The Interplay between Cellular and Extracellular Matrix Aging in Heart: Understanding Cardiac Aging and Developing Therapies for CVD

Myocardial infarction (MI) is the most prevalent among cardiovascular diseases (CVD), and its occurrence is highly associated with age. The elderly (>65-years-old) form the most vulnerable population for MI and post-MI healing is much more difficult in these patients. Unfortunately, there is a big gap in knowledge in cardiac aging, partially because of the lack of adequate models to study it. Young animal and cell models are still considered the gold standard and the age mismatch significantly limits the predictive abilities of the model systems. Relatedly, current regenerative and post-MI recovery therapies fall short to addressing the elderly.

ECM and cell therapies are two common approaches to treating MI, and studies reported an inverse relationship between patient age and treatment success for both. There is a missing link in translating in vitro studies into the clinic and the age component appears to be the key factor. There is a need to develop age-appropriate cardiac models to study CVD and develop therapies without excluding the elderly, who will comprise most of the population soon.

Towards this goal, this dissertation aims to bridge the knowledge gap by integrating insights from three key chapters. Chapter 2 highlights the individual and combined effects of cellular and cardiac extracellular matrix (ECM) aging and reveals the cell-ECM interplay using iPSC-derived cardiomyocytes (iCMs). The study demonstrates that young ECM promotes proliferation and drug responsiveness in young cells, inducing cell cycle re-entry and stress protection in aged cells. Adult ECM improves cardiac function, while aged ECM accelerates aging phenotypes and impairs cardiac function and stress defense machinery.

Chapter 3 emphasizes the need for physiologically relevant models of aging hearts to better understand cardiac aging and to study ECM therapies. Transcriptomic and proteomic changes with human cardiac aging are investigated, and chronologically aged iCMs are shown to recapitulate age-related disease hallmarks. Using these cells, the effects of cell age on young ECM therapy are explored, revealing its potential for post-MI recovery, yet acknowledging the potential harm under normal conditions with no stress. The study demonstrates that the “one-size-fits-all” approach should not be followed in young ECM therapies, especially for the advanced aged groups.

Chapter 4 explores the challenge of maturing iPSC-derived cardiomyocytes for effective cell-based therapies. The study investigates the use of adult human ECM to enhance iPSC cardiac differentiation and maturation. Functional maturation supported by mitochondrial network structure and metabolic maturation was verified in these ECM pretreated cells. Furthermore, critical glycoproteins and proteoglycans in adult ECM were identified that could potentially cause enhanced cardiac differentiation and maturation, as ECM denaturation didn’t nullify the observed benefits of the ECM pretreatment.

Combining these chapters, this dissertation strives to provide a comprehensive understanding of cardiac aging and cell-ECM interactions, the impact of young ECM therapies on iPSC-derived cardiomyocytes, and the importance of age-appropriate models for studying and treating cardiovascular diseases, particularly in the context of myocardial infarction (MI). Additionally, a novel approach of using adult ECM in generating not just structurally, but functionally and metabolically mature cardiac cells was presented in this dissertation.

Through this work, I aimed to contribute to the field of aging, providing age-dependent changes observed in mouse and human hearts as well as in lab grown cells. I specifically focused on the age-dependent cell-ECM interactions that are crucial in the development of more effective and targeted therapies for CVDs. Expanding on both ECM and cell therapies, I highlighted knowledge gaps and challenged the commonly accepted approaches, as needed. The information provided here will be valuable in furthering translational CVD studies and enhancing CVD therapy efficiencies, especially for the elderly.