David Chapman

Introduction: In the US, cardiovascular disease and myocardial infarctions (MI) are leading causes of morbidity and mortality. Approximately 790,000¹ individuals in the US experience an MI annually, with over 100,000 of them resulting in death. Unfortunately, an MI is associated with lasting negative health implications, including irreversibly damaged cardiac tissue with limited regenerative capacity. Decreased heart function is associated with increased risk of subsequent MI². Stem cell research has pioneered approaches to reverse the damages of infarctions. Within the polycomb-repressive complex 1 (PCR1) family, exists a protein that is encoded by the B cell-specific Moloney murine leukemia virus integration site 1 called the polycomb group RING finger protein 4 (PCGF4)³. This protein has shown pivotal as a cell marker for cardiac progenitor cells (CPC), regulating proliferative and self-regenerative properties of stem cells⁴. Emerging research shows that there exists a population of resident PCGF4 CPCs with the capability of maturing into both endothelial and smooth muscle lineages in an adult heart⁴. Recent studies demonstrated that these progenitor cells play a role in de-novo myocardiocyte regeneration following MI⁵. Methods: Using the PCGF4 locus, transgenic mice were induced with Tamoxifen (TM), resulting in PCGF4-yellow fluorescent protein (YFP) mice. Myocardiocytes were studied using flow cytometry, immunofluorescence, and RT-qPCR. For comparison, whole transcriptome analysis of yellow fluorescent protein (YFP⁺) was performed on hearts of same aged mice following MI^4,5. Results: Transgenic mice displayed YFP⁺ cell populations five days following TM-induction, whereas age-matched controls did not. Analysis of gene expression profiles were performed using RT-qPCR and showed an elevated stemness profile of SCA-1⁺ YFP^– cardiac cells⁴. PCGF4 associated CPC clusters were found diffusely in all heart sections using GFP immunostaining⁵.  Following MI, there was an increased number (approximately 1.5 fold) of YFP⁺ cells isolated from PCGF4 associated YFP hearts, when compared to the uninduced littermates. YFP⁺ cells were found clustered in the penumbra and within the infarcted tissue at 15-days following MI. Additionally, cell growth, proliferation, mobility, and cell-cycle activity were evidenced in these cells. PCGF4 associated YFP cells accounted for 13.8% of total myocardiocytes compared to roughly 5% in the same age non-infarcted control hearts at four-months following MI⁵. Conclusions: PCGF4 associated CPCs have proven effective in producing progenitors for stem cell proliferation, regeneration, and repair^4,5. This novel mechanism has the potential to unlock MI therapeutics through the activation of endogenous CPCs.

1. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, Gillespie C, Isasi CR, et al. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation. 2017;135(10):e146-e603.
2. Frangogiannis NG. Pathophysiology of myocardial infarction. Compr Physiol. 2015; 5(4):1841–1875.
3. Gray, F. et al. BMI1 regulates PRC1 architecture and activity through homo- and hetero oligomerization. Nat Commun. 2016;7: 13343.
4. Valiente-Alandi, I., et al. Cardiac Bmi1 (+) cells contribute to myocardial renewal in the murine adult heart. Stem Cell Res Ther. 2015;6: 205.
5. Valiente-Alandi, I., et al. Bmi1 (+) cardiac progenitor cells contribute to myocardial repair following acute injury. Stem Cell Res Ther. 2016;7(1): 100.