Concise Review: Pluripotent Stem Cell-Derived Cardiac Cells, A Promising Cell Source for Therapy of Heart Failure: Where Do We Stand?

Abstract

Heart failure is still a major cause of hospitalization and mortality in developed countries. Many clinical trials have tested the use of multipotent stem cells as a cardiac regenerative medicine. The benefit for the patients of this therapeutic intervention has remained limited. Herein, we review the pluripotent stem cells as a cell source for cardiac regeneration. We more specifically address the various challenges of this cell therapy approach. We question the cell delivery systems, the immune tolerance of allogenic cells, the potential proarrhythmic effects, various drug mediated interventions to facilitate cell grafting and, finally, we describe the pathological conditions that may benefit from such an innovative approach. As members of a transatlantic consortium of excellence of basic science researchers and clinicians, we propose some guidelines to be applied to cell types and modes of delivery in order to translate pluripotent stem cell cardiac derivatives into safe and effective clinical trials. STEM CELLS 2016;34:34-43 SIGNIFICANCE STATEMENTCell therapy of heart failure has emerged as a promising approach for the last decade. However, the use of non cardiogenic stem cells in clinical trials has lead to disapointing results. Here we challenge the use of pluripotent stem cell derived cardiac progenitors as a mean to regnerate diseased hearts.

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

“…Numerous clinical studies have incorporated the usage of broad immunosuppressive agents to reduce the inflammatory response following myocardial infarction and other cardiac diseases in hopes to reduce myocardial injury and increase cardiac repair. Unfortunately, results from these clinical approaches using a variety of different drugs, have led to the conclusion that the broad suppression of the inflammatory response during cardiac repair does not improve cardiac wound healing (18,19,(142)(143)(144)(145). A review of the immunosuppressive agents tested within the clinic and their clinical outcomes are further reviewed in Huang et al These studies emphasize that the broad immunosuppression of an interconnected, multilayered immune response is not the appropriate approach to mediate the cardiac repair process, but rather distinct regulatory mechanisms that can target specific immune cell populations is more efficacious in promoting cardiac repair.…”

“…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.…”

“…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).…”

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

“… 7 Recent advances have been reviewed extensively 8 , 9 and include (1) biomaterial-based approaches, 10 (2) gene therapy using plasmid DNA for gene transfer 11 or silencing/short hairpin RNA, microRNA, and long non-coding RNA for gene modulation, 12 , 13 (3) exogenous administration of growth factors such as neuregulin 14 or fibroblast growth factor, 15 and (4) cell therapies using mesenchymal stromal cells (MSCs), 16 – 18 cardiac and bone marrow-derived c-kit + cells, 19 , 20 cardiosphere cells, 21 , 22 and pluripotent stem cell-derived cardiac cells. 23 While promising results have been obtained in experimental pre-clinical models, many of these approaches still face severe obstacles concerning efficacy of production and delivery, as well as immunological rejection. In particular though, they all share the common hurdle of a hostile inflammatory microenvironment and so far benefits observed in clinical trials are disappointing or inconsistent.…”

Stem Cells in Cardiovascular Medicine: Historical Overview and Future Prospects

“…In recent decades, stem cell (SC) technologies have emerged with a great promise that could be envisaged for almost all human ailments, most importantly for noncommunicable diseases characterized by organ dysfunction and/or degeneration. In this regard, CVDs are certainly the most attractive target for SC-based therapeutic approaches [7][8][9][10]. From a mere improvement of cardiac microenvironment, to partial regeneration and/or compensation of lost functional tissue, and ending with a complete fabrication of a surrogate heart, SCs have set the hopes high.…”