Abstract
Ischemic heart disease can lead to myocardial infarction (MI), a major cause of morbidity and mortality worldwide. Multiple stem cell types have been safely transferred into failing human hearts, but the overall clinical cardiovascular benefits have been modest. Therefore, there is a dire need to understand the basic biology of stem cells to enhance therapeutic effects. Bmi1 is part of the polycomb repressive complex 1 (PRC1) that is involved in different processes including proliferation, survival and differentiation of stem cells. We isolated cortical bones stem cells (CBSCs) from bone stroma, and they express significantly high levels of Bmi1 compared to mesenchymal stem cells (MSCs) and cardiac-derived stem cells (CDCs). Using lentiviral transduction, Bmi1 was knocked down in the CBSCs to determine the effect of loss of Bmi1 on proliferation and survival potential with or without Bmi1 in CBSCs. Our data show that with the loss of Bmi1, there is a decrease in CBSC ability to proliferate and survive during stress. This loss of functionality is attributed to changes in histone modification, specifically histone 3 lysine 27 (H3K27). Without the proper epigenetic regulation, due to the loss of the polycomb protein in CBSCs, there is a significant decrease in cell cycle proteins, including Cyclin B, E2F, and WEE as well as an increase in DNA damage genes, including ataxia-telangiectasia mutated (ATM) and ATM and Rad3-related (ATR). In conclusion, in the absence of Bmi1, CBSCs lose their proliferative potential, have increased DNA damage and apoptosis, and more cell cycle arrest due to changes in epigenetic modifications. Consequently, Bmi1 plays a critical role in stem cell proliferation and survival through cell cycle regulation, specifically in the CBSCs. This regulation is associated with the histone modification and regulation of Bmi1, therefore indicating a novel mechanism of Bmi1 and the epigenetic regulation of stem cells.
Highlights
Worldwide, there are approximately 32.4 million myocardial infarctions (MIs) every year [1]
cortical bone stem cells (CBSCs) have been shown to have unique functions compared to other stem cell types; until now, the detailed epigenetic differences were not as well understood
We show that there is an increase in Bmi1 expression in CBSCs compared to the bone marrowderived mesenchymal stem cells (MSCs) as well as cardiac-derived stem cells (CDCs) in both protein (Figure 1A) and RNA (Figure 1B) using Western blotting and rt-PCR analysis, respectively (p value 0.026 and 0.011 for Western blotting and p value 0.0003 and 0.031 for PCR)
Summary
There are approximately 32.4 million myocardial infarctions (MIs) every year [1]. CBSCs have shown increased paracrine signaling, which is a major attribute for stem cell therapies. Paracrine signaling in stem cells is often attributed to factors that promote cardioprotection [14], through increased proliferation, decreased cell death, and increased cell cycle regulation [15]. These beneficial cellular mechanisms are strongly regulated by epigenetics [16,17]. CBSCs have shown enhanced cardiac wound healing and increased heart function following injury, which was attributed to unique paracrine signaling [12]. This article provides insight into the CBSC mechanism by the epigenetic regulation of the PRC1 protein, Bmi
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