Muscles find their stem cell niche

A highly successful method used in haematopoietic stem cell transplantation has been mimicked to grow new muscle fibres from stem cells in a mouse model, Sydney researchers have reported.

The team, led by Professor Peter Gunning and Professor Edna Hardeman of the University of NSW, has transplanted myoblasts expressing a chemotherapy-resistant gene into mice, with the host muscle ablated by chemotherapy.

When the endogenous cells were destroyed, the stem cells began to proliferate. The researchers observed muscle fibre formation as well as a quite remarkable regeneration of satellite cells, Gunning said.

Research on regenerating muscle fibres using stem cells has been ongoing for decades, particularly in Duchenne muscular dystrophy models, but has always failed.

The major problem was the failure of the stem cells to survive and thrive, with endogenous cells out-competing the donor cells or the cells being rejected by the immune system, Gunning said.

In haematopoietic stem cell transplantation, however, remarkable success had been achieved using a mutant version of the MGMT gene, which codes for a DNA repair enzyme called methylguanine-DNA methyltransferase.

The enzyme has the ability to repair chemotherapy-induced DNA alkylation, thereby reducing chemo drug effectiveness. An inhibitor of MGMT, O6-benzylguanine, is used in conjunction with alkylating chemotherapy to render the drugs more effective.

A mutant form of the gene, MGMT(P140K), however, is chemo-resistant and is used in a haematopoietic stem cell transplantation strategy, primarily developed by Stan Gerson’s lab at Case Western Reserve University in the US, which has been phenomenally effective, Gunning said.

By destroying endogenous cells with chemo, and transplanting chemo-resistant stem cells, the transplanted cells seem to thrive.

“You can start with a very low level of transplantation and if you’ve got chemo-resistant stem cells you can drive them up to 70, 80, 90 per cent of total bone marrow just by using chemotherapy,” he said.

What the researchers have done now is adapt this method to muscle stem cells. Gunning describes it as a very simple idea, and there is no reason to believe it cannot be applied to other tissues, he said.

The research is published in the February issue of Stem Cells.

For the full story, see the March/April issue of Australian Life Scientist.