Cardiac stem cell therapy: Current status and future prospectParacrine Effects of Cell Transplantation: Modifying Ventricular Remodeling in the Failing Heart
Section snippets
Background
In 1996, Li and colleagues provided the first evidence that cell transplantation improves cardiac structure and function after myocardial injury.3 Transplanted fetal cardiomyocytes formed a cardiac tissue that limited scar expansion and improved the systolic function of cryoinjured rat hearts. The field of cell transplantation for cardiovascular disease was ripe for discovery, and the potential to alter the remodeling process was recognized. Since fetal cells were of questionable clinical
Ventricular Remodeling and Progression of Heart Failure
In response to cardiac injury, a maladaptive process is triggered that progressively alters the size, shape, and function of the heart (structural cardiac remodeling).11, 12 The development of heart failure is associated with well-defined clinical, physiologic, and anatomical landmarks. Structural cardiac remodeling, particularly ventricular dilation, is the hallmark of congestive heart failure. Chamber dilation and wall thinning determines the clinical progression of heart failure and has
Molecular Mechanisms Underlying Cell Therapy
The evolving clinical reality that muscle cell transplantation for ischemic cardiomyopathy can limit chamber dilation and the progression of heart failure is overshadowed by a limited understanding of the molecular and cellular mechanisms underlying the beneficial effects of cell engraftment. An improved understanding of the host tissue response to cell implantation may optimize the development of this technique for its evolving therapeutic use and, in so doing, serve to improve our
Paracrine Effects on Angiogenesis
In animal models of myocardial ischemia, administration of angiogenic growth factors, either as recombinant protein or by gene transfer, can improve the perfusion of the ischemic region by inducing angiogenesis.14 While many cytokines have angiogenic activity, the best studied are VEGF and FGF. However, angiogenesis is a complex process that involves numerous growth and signaling factors. Administration of high levels of VEGF or FGF alone can induce angiogenesis within ischemic tissues.
Paracrine Effects on Matrix Homeostasis
Once considered inert physical scaffolding, the extracellular matrix (ECM) is now widely appreciated as a dynamic signaling network that assembles and maintains groups of cells into functional tissues. The ECM can respond to environmental stimuli and tissue injury by altering its abundance, composition, and spatial organization with profound consequences on the structure and function of the tissues that it inhabits. After myocardial infarction, the ECM becomes dysfunctional. Cell to matrix
Paracrine Effects on Apoptosis
The overriding goal of cell therapy is to replace cells lost to injury and thereby repopulate the heart with functional contractile elements. We now understand that myocardial cells are continually lost in the failing heart, even when the inciting injury such as coronary ischemia has subsided. The myocardial capacity for cell renewal is limited and incapable of completely replacing these lost elements. Programmed cell death, known as apoptosis, is a key mediator of maladaptive structural
Paracrine Effects on Cell Recruitment and Endogenous Repair Mechanisms
The innate capacity of the heart to regenerate and repair after substantial injury is limited. However, circulating progenitor cells have been identified, and these stem cells may act as an endogenous repair mechanism. Resident stem cells within the heart have also been identified, and it is possible that cardiac stem cells have some endogenous repair capacity as well. Cell transplantation, particularly with stem cells, may act to trigger or enhance endogenous repair mechanisms. This protective
Conclusions
Cell transplantation offers the promise of cardiac regeneration. To date, the evidence for true myocardial regeneration with cell injection is limited. However, cell transplantation can predictably limit maladaptive ventricular remodeling through multiple synergistic paracrine mechanisms. While not the original aim for this novel therapy, the antiremodeling abilities of cell transplantation can be harnessed to complement our contemporary surgical approaches for patients with cardiac dysfunction
References (48)
- et al.
Restoration and regeneration of failing myocardium with cell transplantation and tissue engineering
Semin Thorac Cardiovasc Surg
(2003) - et al.
Autologous porcine heart cell transplantation improved heart function after a myocardial infarction
J Thorac Cardiovasc Surg
(2000) - et al.
Improved heart function with myogenesis and angiogenesis after autologous porcine bone marrow stromal cell transplantation
J Thorac Cardiovasc Surg
(2002) - et al.
Myoblast transplantation for heart failure
Lancet
(2001) - et al.
Cardiac remodeling and failure from molecules to man (Part II)
Cardiovasc Pathol
(2005) - et al.
Cardiac remodeling and failure: from molecules to man (Part I)
Cardiovasc Pathol
(2005) - et al.
Taking the death toll after cardiomyocyte grafting: a reminder of the importance of quantitative biology
J Mol Cell Cardiol
(2002) - et al.
A relationship between vascular endothelial growth factor, angiogenesis, and cardiac repair after muscle stem cell transplantation into ischemic hearts
J Am Coll Cardiol
(2007) - et al.
Vascular endothelial growth factor receptor upregulation in response to cell-based angiogenic gene therapy
AnnThorac Surg
(2005) - et al.
Effects of cell-based angiogenic gene therapy at 6 months: persistent angiogenesis and absence of oncogenicity
Ann Thorac Surg
(2007)
Enhanced angiogenesis with multimodal cell-based gene therapy
Ann Thorac Surg
Cell transplantation preserves matrix homeostasis: a novel paracrine mechanism
J Thorac Cardiovasc Surg
Transplantation of cryopreserved muscle cells in dilated cardiomyopathy: effects on left ventricular geometry and function
J Thorac Cardiovasc Surg
Autologous smooth muscle cell transplantation improved heart function in dilated cardiomyopathy
Ann Thorac Surg
Endogenous cardiac stem cells
Prog Cardiovasc Dis
Cell-based cardiac repair: reflections at the 10-year point
Circulation
Cellular transplantation: hurdles remaining before widespread clinical use
Curr Opin Cardiol
Cardiomyocyte transplantation improves heart function
Ann Thorac Surg
Cell transplantation to improve ventricular function in the failing heart
Eur J Cardio-Thorac Surg
Autologous transplantation of bone marrow cells improves damaged heart function
Circulation
The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation
Circulation
Angiogenesis: protein, gene, or cell therapy?
Heart Surg Forum
Endothelial progenitor cells: new hope for a broken heart
Circulation
Paracrine effects of transplanted myoblasts and relaxin on post-infarction heart remodeling
J Cell Mol Med
Cited by (46)
Commentary: Cell therapy goes subcellular
2022, Journal of Thoracic and Cardiovascular SurgeryCommentary: Transplanting the powerhouse of the cell to enhance cardiopulmonary repair
2022, Journal of Thoracic and Cardiovascular SurgeryA prostacyclin agonist and an omental flap increased myocardial blood flow in a porcine chronic ischemia model
2018, Journal of Thoracic and Cardiovascular SurgeryMind the Gap: Current Challenges and Future State of Heart Failure Care
2017, Canadian Journal of CardiologyCitation Excerpt :To date, there is substantial evidence from preclinical studies that outlines the cardioprotective benefits of ECM biomaterials in the failing heart.74,75 Given that cell therapy may confer functional benefits through paracrine effects,76 it is conceivable that bioactive acellular matrix scaffolds could have similar paracrine effects without the need for donor cells. An optimal therapy may in fact combine progenitor cells with bioactive scaffolds to enhance engraftment and proreparative effects.
Umbilical-cord-blood-derived mesenchymal stem cells seeded onto fibronectin-immobilized polycaprolactone nanofiber improve cardiac function
2014, Acta BiomaterialiaCitation Excerpt :These findings suggest that the positive results seen in the UCB-MSC/FN-PCL group compared with the control and FN-PCL groups might be related to paracrine activities. Likewise, previous accumulating evidence has suggested that the main beneficial effects derived from implanted cells are through the paracrine effects of cytokines secreted by the implanted cells and even a few cells could activate different regeneration pathways such as cell survival, stem cell homing, angiogenesis and matrix remodeling if they produce crucial bioactive mediators [2,6,14,40]. To identify potential paracrine effects of UCB-MSCs seeded in FN-immobilized PCL nanofibers, we evaluated gene expressions of multiple paracrine factors using a PCR gene array study.
Epicardial infarct repair with basic fibroblast growth factor-enhanced CorMatrix-ECM biomaterial attenuates postischemic cardiac remodeling
2014, Journal of Thoracic and Cardiovascular SurgeryCitation Excerpt :We believe epicardial infarct repair is a promising platform technology that can be tailored to the individual patient. We aim to explore material enhancement with additional matricellular proteins known to regulate tissue remodeling after injury, such as endogenous tissue inhibitors of metalloproteinases to suppress ECM turnover35 and vascular endothelial growth factor, to stimulate angiogenesis.36,37 There are a number of study limitations to consider.
PWMF is a clinical investigator of the Alberta Heritage Foundation for Medical Research.