Differentiated mammalian muscle cells are not normally able to divide but the team found that mouse myocytes can be induced to re-enter the cell cycle and begin proliferating by blocking the expression of two tumour suppressors, retinoblastoma protein (Rb) and ARF, a protein transcribed from an alternate reading frame of the INK4a locus. ARF is found in birds and mammals but not in lower vertebrates and, interestingly, is expressed at lower than normal levels in mammalian livers – the only organ with some regenerative capacity. When RNA interference was used to temporarily block expression of Rb and Arf in cultured mouse myocytes, the cells lost their differentiated properties, re-entered the cell cycle and began to proliferate. The cells are incorporated into existing muscle fibres when transplanted into mice, but only if Rb function was restored. Without functioning Rb, the new cells proliferated excessively and disrupted the structure of the muscle tissue.
Previous studies had shown that suppression of the Rb gene alone causes newt muscle cells, but not mammalian muscle cells, to re-enter the cell cycle.
Although knocking down tumour suppressor genes has obvious potential dangers, temporary silencing of gene expression may eventually allow regeneration of cardiac or pancreatic tissue if the technique is also successful in other cell types.
The study is published in the journal Cell Stem Cell.