Abstract
High-mobility group box 1 protein (HMGB1) fragment enhances bone marrow-derived mesenchymal stem cell (BM-MSC) recruitment to damaged tissue to promote tissue regeneration. This study aimed to evaluate whether systemic injection of HMGB1 fragment could promote tissue repair in a rat model of myocardial infarction (MI). HMGB1 (n = 14) or phosphate buffered saline (n = 12, control) was administered to MI rats for 4 days. Cardiac performance and left ventricular remodeling were evaluated using ultrasonography and immunostaining. BM-MSC recruitment to damaged tissue in green fluorescent protein-bone marrow transplantation (GFP-BMT) models was evaluated using immunostaining. At four weeks post-treatment, the left ventricular ejection fraction was significantly improved in the HMGB1 group compared to that in the control. Interstitial fibrosis and cardiomyocyte hypertrophy were also significantly attenuated in the HMGB1 group compared to the control. In the peri-infarction area, VEGF-A mRNA expression was significantly higher and TGFβ expression was significantly attenuated in the HMGB1 group than in the control. In GFP-BMT rats, GFP+/PDGFRα+ cells were significantly mobilized to the peri-infarction area in the HMGB1 group compared to that in the control, leading to the formation of new vasculature. In addition, intravital imaging revealed that more GFP+/PDGFRα+ cells were recruited to the peri-infarction area in the HMGB1 group than in the control 12 h after treatment. Systemic administration of HMGB1 induced angiogenesis and reduced fibrosis by recruiting PDGFRα+ mesenchymal cells from the bone marrow, suggesting that HMGB1 administration might be a new therapeutic approach for heart failure after MI.
Highlights
At four weeks post-treatment, the left ventricular ejection fraction was significantly improved in the High-mobility group box 1 protein (HMGB1) group compared to that in the control
Interstitial fibrosis and cardiomyocyte hypertrophy were significantly attenuated in the HMGB1 group compared to the control
In GFPBMT rats, GFP+/PDGFRα+ cells were significantly mobilized to the peri-infarction area in the HMGB1 group compared to that in the control, leading to the formation of new vasculature
Summary
The rate of mortality owing to acute myocardial infarction (MI) has decreased considerably in recent years concomitant with the evolution of coronary reperfusion interventions, MI remains one of the leading causes of chronic heart failure (CHF) that occurs as a consequence of adverse left ventricular (LV) remodeling [1, 2]. There has been significant progress in regenerative therapies using different types of stem cells for suppressing adverse LV remodeling. There are several endogenous regenerative mechanisms that function in the repair of injured organs. BM-MSCs, in particular, show a strong potential to repair damaged organs by recruiting other host cells, secreting different growth factors, or differentiating into various cells, such as endothelial cells [5], thereby promoting angiogenesis and inhibiting adverse fibrosis in various injuries and diseases including injured muscles [6], cerebral infarction [7], and MI [8, 9]. As an alternative to conventional cellular therapy, by enhancing endogenous repair mechanisms with stem cells or pharmacological agents, or by accelerating endogenous regenerative function, could offer a less invasive regenerative treatment
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