Pre-transplantation Specification of Stem Cells to Cardiac Lineage for Regeneration of Cardiac Tissue

Abstract

Myocardial infarction (MI) is a lead cause of mortality in the Western world. Treatment of acute MI is focused on restoration of antegrade flow which inhibits further tissue loss, but does not restore function to damaged tissue. Chronic therapy for injured myocardial tissue involves medical therapy that attempts to minimize pathologic remodeling of the heart. End stage therapy for chronic heart failure (CHF) involves inotropic therapy to increase surviving cardiac myocyte function or mechanical augmentation of cardiac performance. Not until the point of heart transplantation, a limited resource at best, does therapy focus on the fundamental problem of needing to replace injured tissue with new contractile tissue. In this setting, the potential for stem cell therapy has garnered significant interest for its potential to regenerate or create new contractile cardiac tissue. While to date adult stem cell therapy in clinical trials has suggested potential benefit, there is waning belief that the approaches used to date lead to regeneration of cardiac tissue. As the literature has better defined the pathways involved in cardiac differentiation, preclinical studies have suggested that stem cell pretreatment to direct stem cell differentiation prior to stem cell transplantation may be a more efficacious strategy for inducing cardiac regeneration. Here we review the available literature on pre-transplantation conditioning of stem cells in an attempt to better understand stem cell behavior and their readiness in cell-based therapy for myocardial regeneration. KeywordsStem cells; mesenchymal stem cells; in vitro lineage specification; myocardium infarct; cardiac differentiation; cardiac tissue recovery The promise of stem cell-based therapyThe success in treatments for a variety of acute conditions has led to the development of a number of unmet clinical needs of patients with chronic end organ dysfunction. The ultimate goal of the treatment of end organ dysfunction is either to prevent the end organ dysfunction initially, or to regenerate the lost tissue to restore function. The increased interest in regeneration and stem cells (SC) during the last decades has suggested the feasibility of stem cell strategies to potentially regenerate lost tissue and repair end-organ function 14,15. It is Clinically the most studied form of stem cell therapy is the use of ASC. The most commonly implemented source of ASC to date is whole bone marrow transplantation for the treatment of blood borne malignancies 37. This treatment is widely accepted and results in the regeneration of the bone marrow. While successful, it is noteworthy for the purposes of this review that the stem cells used for this purpose do not require differentiation into other forms of tissue, as bone marrow transplantation uses donor adult hematopoietic stem cells to replace host hematopoietic stem cells. Thus, one can hypothesize that for other applications of stem cell therapy to be successful; we may need to effectively and efficiently differentiate stem cel...

New Frontiers in Regenerative Medicine in Cardiology: The Potential of Wharton’s Jelly Mesenchymal Stem Cells

“…Moreover, transplantation methods and post-transplantation efficiency of these cells need to be better improved, due to their poor survival, the reduced engraftment potential, and the safety issues. As reviewed in literature, the drug or hypoxic preconditioning of stem cells populations, in addition with growth factor cocktails, resulted in an upregulation of all those factors involved in survival, migration, myocardial tolerance, and possible differentiation towards a cardiac fate [43,44].…”

Repair of the Injured Adult Heart Involves New Myocytes Potentially Derived From Resident Cardiac Stem Cells

“…These cKit+/CD45− cells have been shown 8 to have cardiogenic potential, both in-vitro and in-vivo. There are numerous varieties of putative cardiac precursor cells 10–12 , but their roles in the normal physiology of the heart, or their ability and capacity for cardiac repair after injury is still not well known, especially in large animals and humans 13 . This topic is clearly of clinical relevance since human heart disease that culminates in cardiac performance deficits is largely the result of the loss of contractile cardiocytes, such as after a myocardial infarction 14, 15 .…”

Cardiac Cell Therapy: The Next (Re)Generation

“…For this purpose, different approaches can be used, such as gene therapy to over-express transcription factors, and modulation of crucial pathways by cocktails of cytokines and growth factors, small molecules, miRNA or modified RNAs [1]. Furthermore it has been observed that exposure of CSps and CDCs to extremely low-frequency electromagnetic fields (ELF-EMFs), tuned at Ca 2+ ion cyclotron energy resonance (Ca 2+ -ICR), modulates their differentiation, turning on cardiogenesis and turning off vasculogenesis, without any pharmacological or genetic manipulation [94].…”

“…Current treatments provide limited benefits and amelioration of symptoms, but they do not recover the function of the damaged tissue. Treatment of acute myocardial infarction (AMI) is focused on restoring the ante-grade flow in order to inhibit further tissue loss, while chronic therapy for injured tissue is aimed at minimizing pathologic remodeling of the heart, and endstage therapy for chronic heart failure (CHF) is based on inotropic drugs to improve the function of surviving cardiomyocytes and/or their mechanical performance [1]. The only routinely used therapeutic approach to replace the injured tissue is heart transplantation, which is a last chance treatment, given the limited donor pool [2].…”