Novel Approach to Generate Stem Cell Induced Cardiac Pericytes
by Micaela Harris
February 8, 2023
Heart cells known as cardiac pericytes help maintain balance and longevity in the coronary microvasculature. Although their role is important for the functioning of the coronary arteries, they are among the most underappreciated and ambiguous cell types. Evidence suggests that cardiac pericytes play an important role in many cardiovascular complications. However, due to a lack of tools and cell markers to properly source and trace cardiac pericytes, it has been challenging to understand their specific contribution to cardiovascular dysfunction.
To develop successful lineage tracing of cardiac pericytes, a team of researchers at Stanford University, led by Mengcheng Shen, PhD and Joseph C. Wu, MD, PhD, recently published in Circulation, developed a stepwise approach to generate cardiac pericytes from human induced pluripotent stem cells, which were shown to mimic the transcriptional and functional characteristics of their counterparts. In order to derive stem cell-generated cardiac pericytes, the researchers first generated epicardial cells, which are essentially the parent cell of cardiac pericytes. They then developed several subsequent steps to generate stem cell cardiac pericytes and established that they had similar potency to their in vivo counterparts, such as promoting vascularization and neovessel maturation.
In addition, previous studies have reported that cardiac pericytes are very susceptible to cell damage from a common medication used in cancer treatment called sunitinib. The investigators treated the stem cell-derived cardiac pericytes, pericyte-endothelial cells, and cardiomyocytes with sunitinib and compared the response of the three different groups of cells. The stem cell-derived cardiac pericytes exhibited a similar toxicity profile when treated with sunitinib compared to the pericyte-endothelial cells, and both were more sensitive compared to the cardiomyocytes. Furthermore, thalidomide, a drug that is used to help rescue sunitinib-induced cell damage in mice, significantly helped preserve the cardiac pericytes from cell death. Creating a stem cell model of cardiac pericytes that respond to sunitinib will allow future studies to explore why cardiac pericytes are susceptible to sunitinib-induced death. This model can therefore be used to identify future therapies to help prevent cardiotoxicity in cancer-related treatments.
In conclusion, the step-by-step approach of generating human induced pluripotent stem cell-derived cardiac pericytes is a novel system that can promote deeper understanding on coronary microvascular dysfunction and how to prevent cancer drug-induced cardiotoxicity. The similarity between stem cell-derived cardiac pericytes and their in vivo counterparts will provide a deeper understanding of cardiac microvascular function and stimulate new approaches to prevent cardiac drug toxicity and facilitate neovascularization post-ischemic heart injury.
Additional Stanford Cardiovascular Institute-affiliated investigators who contributed to this study include Chun Liu, Shane Rui Zhao, Amit Manhas, Laksshman Sundaram, and Mohamed Ameen.