The overarching objective of this project is to establish the mechanistic relationships between pathological inflammation and cardiac progenitor cell (CPC)-mediated tissue repair. After myocardial infarction (Ml), CPCs are increased in number but fail to produce sufficient endogenous healing, suggesting that factors in the microenvironment compromise their reparative capacity. During LV remodeling, there is sustained elaboration of the pro-inflammatory cytokine tumor necrosis factor-a (TNF). The effects of TNF in the post-MI heart are heterogeneous and depend on its two cell-surface receptors (TNFRs) - TNFRl promotes LV remodeling and activation of nuclear factor (NF)-KB and p38 MAPK, whereas TNFR2 opposes these effects and is beneficial. However, whether divergent TNFR-specific effects extend to CPCs and modulate their reparative capacity is unknown. In our preliminary studies, we have uncovered the novel finding that TNF inhibits cardiomyocyte differentiation of CPCs and instead promotes an adrenergic phenotype that can potentiate remodeling. This response is dependent on TNFR1 and associated with NF-KB, and can be opposed by TNFR2, Hence, we hypothesize that differential TNF signaling via TNFR1, TNFR2, and NF-KB plavs a critical role in determining adrenergic versus cardiomyogenic fate and, conseguentiv, the reparative capacity of CPCs following Ml. We propose three Aims.
In Aim 1, we will determine the effects of TNFR- dependent signaling on CPC competence and adrenergic versus cardiogenic differentiation in vitro using GFP-labeled lin-/c-kit+ CPCs from wild-type (WT), TNFRl-/-, TNFR2-/-, dominant-negative (DN)-lKBa transgenic (Tg), and Tg-DN-p38a MAPK mouse hearts. We will also establish that neuroadrenergic-type cells are derived from cardiac and not resident neural progenitors.
In Aim 2, we will delineate the role of CPC-localized TNFR-signaling during cardiac repair in vivo. In a murine reperfused Ml model, we will deliver GFP-labeled lin-/c-kit+ WT, TNFR1-/-, TNFR2-/-, or Tg-DN-kBa CPCs and determine cell fate and their effects on LV remodeling and tissue adrenergic activation.
In Aim 3, we will determine the effects of TNF in the tissue microenvironment on CPC-mediated repair and adrenergic differentiation by defining remodeling responses upon transplantation of GFP-labeled WT lin-/c-kit+ CPCs following reperfused Ml in WT and TNF- /- mice, or upon circumscribed systemic TNF inhibition with etanercept. Collectively, these studies will: 1) uncover a novel role for TNF as an inhibitor of CPC function and CPC-mediated repair via TNFR1 and NF- KB;2) define a heretofore unknown CPC-derived origin for adrenergic cells in the failing heart;and 3) target potential therapeutic avenues related to TNF signaling to enhance the efficacy of CPC transplantation
These studies will establish the novel paradigm that tumor necrosis factor-a (TNF) profoundly influences cardiac progenitor cell (CPC) behavior through the divergent effects of its two receptors, and channels these cells toward either beneficial (cardiac cell) or detrimental (adrenergic cell) fates for tissue repair. The results will shed light on potential therapeutic avenues related to TNF signaling that can both enhance the efficacy of exogenous progenitor cell transplantation and augment the heart's intrinsic capacity to repair itself after myocardial infarction in the absence of progenitor cell therapy.
|Gibb, Andrew A; Epstein, Paul N; Uchida, Shizuka et al. (2017) Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth. Circulation 136:2144-2157|
|Jones, Steven P (2017) I'll Have the Rigor, but Hold the Mortis. Circ Res 120:1852-1854|
|Dassanayaka, Sujith; Brainard, Robert E; Watson, Lewis J et al. (2017) Cardiomyocyte Ogt limits ventricular dysfunction in mice following pressure overload without affecting hypertrophy. Basic Res Cardiol 112:23|
|Wysoczynski, Marcin; Adamiak, Mateusz; Suszynska, Malwina et al. (2017) Poor Mobilization in T-Cell-Deficient Nude Mice Is Explained by Defective Activation of Granulocytes and Monocytes. Cell Transplant 26:83-93|
|Bolli, Roberto (2017) Repeated Cell Therapy: A Paradigm Shift Whose Time Has Come. Circ Res 120:1072-1074|
|Guo, Yiru; Wysoczynski, Marcin; Nong, Yibing et al. (2017) Repeated doses of cardiac mesenchymal cells are therapeutically superior to a single dose in mice with old myocardial infarction. Basic Res Cardiol 112:18|
|Wysoczynski, Marcin; Guo, Yiru; Moore 4th, Joseph B et al. (2017) Myocardial Reparative Properties of Cardiac Mesenchymal Cells Isolated on the Basis of Adherence. J Am Coll Cardiol 69:1824-1838|
|Singh, Mahavir; Kapoor, Aniruddh; McCracken, James et al. (2017) Aldose reductase (AKR1B) deficiency promotes phagocytosis in bone marrow derived mouse macrophages. Chem Biol Interact 265:16-23|
|Kingery, Justin R; Hamid, Tariq; Lewis, Robert K et al. (2017) Leukocyte iNOS is required for inflammation and pathological remodeling in ischemic heart failure. Basic Res Cardiol 112:19|
|Eschenhagen, Thomas; Bolli, Roberto; Braun, Thomas et al. (2017) Cardiomyocyte Regeneration: A Consensus Statement. Circulation 136:680-686|
Showing the most recent 10 out of 174 publications