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The Dying Stem Cell Hypothesis

Immune Modulation as a Novel Mechanism for Progenitor Cell Therapy in Cardiac Muscle

Thomas Thum, MD^_*,,_*, Johann Bauersachs, MD, Philip A. Poole-Wilson, MD, FRCP^_*, Hans-Dieter Volk, MD, PhD and Stefan D. Anker, MD, PhD^_*,,_*

^_* Department of Clinical Cardiology, National Heart and Lung Institute, Imperial College of Medicine, London, United Kingdom
Medizinische Klinik I, Universitätsklinikum, Bayerische Julius-Maximilians-Universität, Würzburg, Germany
Institute of Medical Immunology, Charité Campus Mitte, Berlin, Germany
Applied Cachexia Research, Department of Cardiology, Charité Campus Virchow-Klinikum, Berlin, Germany

View larger version (61K): [in a new window]   Figure 1 (A) Immune pathophysiology of myocardial injury. Ischemic injury damages parenchymal cells, resulting in exposition of heat-shock proteins (HSPs) that trigger tissue-resident macrophages and immature dendritic cells (DCs) via Toll-like receptor 4 (TLR-4) activation. Activated macrophages release several inflammatory cytokines, further amplifying tissue injury, whereas immature DCs undergo maturation and migration to secondary lymphoid tissues. After DC–T-cell interaction, HSP-specific T cells undergo clonal expansion and effector–T-cell differentiation. Homing of these cells to the injured tissue further amplifies local inflammation. (B) Apoptotic cells interact with the immune pathophysiology of myocardial injury. Transplanted, ex vivo, induced apoptotic cells or cells undergoing in vivo massive apoptosis inhibit macrophages and DCs via interaction of their surface phosphatidylserine with the respective receptors (PS-R) on the immune cells. As a result, local release of anti-inflammatory cytokines like transforming growth factor (TGF)-beta and interleukin (IL)-10 rises (14,20), maturation and migration of DCs and T helper type 1 (Th1) activation is inhibited (16,17), and activation of regulatory T cells (Treg) is enhanced (18). Consequently, less myocardial inflammation is observed, resulting in less myocardial apoptosis and scar formation as well as enhanced angiogenesis.