The adaptive immune response to cardiac injury—the true roadblock to effective regenerative therapies?

Abstract

The regenerative capacity of adult human tissues and organs is limited, but recent developments have seen the advent of promising new technologies for regenerative therapy. The human heart is of particular interest for regenerative medicine, as cardiac tissue damage is repaired by the formation of rigid scar tissue, which causes inevitable structural changes and progressive functional decline leading to heart failure. Cardiac regenerative medicine aims to prevent scar formation or replace existing scars to halt or reverse adverse remodeling and therapeutic approaches include the use of biomaterials, gene therapies, delivery of growth factors, and (stem) cell therapies. Regenerative therapies, however, face significant obstacles in a hostile microenvironment. While the early immune response to a myocardial infarct is essential to ensure tissue integrity and to avoid fatal cardiac rupture, excessive activation of endogenous repair mechanisms may lead to ongoing inflammation, fibrosis, and sustained autoimmune-mediated tissue damage. Anti-cardiac autoreactivity of the adaptive immune system has been suggested to be involved in structural remodeling, functional decline, and the development of heart failure. It is, therefore, crucial to first understand the endogenous response to cardiac tissue damage and how to restore immune tolerance to cardiac tissue, before additional regenerative therapies can achieve their full potential.

Healing the Broken Heart; The Immunomodulatory Effects of Stem Cell Therapy

“…Several cell types have been introduced to the injured myocardium and have reported varying levels of myocardial repair; therefore, it is reasonable to propose the immunomodulatory effects of cell-based therapy is highly dependent on cell type (3,7,19,(157)(158)(159)(160)(161). In the subsequent sections of this review we will summarize the status of cell therapy in modulating the immune response after myocardial injury.…”

“…Current therapies being administered within the clinic, such as beta-blockers, diuretics, vasodilators, angiotensin converting enzyme (ACE) inhibitors, left ventricular assisted devices (LVADs), pacemakers, defibrillators, and/or stents (3,4), have significantly increased patient survival outcome and can slow heart failure progression (3,5). Unfortunately, these therapies do not prevent or reverse the activation of a deleterious cycle that perpetuates adverse cardiac remodeling resulting in depressed cardiac function and heart failure progression (3,(6)(7)(8)(9). Consequently, there are an increasing number of patients who are now faced with long-term health burdens associated with AMI and heart failure pathology.…”

“…However, the efficacy of cell delivery, engraftment, and differentiation of these populations within the infarcted Abbreviations: CVD, Cardiovascular disease; AMI, acute myocardial infarction; DAMPs, Danger Associated Molecular Patterns; M s, macrophages; Tregs, T-regulatory cells; ACE, angiotensin converting enzyme; LVADs, left ventricular assist devices; TNFα, tumor necrosis factor α; IL, interleukin; MPO, myeloperoxidase; MMP9, matrix metalloproteinase 9; CCR, Chemokine receptor; MCP-1, monocyte chemoattractant protein-1; NO, nitric oxide; Ly6c, lymphocyte antigen 6 complex; TGF-β, transforming growth factor β; VEGF, vascular-endothelial growth factor; IGF-1, insulin-like growth factor 1; PDGFα, platelet-derived growth factor α; I/R, ischemia/reperfusion; RAG1 KO, recombination activating 1 knock out; MHC, major histocompatibility complexes; HGF, hepatocyte growth factor; FoxP3, Forkhead box P3; TCR, T-cell receptor repertoire; LAD, left anterior descending artery; MSCs, mesenchymal stem cells; CDCs/CPCs, Cardiosphere Derived Cells; ESCs, Embryonic Stem Cells; CBSCs, Cortical Bone Derived Stem Cells; CDCs, cardiac derived progenitor cells; CXCL, CXC chemokine ligand; PGE2, prostaglandin E2; Edu+, 5-Ethynyl-2-deoxyuridine; FGF, fibroblast growth factor; Ang-1, Angiopoietin-1; FasL, Fas ligand; TRAIL, TNF-related apoptosis-inducing ligand; iNOS, inducible NO synthase; IDO, indoleamine-pyrrole 2,3-dioxygenase; PD-1, programmed cell death 1 receptor, TLRs, Toll-Like Receptors; hCPCs, Human cardiac progenitor cells populations. myocardium has proven to be challenging and a major limitation of cell-based therapy (3,(18)(19)(20)(21)(22). Despite these limitations, cell therapy has demonstrated the efficacy to elicit improved cardiac function and limit the adverse cardiac remodeling processes that occur following an AMI event (7,23,24).…”

“…These signaling factors retain the ability to directly mediate the injured microenvironment of the infarcted heart without direct cell-tocell contact; this theory is commonly referred to as the paracrine hypothesis (25). The direct effects of stem cell secretome on other cell types within the infarcted heart is under intense investigation (3,7,26,27).…”

Immunomodulatory interventions in myocardial infarction and heart failure: a systematic review of clinical trials and meta-analysis of IL-1 inhibition

“…Once acute inflammation has been cleared, development towards HF may still be exacerbated by a persistent autoimmune-inflammatory condition which maintains low levels of tissue damage sustaining cardiomyocyte loss, fibrosis, and pathological ventricular remodelling. 6 …”