Abstract
As heart failure due to myocardial infarction remains a leading cause of morbidity worldwide, cell-based cardiac regenerative therapy using cardiac progenitor cells (CPCs) could provide a potential treatment for the repair of injured myocardium. As adult CPCs may have limitations regarding tissue accessibility and proliferative ability, CPCs derived from embryonic stem cells (ESCs) could serve as an unlimited source of cells with high proliferative ability. As one of the CPCs that can be derived from embryonic stem cells, Isl1 expressing cardiac progenitor cells (Isl1-CPCs) may serve as a valuable source of cells for cardiac repair due to their high cardiac differentiation potential and authentic cardiac origin. In order to generate an unlimited number of Isl1-CPCs, we used a previously established an ESC line that allows for isolation of Isl1-CPCs by green fluorescent protein (GFP) expression that is directed by the mef2c gene, specifically expressed in the Isl1 domain of the anterior heart field. To improve the efficiency of cardiac differentiation of Isl1-CPCs, we studied the role of Bmp4 in cardiogenesis of Isl1-CPCs. We show an inductive role of Bmp directly on cardiac progenitors and its enhancement on early cardiac differentiation of CPCs. Upon induction of Bmp4 to Isl1-CPCs during differentiation, the cTnT+ cardiomyocyte population was enhanced 2.8±0.4 fold for Bmp4 treated CPC cultures compared to that detected for vehicle treated cultures. Both Bmp4 treated and untreated cardiomyocytes exhibit proper electrophysiological and calcium signaling properties. In addition, we observed a significant increase in Tbx5 and Tbx20 expression in differentiation cultures treated with Bmp4 compared to the untreated control, suggesting a link between Bmp4 and Tbx genes which may contribute to the enhanced cardiac differentiation in Bmp4 treated cultures. Collectively these findings suggest a cardiomyogenic role for Bmp4 directly on a pure population of Isl1 expressing cardiac progenitors, which could lead to enhancement of cardiac differentiation and engraftment, holding a significant therapeutic value for cardiac repair in the future.
Highlights
Heart failure caused by myocardial infarction remains a leading cause of morbidity and mortality in the developed world [1]
In order to isolate Isl1-cardiac progenitor cells (CPCs) in large quantities for further characterization, we have used an established embryonic stem cells (ESCs) line-derived from a transgenic mouse strain (AHFGFP) in which green fluorescent protein (GFP) expression is directed by a promoter containing the minimal enhancer sequence from Isl-1 target gene, MEF2c, which has been shown to be expressed within the Isl1 domain of the anterior heart field (AHF) [18, 19]
Isl1-CPCs derived from this transgenic ESC line could differentiate into cardiomyocytes, the characteristics of these cardiomyocytes remains largely unknown and the cardiac differentiation efficacy of these Isl1CPCs needs to be improved
Summary
Heart failure caused by myocardial infarction remains a leading cause of morbidity and mortality in the developed world [1]. Current therapies can slow the progression of heart failure, but there are limited options to repair or reverse injury to the myocardium. Many are exploring the potential of injecting stem cells into the heart to generate new myocardium to develop cell-based cardiac regenerative therapies. Various cell types have been tested for cardiac regeneration and some have shown improvement in cardiac function. The differentiation and long-term engraftment of the injected stem cells has been challenging. Some of the early human clinical trials have shown promising, but limited differentiation capacity and variable improvements in heart function after myocardial injury [1]
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