Cell therapy, 3D culture systems and tissue engineering for cardiac regeneration

Abstract

Ischemic Heart Disease (IHD) still represents the “Number One Killer” worldwide accounting for the death of numerous patients. However the capacity for self-regeneration of the adult heart is very limited and the loss of cardiomyocytes in the infarcted heart leads to continuous adverse cardiac-remodeling which often leads to heart-failure (HF). The concept of regenerative medicine comprising cell-based therapies, bio-engineering technologies and hybrid solutions has been proposed as a promising next-generation approach to address IHD and HF. Numerous strategies are under investigation evaluating the potential of regenerative medicine on the failing myocardium including classical cell-therapy concepts, three-dimensional culture techniques and tissue-engineering approaches. While most of these regenerative strategies have shown great potential in experimental studies, the translation into a clinical setting has either been limited or too rapid leaving many key questions unanswered. This review summarizes the current state-of-the-art, important challenges and future research directions as to regenerative approaches addressing IHD and resulting HF.

Introduction

Ischemic Heart Disease (IHD) still represents the “Number One Killer” worldwide accounting for the death of numerous patients and a tremendous socio-economic impact [1]. IHD leads to myocardial infarction (heart attack) which in turn leads to myocardial necrosis and the loss/death of cardiomyocytes. Unfortunately, the capacity for self-regeneration of the adult heart is very limited. On the one hand the cardiomyocytes do not have the capability to divide and on the other hand the heart lacks a sufficient reservoir of remnant cardiac stem cells (CSCs). Although the treatment options for IHD comprising medical drug therapy, percutaneous interventions (PCI) and surgical revascularization have emerged over the past decades, the loss of cardiomyocytes in the infarcted heart leads to a continuous adverse cardiac remodeling. This includes typical phenomena such as progressive myocardial wall thinning, fibrosis and dilation leading to a significant reduction of cardiac function over time. If IHD remains untreated or is not treated timely and efficiently, IHD may lead to heart failure (HF). Approximately five million people in the U.S. are affected by HF today, with an incidence approaching 10 per 1000 population among individuals older than 65 years of age [2].

To date, heart transplantation still represents the most effective option for patients suffering from HF. However, in addition to the logistical and medical complexity of this therapeutic option, donor organ shortage represents a major limitation and up to 20% of the patients die while on the “waiting list” [3]. Therefore, there is a substantial and urgent therapeutic need to develop alternative therapy options.

In this regard, the concept of regenerative medicine comprising of cell-based therapies, bio-engineering technologies and hybrid solutions has been proposed as a promising next generation approach to address IHD and resulting HF. Numerous strategies are under evaluation for their beneficial effects on the failing myocardium comprising of cell therapy concepts, cardiac tissue engineering approaches and hybrid technologies. However, despite their great potential as demonstrated in experimental studies, the translation of such strategies into a clinical setting has either been limited or too rapid leaving many key questions unanswered.

This review article provides an overview of the current state-of-the-art for using regenerative strategies to address IHD and resulting HF. Considering these therapeutic approaches and their modes of action they can be classified as a form of drug delivery. As shown in this review, the transplanted cells and tissue provide not only the precursors that can differentiate into functioning myocardial cells but also through paracrine effects to recruit cells, mediate inflammatory response, remodel the extracellular matrix (ECM) and prevent deleterious downstream effects of fibrotic scar tissue formation subsequent to IHD. In this light, transplanted cells and tissue may be seen as a promising and highly effective means of drug delivery.