)
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Special Emphasis Panel (ZHL1-CSR-O (F2))
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Ebert, Ray F
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Stanford University
Internal Medicine/Medicine
Schools of Medicine
United States
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Yang, Phillip C (2018) Induced Pluripotent Stem Cell (iPSC)-Derived Exosomes for Precision Medicine in Heart Failure. Circ Res 122:661-663
Jokerst, Jesse V; Cauwenberghs, Nicholas; Kuznetsova, Tatiana et al. (2017) Circulating Biomarkers to Identify Responders in Cardiac Cell therapy. Sci Rep 7:4419
Perin, Emerson C; Murphy, Michael P; March, Keith L et al. (2017) Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease: The CCTRN PACE Trial (Patients With Intermittent Claudication Injected With ALDH Bright Cells). Circulation 135:1417-1428
Venkatesh, Bharath Ambale; Nauffal, Victor; Noda, Chikara et al. (2017) Baseline assessment and comparison of arterial anatomy, hyperemic flow, and skeletal muscle perfusion in peripheral artery disease: The Cardiovascular Cell Therapy Research Network ""Patients with Intermittent Claudication Injected with ALDH Bright Cells" Am Heart J 183:24-34
Youssef, Amr A; Yang, Phillip C (2017) T1 Map of Post-Myocardial Infarction for Precise Tissue Characterization. Circ Cardiovasc Imaging 10:
Theruvath, Ashok J; Ilivitzki, Anat; Muehe, Anne et al. (2017) A PET/MR Imaging Approach for the Integrated Assessment of Chemotherapy-induced Brain, Heart, and Bone Injuries in Pediatric Cancer Survivors: A Pilot Study. Radiology 285:971-979
Tada, Yuko; Yang, Phillip C (2017) Myocardial Edema on T2-Weighted MRI: New Marker of Ischemia Reperfusion Injury and Adverse Myocardial Remodeling. Circ Res 121:326-328
Son, Myeongjoo; Kang, Woong Chol; Oh, Seyeon et al. (2017) Advanced glycation end-product (AGE)-albumin from activated macrophage is critical in human mesenchymal stem cells survival and post-ischemic reperfusion injury. Sci Rep 7:11593
Jung, Ji-Hye; Fu, Xuebin; Yang, Phillip C (2017) Exosomes Generated From iPSC-Derivatives: New Direction for Stem Cell Therapy in Human Heart Diseases. Circ Res 120:407-417
Contreras, Ariadna; Orozco, Aaron F; Resende, Micheline et al. (2017) Identification of cardiovascular risk factors associated with bone marrow cell subsets in patients with STEMI: a biorepository evaluation from the CCTRN TIME and LateTIME clinical trials. Basic Res Cardiol 112:3

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