Myocardial infarction (MI) is a cardiovascular pathology characterized by the loss of molecular oxygen, which correlates with the death of the cellular constituents of the myocardium, most notably cardiomyocytes. MI is highly prevalent, effecting approximately 1.5 million Americans each year, with more than 400,000 of these cases resulting in fatality (ww.WHO.org). The loss of functional myocytes negatively affects cardiac function, often leading to heart failure in individuals who survive the acute effects of MI. Cardiac regeneration has emerged as a promising alternative to current pharmacological and surgical interventions aimed towards alleviating symptoms of MI. Cardiac regeneration, specifically cell therapy, has exhibited the capacity to variably restore structure and function of infarcted myocardium. Several potential cell therapeutic populations have been proposed, including stem cells, both adult and embryonic, as well as cardiovascular (CV) progenitors. CV progenitors are particularly intriguing as these cells possess cardiac-specific potency, giving rise to endothelial cells, smooth muscle cells, and cardiomyocytes, which are all needed to adequately restore damaged cardiac tissue. Although identified CV progenitors generate cardiomyocytes, the myocyte progeny lack a ventricle-specific phenotype, which will be critical for the restoration of infarcted myocardium, as effects of MI primarily manifest in the ventricular chamber. To successfully regenerate infarcted ventricular myocardium, a ventricle-specific progenitor population, exhibiting the ability to generate a sufficient number of ventricular myocytes must be identified. To elucidate this ventricular progenitor population I have chosen Irx4 as a genetic marker. Published data suggest that Irx4 is the earliest marker of ventricular precursors, with transcripts detected as early as embryonic day 7.5 in mice (Bruneau et al 2000). Intra-cardiac localization of Irx4 transcripts is restricted to the ventricular myocardium from E8.5 into adulthood (Christoffels et al 2001). To validate Irx4 as a marker for a ventricular progenitor, I will assess Irx4 translation, ensuring that protein expression reflects gene transcription patterns. To utilize Irx4 as a genetic marker for identification of a cardiac progenitor, I will tag Irx4 with fluorescent and luminescent reporters, which will facilitate purification and in vivo tracking of the Irx4+ progenitor population. Once purified, the Irx4[+] population will be assessed for its progenitor identity, evaluating potency and proliferative capacity.
Myocardial infarction, or heart attack, is responsible for approximately 400,000 fatalities in the US annually. Heart attacks not only affect health, this devastating pathology depreciates federal funds as well, with over 60 billion dollars being devoted to infarction-related care each year (www.americanheart.org).
|Nelson, Daryl O; Lalit, Pratik A; Biermann, Mitch et al. (2016) Irx4 Marks a Multipotent, Ventricular-Specific Progenitor Cell. Stem Cells 34:2875-2888|
|Nelson, Daryl O; Jin, Dexter X; Downs, Karen M et al. (2014) Irx4 identifies a chamber-specific cell population that contributes to ventricular myocardium development. Dev Dyn 243:381-92|