Bmi1-Progenitor Cell Ablation Impairs the Angiogenic Response to Myocardial Infarction

Abstract

Objective- Cardiac progenitor cells reside in the heart in adulthood, although their physiological relevance remains unknown. Here, we demonstrate that after myocardial infarction, adult Bmi1 (B lymphoma Mo-MLV insertion region 1 homolog [PCGF4]) cardiac cells are a key progenitor-like population in cardiac neovascularization during ventricular remodeling. Approach and Results- These cells, which have a strong in vivo differentiation bias, are a mixture of endothelial- and mesenchymal-related cells with in vitro spontaneous endothelial cell differentiation capacity. Genetic lineage tracing analysis showed that heart-resident Bmi1 progenitor cells proliferate after acute myocardial infarction and differentiate to generate de novo cardiac vasculature. In a mouse model of induced myocardial infarction, genetic ablation of these cells substantially deteriorated both heart angiogenesis and the ejection fraction, resulting in an ischemic-dilated cardiac phenotype. Conclusions- These findings imply that endothelial-related Bmi1 progenitor cells are necessary for injury-induced neovascularization in adult mouse heart and highlight these cells as a suitable therapeutic target for preventing dysfunctional left ventricular remodeling after injury.

Age-related oxidative stress confines damage-responsive Bmi1+ cells to perivascular regions in the murine adult heart

“…To identify Bmi1 + cells in heart sections we used tamoxifen (Tx)-inducible Bmi1 CreERT/+ Rosa26 tdTomato/+ mice (denoted hereafter as Bmi1-cre Tomato ), since GFP signal in cryosections from Bmi1 GFP/+ mice was difficult to distinguish from background. Tomato expression 5 days post-Tx induction in Bmi1-cre Tomato mice resembles GFP expression in Bmi1 GFP/+ mice [12] and the percentage of Tomato + cells was similar to that assessed by fluorescence-activated cell sorting (FACS), indicating that the immunohistochemistry analysis was robust (Fig. S1A).…”

“…Many of the endothelial-Bmi1 + DR-cell interactions are challenging to study in vivo . We attempted to mimic these interactions by co-culturing primary Bmi1 + cardiac DR-cells isolated from 5 days Tx-induced adult Bmi1-cre Tomato mice [12] with the endothelial 1g11 cell line [39] and also with primary cardiac endothelial cells (CD31 + ). Co-culture with primary mesenchymal cardiac cells (PDGFRα + ) was used as a control (Fig.…”

“…Unlike cardiomyogenesis, cardiac endothelial and mesenchymal cells (including fibroblasts and stromal cells) are highly proliferative, with estimates ranging from 5% to 20% per year [1,5]. Several studies show that adult cardiac progenitor cells contribute actively to cardiac myofibroblasts and endothelial cells [[10], [11], [12], [13], [14], [15], [16]]. These cardiac progenitor cells respond to cardiac injury contributing to the, clearly limited, regenerative process [10,11,17,18].…”

“…In the adult heart, high BMI1 expression distinguishes a mixture of endothelial- and mesenchymal-related Sca1 + cells able to contribute in vivo to the three main cardiac lineages [27,28]. More importantly, these cells are necessary for injury-induced angiogenesis and for the physiological cardiac remodeling after myocardial infarction [12], thus identifying a population of cardiac DR-cells.…”

BMI1 in the heart: Novel functions beyond tumorigenesis

“…RT-qPCR analysis showed that BMI1 was preferentially expressed in the YFP + non-CM fraction, and western blot analysis furtherly confirmed that little BMI1 protein was detected in CM fraction and YFP − non-CM compartment [22] . Similarly, Herrero and coworkers used Bmi1 GFP/+ mice to analyze the expression of BMI1 in the heart tissue, and the FACS results showed that BMI1 was highly expressed in a subpopulation of non-CMs in adult mice, in contrast, low levels of BMI1 were detected in the adult myocytes [25] .…”