Recent clinical studies have suggested that elevated levels of circulating stem cells may decrease the risk of death from cardiovascular disease. Aging has been linked to decreased stem cell functional capacity under conditions of stress, a lower number of circulating stem cells, and an attenuation of the stress induced increase in these circulating cells. In addition, the use of human embryonic stem cells (ESCs) has been faced with tremendous controversy. Therefore adult bone marrow mesenchymal stem cells (aBMSCs) and ESCs may not be optimal for stem cell transplantation after cardiac injury. BMSCs from younger hosts, such as neonates (nBMSC), may be better equipped to survive during conditions of ischemia, and may provide a greater degree of protection during I/R injury. Our hypothesis therefore, is that nBMSCs will provide greater protection to injured myocardium during I/R induced injury. To make significant advancements toward this goal, we propose the following four specific aims: 1) To determine whether nBMSCs exhibit higher levels of protective growth factors and lower levels of proinflammatory cytokines compared to aBMSCs. 2) To determine whether nBMSCs have a higher rate of proliferation, higher pluripotent potential, or increased levels of activated p38, ERK, JNK, or Akt that contribute to the differences observed in cytokine production. 3) To determine whether nBMSCs confer a greater degree of cardioprotection during I/R injury as measured via isolated Langendorff preparation. 4) To determine whether nBMSCs provide greater cardioprotection by decreasing cellular apoptosis via upregulation of the PI3/Akt, SOCS3 or STATS signaling cascades. Relevance to public health: Stem cells may be a new treatment to help patient's who suffer from many different diseases. Understanding the ways that stem cells help patients will allow scientists to create """"""""super"""""""" stem cells that both survive better in stressful conditions and release protective growth substances. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HL092719-01
Application #
7483978
Study Section
Special Emphasis Panel (ZRG1-F10-H (21))
Program Officer
Mondoro, Traci
Project Start
2008-07-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
1
Fiscal Year
2008
Total Cost
$49,646
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Surgery
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Herrmann, Jeremy L; Weil, Brent R; Abarbanell, Aaron M et al. (2011) IL-6 and TGF-ýý costimulate mesenchymal stem cell vascular endothelial growth factor production by ERK-, JNK-, and PI3K-mediated mechanisms. Shock 35:512-6
Herrmann, Jeremy L; Abarbanell, Aaron M; Weil, Brent R et al. (2011) Optimizing stem cell function for the treatment of ischemic heart disease. J Surg Res 166:138-45
Poynter, Jeffrey A; Herrmann, Jeremy L; Manukyan, Mariuxi C et al. (2011) Intracoronary mesenchymal stem cells promote postischemic myocardial functional recovery, decrease inflammation, and reduce apoptosis via a signal transducer and activator of transcription 3 mechanism. J Am Coll Surg 213:253-60
Abarbanell, Aaron M; Hartley, Jacob A; Herrmann, Jeremy L et al. (2011) Exogenous high-mobility group box 1 improves myocardial recovery after acute global ischemia/reperfusion injury. Surgery 149:329-35
Weil, Brent R; Manukyan, Mariuxi C; Herrmann, Jeremy L et al. (2011) The immunomodulatory properties of mesenchymal stem cells: implications for surgical disease. J Surg Res 167:78-86
Herrmann, Jeremy L; Abarbanell, Aaron M; Wang, Yue et al. (2011) Transforming growth factor-? enhances stem cell-mediated postischemic myocardial protection. Ann Thorac Surg 92:1719-25
Manukyan, Mariuxi C; Weil, Brent R; Wang, Yue et al. (2011) Female stem cells are superior to males in preserving myocardial function following endotoxemia. Am J Physiol Regul Integr Comp Physiol 300:R1506-14
Weil, Brent R; Herrmann, Jeremy L; Abarbanell, Aaron M et al. (2011) Intravenous infusion of mesenchymal stem cells is associated with improved myocardial function during endotoxemia. Shock 36:235-41
Wang, Yue; Abarbanell, Aaron M; Herrmann, Jeremy L et al. (2010) Toll-like receptor signaling pathways and the evidence linking toll-like receptor signaling to cardiac ischemia/reperfusion injury. Shock 34:548-57
Herrmann, Jeremy L; Abarbanell, Aaron M; Weil, Brent R et al. (2010) Gender dimorphisms in progenitor and stem cell function in cardiovascular disease. J Cardiovasc Transl Res 3:103-13

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