Damage to cardiac muscle cells, for which the heart has a limited ability to repair or replace, can ultimately lead to heart failure. Stem cell therapy is emerging as a potential regenerative treatment for heart failure, based on the essentially limitless potential of human embryonic stem cells to become any kind of cell in the human body. However so far there has been limited success in obtaining the desired types of cardiac muscle cell. For example, in vitro experimentation has resulted in human embryonic stem cells differentiating into mixed populations with heterogeneous properties. An understanding of the mechanisms by which stem cells develop into atrial, ventricular and other specialised heart muscle cells is therefore crucial. In a recent study in Stem Cell Research and Therapy, Harold Bernstein, now at Merck Sharp & Dohme Corporation, USA, and colleagues from the University of California, San Francisco, USA, uncover a unique pathway by which microRNA (miRNA) regulates the specialised differentiation of cardiac muscle cells.
miRNAs are short non-coding RNAs that regulate gene expression by forming imperfect base pairing on messenger RNAs (mRNAs), which consequently inhibits translation. miRNAs play a significant role in directing the differentiation of stem cells and are already recognised as important regulators of cardiac development and function. Bernstein and colleagues identified a subset of miRNAs (miR-363, -367, -181a, -181c) that showed differential expression levels during the development of cardiac muscle cells from human embryonic stem cells. These four miRNAs were identified to target heart and neural crest derivative (Hand) genes, Hand1 and Hand2. Hand1 and Hand2 are transcription factors that are known to play an essential role in determining left versus right ventricular development of the heart. In vivo regional expression, in silico predictions and experimental validation demonstrated that miR-363 is a regulator of Hand1 translation. Overexpression of miR-363 was shown to suppress Hand1 mRNA and protein levels, confirming that miR-363 negatively regulates Hand1 expression.
These findings unearth one aspect of the complex mechanisms by which heart development is regulated. Bernstein and colleagues are the first to report on the regulation of Hand1 and Hand2 by miRNAs. Their results also demonstrate that miR-363, by targeting Hand1, is significant in the regulation of cardiac muscle cell differentiation. Suppression of miR-363 could provide a novel strategy for generating functional cells of the left ventricle – and may provide a crucial step forward in tailoring stem cell therapy for the heart.