In Vitro Models of Ischemia-Reperfusion Injury

Abstract

Timely reperfusion after a myocardial infarction is necessary to salvage the ischemic region; however, reperfusion itself is also a major contributor to the final tissue damage. Currently, there is no clinically relevant therapy available to reduce ischemia-reperfusion injury (IRI). While many drugs have shown promise in reducing IRI in preclinical studies, none of these drugs have demonstrated benefit in large clinical trials. Part of this failure to translate therapies can be attributed to the reliance on small animal models for preclinical studies. While animal models encapsulate the complexity of the systemic in vivo environment, they do not fully recapitulate human cardiac physiology. Furthermore, it is difficult to uncouple the various interacting pathways in vivo. In contrast, in vitro models using isolated cardiomyocytes allow studies of the direct effect of therapeutics on cardiomyocytes. External factors can be controlled in simulated ischemia-reperfusion to allow for better understanding of the mechanisms that drive IRI. In addition, the availability of cardiomyocytes derived from human induced pluripotent stem cells (hIPS-CMs) offers the opportunity to recapitulate human physiology in vitro. Unfortunately, hIPS-CMs are relatively fetal in phenotype, and are more resistant to hypoxia than the mature cells. Tissue engineering platforms can promote cardiomyocyte maturation for a more predictive physiologic response. These platforms can further be improved upon to account for the heterogenous patient populations seen in the clinical settings and facilitate the translation of therapies. Thereby, the current preclinical studies can be further developed using currently available tools to achieve better predictive drug testing and understanding of IRI. In this article, we discuss the state of the art of in vitro modeling of IRI, propose the roles for tissue engineering in studying IRI and testing the new therapeutic modalities, and how the human tissue models can facilitate translation into the clinic.

Dissection of heterocellular cross-talk in vascularized cardiac tissue mimetics

“…Our tissue recapitulates cardiac responses to physiologic and pathologic stimuli at the level of tissue growth, vascularization, metabolism and function [28,35] This is particularly striking in the response of the CTMs to high concentrations of PE, where we observed a significant increase in CTM growth, concomitant with the switch in metabolism from glycolysis to glucose oxidation ( Fig. 1G-I).…”

“…However, due to the lack of vascular network development, EC maturation and fibroblasts in these models, they provide limited insight into the dynamics and heterocellular interplay of the angiogenic response to physiologic or pathologic stimuli. Thus, 3D cardiac tissue models that attempt to mimic heterocellular interactions under pathophysiological conditions are sparse and largely fail to accurately mimic native tissue cellular composition, morphology, metabolism and function, and stress response [28].…”

Intensive care for human hearts in pluripotent stem cell models

“…As a consequence, some pharmacological and pathobiological responses can be deficient or anomalous. In some reports, hPSC-CMs do not mirror the TdP risk of drugs with late sodium current effects, like ranolazine 32 , and hiPSC-CMs were less sensitive to hypoxia/reoxygenation than to other death signals 65,96,97 . Such disparities must be taken into account, whether inherent shortcomings or idiosyncratic.…”

4D physiologically adaptable cardiac patch: A 4-month in vivo study for the treatment of myocardial infarction

“…Murine models of I/R injury provide an effective means to simulate clinical acute or chronic heart disease for cardiovascular research (41,42). Hence, a chronic MI model with I/R injury was created to assess the functional effects of cardiac patch implantation (43,44). The cellularized and acellular patches were implanted onto the epicardium of immunodeficient nonobese diabetic severe combined immunodeficient gamma (NSG) mice and were assessed for long-term development 4 months after implantation.…”