Cardiac tissue engineering and regeneration using cell-based therapy

Abstract

Stem cell therapy and tissue engineering represent a forefront of current research in the treatment of heart disease. With these technologies, advancements are being made into therapies for acute ischemic myocardial injury and chronic, otherwise nonreversible, myocardial failure. The current clinical management of cardiac ischemia deals with reestablishing perfusion to the heart but not dealing with the irreversible damage caused by the occlusion or stenosis of the supplying vessels. The applications of these new technologies are not yet fully established as part of the management of cardiac diseases but will become so in the near future. The discussion presented here reviews some of the pioneering works at this new frontier. Key results of allogeneic and autologous stem cell trials are presented, including the use of embryonic, bone marrow-derived, adipose-derived, and resident cardiac stem cells.

Keywords: cardiac surgery; cardiomyocytes; cell sheet and tissue engineering; heart; heart failure; myocardial ischemia; organoids; scaffolds; stem cells.

Figure 1

Progression of stem cells in vitro into cardiomyocytes for in vivo transplantation.

Figure 2

Clinical trials of cell therapy for acute and chronic, ischemic and nonischemic heart failure. Abbreviations: ASTAMI, Autologous Stem-cell Transplantation in Acute Myocardial Infarction; BOOST, BOne marrOw transfer to enhance ST-elevation infarct regeneration; CADUCEUS, CArdiosphere-Derived aUtologous Stem CElls to reverse ventricUlar dySfunction; LateTIME, Use of Adult Autologous Stem Cells in Treating People 2 to 3 Weeks after having a Heart Attack; MYSTAR, MYocardial STem cell Administration after acute myocardial infaRction; POSEIDON, Comparison of Allogeneic versus Autologous Bone Marrow-Derived Mesenchymal Stem Cells Delivered by Trans-Endocardial Injection in Patients with Ischemic Cardiomyopathy; PRECISE, AdiPose-deRived stEm and Regenerative Cells In the Treatment of Patients with non revaScularizable ischEmic myocardium; REGENT, Myocardial REGENeraTion by intracoronary infusion of selected population of stem cells in acute myocardial infarction; REPAIR-AMI, Reinfusion of Enriched Progenitor cells And Infarct Remodeling in Acute Myocardial Infarction; SCIPIO, Stem Cell Infusion in Patients with Ischemic cardiOmyopathy; STAR-heart, The acute and long-term effects of intracoronary Stem cell Transplantation in patients with chronic heARt failure; SWISS-AMI, SWiss Multicenter Intracoronary Stem cells Study in Acute Myocardial Infarction; TOPCARE-AMI, Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction; TOPCARE-CHD, Trans-Coronary Transplantation of Functionally Competent BMD Stem Cells; TOPCARE-DCM, Selective Intracoronary Bone Marrow-Derived Progenitor Cell Infusion in Patients with Non-Ischemic Dilated Cardiomyopathy.

Figure 3

Biomimetic scaffolds Notes: (A) Synthesis of biomatrix: fibroblasts isolated from samples of adult human heart were cultured in confluent state allowing for extracellular matrix (ECM) deposition in vitro. Representative image obtained by immunofluorescent labeling of actin filaments (red), cell nuclei (blue), and fibronectin (green). (B) Decellularization of biomatrix: after nonenzymatic removal of fibroblasts, ECM was observed under fluorescence microscope. Its composition was revealed by indirect immunofluorescent staining of representative ECM proteins: collagen IV (red), laminin (green), fibronectin (blue), and tenascin-C (yellow). (C) Immunoblotting of the decellularized biomatrix further confirmed the presence of these ECM-specific components in the biomatrix. Adapted from: Clotilde Castaldo, Franca Di Meglio, Rita Miraglia, et al., “Cardiac Fibroblast-Derived Extracellular Matrix (Biomatrix) as a Model for the Studies of Cardiac Primitive Cell Biological Properties in Normal and Pathological Adult Human Heart,” BioMed Research International, vol. 2013, Article ID 352370, 7 pages, 2013. doi:10.1155/2013/352370. (D) Decellularization of embryonic cardiac tissue and recellularization with E16.5 ventricular cells. The constructs create a favorable microenvironment for the cells to integrate and migrate on the scaffold. Macroscopic appearance of the supporting matrix changed from translucent to opaque following cell inclusion into the construct. This was further confirmed by hematoxylin and eosin (H&E) and toluidine blue staining of the reseeded scaffolds, revealing a highly cellular environment on the host matrix. Collagen structures also became more physically compact after incubation of the scaffold with the cells, as shown by electron microscopy (EM). Adapted from Cree Chamberland, Almudena Martinez-Fernandez, Rosanna Beraldi, and Timothy J. Nelson, “Embryonic Decellularized Cardiac Scaffold Supports Embryonic Stem Cell Differentiation to Produce Beating Cardiac Tissue,” ISRN Stem Cells, vol. 2014, Article ID 625164, 10 pages, 2014. doi:10.1155/2014/625164. Abbreviations: Bm-N, biomatrix from patient with a normal heart; Bm-P, biomatrix from patients with heart failure; dpc, day post conception.