Uncovering the right targets: Refining cardiovascular regenerative medicine

Heart failure (HF) is a serious condition, where the heart’s ability to function deteriorates over time. The condition affects at least 26 million people worldwide, and 915,000 new cases are reported in the US every year.1 In the past decade, most therapeutic options have addressed the progressive nature of the disease; however, none (except heart transplantation) have shown the potential to address the fundamental pathology of the disease, namely, the loss of cardiomyocytes. At AstraZeneca, the IMED Biotech Unit are striving to dig deeper and understand the cells involved in cardiac regeneration, which could shine a light on how future therapies may one day help to improve cardiac function in those with HF. We caught up with Qing Dong Wang to discuss his latest cardiovascular regenerative research published in Circulation, Cell Research and Nature Medicine.

The playing field

As the Senior Principal Scientist in the Department of Biosciences HF within AstraZeneca’s Innovative Medicines and Early Development (IMED) Biotech Unit, I am responsible for the HF research strategy, as well as developing our early pipeline of projects in this area. I am a Cardiologist by training and joined AstraZeneca in 1997 after I received my PhD at the Karolinska Institute.

I was part of a team that, some years ago, began studying cardiac progenitor cells from human adult and embryonic stem cells. This seemed to be the most logical place to start our research efforts to uncover new information about regenerative cells in cardiology.

The scientific literature at the time indicated that c-Kit-positive cells and stem cell antigen-1 (Sca-1)-positive cells in the heart were cardiac stem cells, and were thought to play an intrinsic role in myocardial development and regeneration. These cells were shown to differentiate into cardiomyocytes when cultured in vitro or after heart transplantation,2,3 neither of which is a true representation of the endogenous c-Kit+ or Sca-1+ cell environment. Some genetic lineage tracing in vivo studies had also reported that c-Kit+/Sca-1+ cells contributed to new cardiomyocyte formation in adult mice.4,5 However, recently the cardiomyogenic potential of these cells has become a hot topic of debate.

This topic ignited a spark in me and other members in the department, where we wanted to try and uncover the truth behind the elusive nature of the putative cardiac progenitor cells, because basing scientific decisions on inaccurate perspectives could have serious implications on the development of future therapeutics.

Defining our next move

We wanted to better understand the putative cardiac progenitor cells (particularly cKit+ and Sca-1+ cells in the heart) and their differentiation into cardiomyocytes, as well as how these cells potentially contribute to cardiac regeneration post cardiac injury. To do this, we conducted initial in vitro experiments, where we did not see any evidence for the differentiation of cKit+ and Sca-1+ progenitor cells into cardiomyocytes, and it was clear that these findings were not giving us the full picture of cell behaviour in the in vivo setting. So to confirm this in vivo, we turned to one of our close collaborators, Professor Bin Zhou, who is a world-renowned expert in genetic lineage tracing technology. Professor Zhou, who is based at the Chinese Academy of Sciences in Shanghai, also had a passion about finding out the true potential of these putative cardiac progenitor cells. He and his team were able to create the right genetic tools to perform lineage tracing studies in mice and helped produce new insights into the biology.

Our data showed that neither cKit+ nor Sca-1+ contributed to new cardiomyocyte formation under physiological conditions or after myocardial infarction, which contradicts conclusions from previous studies. Our data suggests that during cardiac repair and regeneration, new cardiomyocytes are more likely to be derived from pre-existing cardiomyocytes via proliferation, rather than through the differentiation of endogenous cardiac progenitor cells. This made us stop and think – progenitor cells in the adult heart may not exhibit cardiomyogenic potential, which changes the whole way we think about how these cell types work and what this means going forward. Our data have been published in three high profile journal publications, specifically Circulation, Cell Research and Nature Medicine.

What does the future hold?

Regeneration of cardiac tissue is considered the “holy grail” in cardiovascular medicine. These are exciting times. By understanding the fundamental mechanisms of cardiac renewal, we will continue to tackle HF and hope to identify the right targets that promote cardiomyocyte function and formation. Our data could help change the current perception of regenerative cell types in this field. Using this insight, the IMED Biotech Unit are on the hunt and looking into how we can stimulate adult cardiomyocytes into self-renewal and assessing cell therapy with truly regenerative cells, e.g. pluripotent stem cell-derived cardiac cells, in order to explore the true potential of cardiac regeneration therapies for those who are affected by this serious condition.
 

References:

1.     Savarese G and Lund LH. Card Fail Rev. 2017; 3(1): 7–11.

2.     Smits AM, van Vliet P, Metz CH, Korfage T, Sluijter JP, Doevendans PA, Goumans MJ. Nat Protoc. 2009;4(2):232–43.

3.     Noseda M, Harada M, McSweeney S, Leja T, Belian E, Stuckey DJ, Abreu Paiva MS, Habib J, Macaulay I, de Smith AJ, al-Beidh F, Sampson R, Lumbers RT, Rao P, Harding SE, Blakemore AI, Jacobsen SE, Barahona M and Schneider MD. Nat Commun. 2015;6:6930.

4.     Ellison GM, Vicinanza C, Smith AJ, Aquila I, Leone A, Waring CD, Henning BJ, Stirparo GG, Papait R, Scarfo M, Agosti V, Viglietto G, Condorelli G, Indolfi C, Ottolenghi S, Torella D and Nadal-Ginard B. Cell. 2013;154:827–42.

5.     Uchida S, De Gaspari P, Kostin S, Jenniches K, Kilic A, Izumiya Y, Shiojima I, Grosse Kreymborg K, Renz H, Walsh K and Braun T. 2013;1:397–410.