Bevan Johnson

Introduction: Approximately 790,000 people in the United States experience a myocardial infarction (MI) each year and over 100,000 of them are fatal¹. Post MI, individuals are left with an irreversibly damaged heart and limited regenerative capacity. Using stem cells, modern research efforts strive to reverse the damage and regenerate the infarcted heart². BMI-1, a member of the polycomb repressive complex 1 (PRC1)³, is evidenced to be an important cell marker for cardiac progenitor cells (CPC)⁴. BMI-1 is a known regulator of the proliferative and self-renewal capacity of stem cells. Recent studies show resident populations of BMI-1 cardiac progenitor cells (B-CPC) developing into endothelial cells, smooth muscle cells, and de novo cardiomyoctes (following acute MI) in the heart^{4, 5}. Other studies demonstrate that the central domain of BMI-1 is mechanistically critical to its action³. Methods: Studies used transgenic mice expressing YFP (yellow fluorescent protein) from BMI⁺ cells. Cardiomyocytes were studied using flow cytometry, immunofluorescence, RT-qPCR and whole transcriptome analysis^{4, 5}. Additionally, NMR spectroscopy, pull-down, co-immunoprecipitation, and crystallization experiments were utilized³. Results: YFP⁺ cell populations (BMI-1 expressing cells) were found diffusely inside heart sections of transgenic mice, but not in aged matched controls. RT-qPCR gene expression profiles revealed a higher stemness profile in these cells as compared to SCA-1⁺ cell populations. A small percentage of YFP⁺ B-CPC cells developed networks of vascular endothelial-cadherin⁺, smooth muscle actin (SMA⁺), and sarcomeric a-actin⁺ cells—suggesting a CPC population capable of contributing to all three main heart lineages⁴. Post MI, the number of YFP⁺ cells isolated from BMI1-YFP mouse hearts was significantly higher (~1.5 fold) than found in healthy littermates. 15 days post-MI, YFP⁺ cells were detected in clusters near and within the infarct. Likewise, these cells differentially expressed more genes related to cell growth, proliferation, movement, and cell cycling. 4 months post-MI, BMI1-YFP cells made up 13.8% of total cardiomyocytes compared to 4.7% in aged paired non-infarcted hearts⁵. NMR studies show BMI-1’s central domain is essential to its repressive ability. BMI1-BMI1 and BMI1-PHC interactions were essential for function. Mutations in this region impaired function³. Conclusions: B-CPC cells appear to be a sound source of progenitor cells for cardiac turnover, proliferation, and repair^{4, 5}. The central domain of BMI-1 is critical to its function in the PRC1 complex³. Further characterization of BMI-1’s interactions in activating endogenous cardiac progenitor cells could unveil new therapeutic opportunities.

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,, 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.