Browsing by Author "March, Keith"
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Item Complementary Embryonic and Adult Cell Populations Enhance Myocardial Repair in Rat Myocardial Injury Model(Hindawi, 2019-11-03) Li Calzi, Sergio; Cook, Todd; Della Rocca, Domenico G.; Zhang, Juan; Shenoy, Vinayak; Yan, Yuanqing; Espejo, Andrew; Rathinasabapathy, Anandharajan; Jacobsen, Max H.; Salazar, Tatiana; Sandusky, George E.; Shaw, Lynn C.; March, Keith; Raizada, Mohan K.; Pepine, Carl J.; Katovich, Michael J.; Grant, Maria B.; Medicine, School of MedicineWe compared the functional outcome of Isl-1+ cardiac progenitors, CD90+ bone marrow-derived progenitor cells, and the combination of the two in a rat myocardial infarction (MI) model. Isl-1+ cells were isolated from embryonic day 12.5 (E12.5) rat hearts and expanded in vitro. Thy-1+/CD90+ cells were isolated from the bone marrow of adult Sprague-Dawley rats by immunomagnetic cell sorting. Six-week-old female Sprague-Dawley rats underwent permanent left anterior descending (LAD) coronary artery ligation and received intramyocardial injection of either saline, Isl-1+ cells, CD90+ cells, or a combination of Isl-1+ and CD90+ cells, at the time of infarction. Cells were delivered transepicardially to the peri-infarct zone. Left ventricular function was assessed by transthoracic echocardiography at 1- and 4-week post-MI and by Millar catheterization (-dP/dt and +dP/dt) at 4-week post-MI. Fluorescence in situ hybridization (Isl-1+cells) and monochrystalline iron oxide nanoparticles labeling (MION; CD90+ cells) were performed to assess biodistribution of transplanted cells. Only the combination of cells demonstrated a significant improvement of cardiac function as assessed by anterior wall contractility, dP/dt (max), and dP/dt (min), compared to Isl-1+ or CD90+ cell monotherapies. In the combination cell group, viable cells were detected at week 4 when anterior wall motion was completely restored. In conclusion, the combination of Isl-1+ cardiac progenitors and adult bone marrow-derived CD90+ cells shows prolonged and robust myocardial tissue repair and provides support for the use of complementary cell populations to enhance myocardial repair.Item Mesenchymal Stem Cell Secretions Improve Donor Heart Function 1 Following Ex-vivo Cold Storage(Elsevier, 2020) Wang, Meijing; Yan, Liangliang; Li, Qianzhen; Yang, Yang; Turrentine, Mark; March, Keith; Wang, I-wen; Surgery, School of MedicineObjectives Heart transplantation is the gold standard of treatments for end-stage heart failure, but its use is limited by extreme shortage of donor organs. The time “window” between procurement and transplantation sets the stage for myocardial ischemia/reperfusion injury, which constrains the maximal storage time and lowers use of donor organs. Given mesenchymal stem cell (MSC)-derived paracrine protection, we aimed to evaluate the efficacy of MSC-conditioned medium (CM) and extracellular vesicles (EVs) when added to ex vivo preservation solution on ameliorating ischemia/reperfusion–induced myocardial damage in donor hearts. Methods Mouse donor hearts were stored at 0°C-4°C of <1-hour cold ischemia (<1hr-I), 6hr-I + vehicle, 6hr-I + MSC-CM, 6hr-I + MSC-EVs, and 6hr-I + MSC-CM from MSCs treated with exosome release inhibitor. The hearts were then heterotopically implanted into recipient mice. At 24 hours postsurgery, myocardial function was evaluated. Heart tissue was collected for analysis of histology, apoptotic cell death, microRNA (miR)-199a-3p expression, and myocardial cytokine production. Results Six-hour cold ischemia significantly impaired myocardial function, increased cell death, and reduced miR-199a-3p in implanted hearts versus <1hr-I. MSC-CM or MSC-EVs in preservation solution reversed the detrimental effects of prolong cold ischemia on donor hearts. Exosome-depleted MSC-CM partially abolished MSC secretome-mediated cardioprotection in implanted hearts. MiR-199a-3p was highly enriched in MSC-EVs. MSC-CM and MSC-EVs increased cold ischemia–downregulated miR-199a-3p in donor hearts, whereas exosome-depletion neutralized this effect. Conclusions MSC-CM and MSC-EVs confer improved myocardial preservation in donor hearts during prolonged cold static storage and MSC-EVs can be used for intercellular transport of miRNAs in heart transplantation.Item Quantifiable Soft Tissue Manipulation (QSTM): A Requisite to Advance the Field of Manual Therapy(2017) Loghmani, Marry Terry; Neff, Bruce; Alotaibi, Ahmed M; Anwar, Sohel; Chien, Stanley; March, Keith; Physical Therapy, School of Health and Rehabilitation SciencesQuantifiable soft tissue manipulation (QSTM) that can characterize the motion and forces delivered during soft tissue examination and treatment of common musculoskeletal (MS) conditions in a real-time and clinically applicable manner is needed to achieve optimal outcomes. Soft tissue manipulation (STM), e.g. massage, is a type of mechanotherapy that has been used with benefit frequently by clinicians worldwide since ancient times. Instrument-assisted STM (IASTM) is a type of STM that uses rigid devices to assess and treat soft tissue abnormalities in a targeted and precise manner. Remarkably, however, the forces delivered during STM approaches have not been adequately quantified. Unlike other mechano-therapeutic approaches, e.g. ultrasound, traction, exercise, electrical stimulation, current manual therapy practice relies mostly on subjective description of STM evaluation findings and treatment parameters. This makes documentation, analysis, comparison, progression and optimization of this non-invasive intervention difficult to establish and validate. It is the authors’ strong opinion that there is need for QSTM to objectively measure, characterize and record the 3-dimensional (3D) forces and motion trajectories of STM evaluation and intervention. Innovative technology aimed to help address this void in research, educational and clinical practice has been developed by our research team and introduced in this article. The QSTM system has two components: an electronic, handheld device (applicator) for 3D characterization of force and a computer with software for data acquisition and analysis. Preliminary testing has demonstrated that the QSTM prototype can provide accurate sensed values and good intra-, inter-rater reliability. Device revisions are in progress and further testing is planned in animals and humans. QSTM is an essential technology needed for the standardization, comparison and optimization of STM therapies and a requisite to advance the field of manual therapy.Item Rationale and Design of the SENECA (StEm cell iNjECtion in cAncer survivors) Trial(Elsevier, 2018) Bolli, Roberto; Hare, Joshua M.; Henry, Timothy D.; Lenneman, Carrie G.; March, Keith; Miller, Kathy; Pepine, Carl J.; Perin, Emerson C.; Traverse, Jay H.; Willerson, James T.; Yang, Phillip C.; Gee, Adrian P.; Lima, João A.; Moyé, Lem; Vojvodic, Rachel W.; Sayre, Shelly L.; Bettencourt, Judy; Cohen, Michelle; Ebert, Ray F.; Simari, Robert; Medicine, School of MedicineObjectives SENECA (StEm cell iNjECtion in cAncer survivors) is a phase I, randomized, double-blind, placebo-controlled study to evaluate the safety and feasibility of delivering allogeneic mesenchymal stromal cells (allo-MSCs) transendocardially in subjects with anthracycline-induced cardiomyopathy (AIC). Background AIC is an incurable and often fatal syndrome, with a prognosis worse than that of ischemic or nonischemic cardiomyopathy. Recently, cell therapy with MSCs has emerged as a promising new approach to repair damaged myocardium. Methods The study population is 36 cancer survivors with a diagnosis of AIC, left ventricular (LV) ejection fraction ≤40%, and symptoms of heart failure (NYHA class II-III) on optimally-tolerated medical therapy. Subjects must be clinically free of cancer for at least two years with a ≤ 30% estimated five-year risk of recurrence. The first six subjects participated in an open-label, lead-in phase and received 100 million allo-MSCs; the remaining 30 will be randomized 1:1 to receive allo-MSCs or vehicle via 20 transendocardial injections. Efficacy measures (obtained at baseline, 6 months, and 12 months) include MRI evaluation of LV function, LV volumes, fibrosis, and scar burden; assessment of exercise tolerance (six-minute walk test) and quality of life (Minnesota Living with Heart Failure Questionnaire); clinical outcomes (MACE and cumulative days alive and out of hospital); and biomarkers of heart failure (NT-proBNP). Conclusions This is the first clinical trial using direct cardiac injection of cells for the treatment of AIC. If administration of allo-MSCs is found feasible and safe, SENECA will pave the way for larger phase II/III studies with therapeutic efficacy as the primary outcome.Item Vascular and Cardiac Adult Stem Cell Therapy Center(Office of the Vice Chancellor for Research, 2010-04-09) March, Keith; Murphy, Michael; Petrache, Irina; Evans-Molina, Carmella; Farag, Sherif; Traktuev, Dmitry; Saadatzadeh, Reza; Johnstone, Brian; Schweitzer, Kelly; Rosen, Elliot; Chen, Peng-ShengThe mission of the Vascular and Cardiac Adult Stem Cell Therapy Center (VC-CAST) is the discovery and clinical translation of therapies involving transplantation of adult stem cells into patients with debilitating diseases. To accomplish this, VC-CAST fosters multidisciplinary research collaborations that address both biology of adult stem cells that are readily available, and the translation of their study from the laboratory into clinical trials. The use of such cells is highly feasible, and not ethically controversial, as they are derived from readily-available tissues such as fat and bone marrow. Since its inception, VC-CAST projects have been multidisciplinary, involving multiple clinical as well as basic departments of the School of Medicine. VC-CAST projects are also collaborative, with most of the projects having one or more industrial partners. A key partnership has also been established by the creation of the Veterans Affairs Center for Regenerative Medicine (VACRM) at the Roudebush VA Medical Center in Indianapolis, which will provide a unique referral site focusing on research and implementation of first-in-human trials in the fields of poor circulation, arthritis, wound healing, diabetes, and emphysema. Given the focus of VC-CAST researchers on translation, the center is active in pursuit of intellectual property that is critical to building corporate engagement and thus the enablement of translation to clinical trials. Signature center funding has allowed IUPUI investigators to try high-risk, high-reward ideas, which could not otherwise be funded readily, via either NIH or venture-capital methods. Most of these experiments are still ongoing, but have already led to discoveries of potentially critical significance to patients. The novelty of some of these discoveries promises to attract new funding, as well as to provide bases for potential licensing revenues and startup opportunities. This poster will highlight several of these projects, representative of center activities in their collaborative, multidisciplinary and translational and potentially commercializable aspects. Some key projects are as follows: • Based on recent completion of the Phase I/II clinical trial, “Stem cell Angiogenesis to promote limb salVagE (SAVE), a new randomized Phase III clinical trial testing the use of one’s own bone marrow-derived stem cells to save legs from amputation has been initiated, with Dr. Murphy as the national PI. • Adipose Stem Cells for Peripheral Arterial Disease. • Endometrial Regenerative Cells for Peripheral Arterial Disease. • Adipose Stem Cells for treatment of Heart Attack and prevention of Heart Failure. • Adipose Stem Cells for Emphysema and other Lung Diseases • Adipose Stem Cells for Prevention and Treatment of Diabetes • Isolation and Characterization of Endothelial and Mesenchymal Stem Cells from Term Human Placenta. • Isolation and Characterization of Endothelial Colony Forming Cells (ECFCs) from Human Adult Blood VesselsItem Vascular and Cardiac Adult Stem Cell Therapy Center (VC-CAST)(Office of the Vice Chancellor for Research, 2011-04-08) March, Keith; Murphy, Michael; Petrache, Irina; Evans-Molina, Carmella; Traktuev, Dmitry; Johnstone, Brian; Clauss, Matthias; Hong, Soonjun; Gangaraju, Rajashekhar; Saadatzadeh, M. Reza; Schweitzer, Kelly; Rosen, Elliot; Farag, Sherif; Du, Yansheng; Chen, Peng-ShengThe mission of the Vascular and Cardiac Adult Stem Cell Therapy Center (VC-CAST) is the discovery and clinical translation of therapies involving transplantation of adult stem cells into patients with debilitating diseases. VC-CAST fosters multidisciplinary research collaborations that address the biology of adult stem cells that are readily available, as well as the translation of their study from the laboratory into clinical trials. The use of such cells is highly feasible, and not ethically controversial, as they are derived from readily-available tissues such as fat and bone marrow. VC-CAST projects involve partners from multiple clinical and basic departments of the School of Medicine. VC-CAST projects are also collaborative externally, with most projects having one or more industrial or academic external partners. A key partnership has also been established at the Roudebush VA Medical Center in Indianapolis by creation of the Veterans Affairs Center for Regenerative Medicine (VACRM), which will provide a unique referral site focusing on research and implementation of first-in-human trials in the fields of poor circulation, stroke, arthritis, wound healing, diabetes, and emphysema. Given the focus on translation, the center is active in pursuit of intellectual property that is critical to building corporate engagement and thus the enablement of translation to clinical trials. Signature Center funding has allowed IUPUI investigators to try high-risk, high-reward ideas, which could not otherwise be funded readily, via either NIH or venture-capital methods. Most of these experiments have already led to discoveries of potentially critical significance to patients. The novelty of some of these discoveries has attracted new funding, as well as provided bases for potential licensing revenues and startup opportunities. This poster will highlight several such projects, representative of center activities in their multidisciplinary, translational, and potentially commercializable aspects. Several key projects are as follows: • Saving Legs from Amputation o Bone Marrow Stem Cells: Based on our completion of the Phase I/II clinical trial, “Stem cell Angiogenesis to promote limb salVagE (SAVE), we have initiated a randomized Phase III clinical trial testing one’s own bone marrow-derived stem cells to save legs from amputation, with Dr. Murphy as national PI. o Fat-derived (Adipose) Stem Cells– we are testing the hypothesis that these are more potent than Bone Marrow-derived stem cells with new funding from a corporate partner as well as the Department of Defense. o Endometrial Regenerative Cells– further extending above efforts, with new NIH funding to study this allogeneic (non-self, “off-the-shelf”) cell type. • Treatment of Heart Attack and prevention of Heart Failure. New data this year shows Adipose Stem Cells protect from heart damage when given systemically. • Treatment of Emphysema and other Lung Diseases. Adipose Stem Cells markedly protect from cigarette smoke-induced emphysema, a generally untreatable condition. • Prevention and Treatment of Diabetes– Adipose Stem Cells can ameliorate diabetes. This work has attracted new Veterans Affairs funding this past year. • Treatment of Parkinson’s Disease by rescue of dopaminergic neurons from death. New funding attracted in the past year by the Signature Center led to preclinical data that extended prior work in stroke models to models of Parkinson’s Disease. These data suggest that the conditioned medium from ASCs can be useful in this debilitating condition, and form the basis for a new NIH application. • Treatment of Diabetic Retinopathy by vascular stabilization using adipose stem cells. This is a new project in the past year, and has generated encouraging early data which is being used in seeking further (external) funding. • Human Placenta as a stem cell source: Isolation and Characterization of Endothelial and Mesenchymal Stem Cells from Term Placenta. • Human Saphenous Vein as a cell source: Isolation and Characterization of Endothelial Colony Forming Cells (ECFCs) from Human Saphenous Vein can form the basis for vascular network formation.Item Whole-Body Vibration Training Increases Stem/Progenitor Cell Circulation Levels and May Attenuate Inflammation(Oxford, 2020-01) Jawed, Yameena; Beli, Eleni; March, Keith; Kaleth, Anthony; Loghmani, M Terry; Medicine, School of MedicineIntroduction Whole-body vibration training (WBVT) may benefit individuals with difficulty participating in physical exercise. The objective was to explore the effects of WBVT on circulating stem/progenitor cell (CPC) and cytokine levels. Methods Healthy male subjects each performed three activities randomly on separate days: (1) standing platform vibration, (2) repetitive leg squat exercise; and (3) in combination. Pre- and post-activity blood samples were drawn. Cell populations were characterized using flow cytometry. Biomarkers were analyzed using enzyme-linked immunosorbent assays. Results CPC levels increased significantly 21% with exercise alone (1465 ± 202–1770 ± 221 cells/mL; P = 0.017) and 33% with vibration alone in younger participants (1918 ± 341–2559 ± 496; P = 0.02). Angiogenic CPCs increased 39% during combined activity in younger (633 ± 128–882 ± 181; P = 0.05). Non-angiogenic CPCs increased 42% with vibration alone in younger (1181 ± 222–1677 ± 342; P = 0.04), but 32% with exercise alone in older participants (801 ± 251–1053 ± 325; P = 0.05). With vibration alone, anti-inflammatory cytokine interleukin-10 increased significantly (P < 0.03), although inflammatory interleukin-6 decreased (P = 0.056); tumor necrosis factor-alpha (P < 0.01) and vascular endothelial growth factor levels increased (P < 0.005), which are synergistically pro-angiogenic. Conclusions WBVT may have positive vascular and anti-inflammatory effects. WBVT could augment or serve as an exercise surrogate in warfighters and others who cannot fully participate in exercise programs, having important implications in military health.