You can鈥檛 keep a good cell down. A phenomenon that just two years ago was seen as the death knell for many stem-cell therapies is now being investigated as a possible fast track into medical use. It all centres around encouraging stem cells from bone marrow to fuse with cells elsewhere in the body.
Our bodies contain populations of 鈥渁dult鈥� stem cells that divide and replenish tissues that would otherwise wear out. Medical interest in using these cells for therapies exploded after early experiments suggested that under some circumstances, they can colonise other tissues and 鈥渢ransdifferentiate鈥� to replenish the cells in their new home. This opened up the possibility of using the plentiful stem cells found in bone marrow 鈥� known as haematopoietic stem cells or HSCs 鈥� to treat a wide variety of diseases.
But those hopes were deflated in 2003 when it became clear that rather than undergoing a transformation, migrant HSCs were fusing with cells in the other tissues (New 杏吧原创, 5 April 2003, p 17). 鈥淎t first people said it was 鈥榤erely鈥� fusion,鈥� says Helen Blau of Stanford University in California. 鈥淭hey couldn鈥檛 imagine that it was a useful thing. But maybe this is something the body uses for repair.鈥�
Advertisement
鈥淎t first people said it was 鈥榤erely鈥� fusion, and couldn鈥檛 imagine it was useful. But maybe this is something the body uses鈥�
Markus Grompe and his team at the Oregon Health and Science University in Portland studied mice with a disease called tyrosinemia type 1, which is caused by the lack of an enzyme that breaks down the amino acid tyrosine. Its symptoms include jaundice, lethargy and cirrhosis of the liver, but the mice can be cured by infusing their livers with HSCs from healthy mice. In 2003 Grompe鈥檚 team showed that this is a result of the HSCs fusing with liver cells, and providing the gene for the missing enzyme.
Now the finding is being seen as an important proof of principle for fusion therapy. 鈥淚n much of the stem-cell field, the promise is way down the line,鈥� says Arnold Kriegstein, who heads the Institute for Stem Cell and Tissue Biology at the University of California, San Francisco. 鈥淏ut this is something that has already shown potential.鈥�
Fusion will probably not be used to treat children with tyrosinemia type 1, which affects one in 100,000 babies, because there is already an effective drug. For other diseases, realising the potential of fusion will mean boosting the number of cells that fuse, or encouraging the fused cells to proliferate. Fused cells contain twice the usual number of chromosomes. Although this is often considered abnormal, cells with doubled-up chromosomes are common in some organs, including the liver. The catch is that such cells often have trouble dividing normally, which poses a problem if you want them to proliferate. 鈥淭his is an obstacle,鈥� Grompe admits.
At the American Society for Cell Biology meeting in San Francisco this week, Grompe presented evidence that fused cells can undergo 鈥渞eduction divisions鈥�, restoring the usual number of chromosomes. That means it might be possible to boost cell proliferation after fusion. 鈥淚 think reduction divisions occur routinely,鈥� he says, although other researchers remain to be convinced.
While the jury is still out on reduction divisions, Grompe鈥檚 team and Blau鈥檚 are now working on methods to increase the rate of cell fusion. Blau has found that, in mice, a signalling molecule called insulin-like growth factor 1 causes a fourfold increase in fusions between muscle fibres and cells derived from HSCs.
Effective therapies may depend on boosting cell fusion even further, however. For instance, curing haemophilia, which is caused by a lack of blood-clotting factors made in the liver, could require a 200-fold increase on the fusion rates seen in Grompe鈥檚 mice. Grompe and Blau are now both experimenting with proteins found on the surface of some viruses that can make mammalian cells fuse, although there are worries that these viral proteins can prompt cells to become cancerous.
