A comprehensive study from Canada’s Robarts Research Institute has pinpointed two genes that shed significant light on why stem cells divide and develop less vigorously as we age.
This research is the first to provide an explanation of how a range of genes regulates human stem cell behavior -- and the first to suggest that this behavior may be regulated by genetic mechanisms found in most human cells. The study was led by Robarts Scientist Dr. Mick Bhatia and published in this month’s issue of the journal Developmental Cell, available online as of May 2.
“The current thinking is that there must be some unique ‘stemness’ gene that no other cell expresses, but what we found is that what makes stem cells special -- their ability to renew themselves and differentiate into other tissue types -- may be attributed to fundamental mechanisms of cell physiology common to all cells,” said Dr. Bhatia, Director of the Krembil Centre for Stem Cell Biology at Robarts Research Institute and Canada Research Chair in Stem Cell Biology and Regenerative Medicine at The University of Western Ontario's Schulich School of Medicine in London, Ontario.
“The difference between those robust, self-replicating young hematopoietic (blood-forming) stem cells and older cells appears to be the degree of expression of these two regulatory genes governing fundamental cell physiology. This basic biological understanding is of critical importance as we explore ways to safely and effectively harness the clinical potential of these cells to repair and regenerate damaged tissue.”
Using leading technology in cell purification, genomics and bioinformatics, Dr. Bhatia’s team compared the genetic profiles of 112 individual samples of highly purified populations of human blood-forming stem cells found in early gestational blood, umbilical cord blood and adult bone marrow samples collected and meticulously analyzed over the past seven years.
Among their broad research questions: What it is that gives young stem cells their ability to divide and develop so vigorously? What causes this activity to drop off over time, such as in the adult bone marrow where blood cells are renewed more slowly as we age?
The team honed in on two regulatory genes -- called HES-1 and HLF -- that function in high gear in the developing embryo to drive the complex cellular processes that form the human blood system. The expression of these genes drops off significantly as blood-forming stem cells age in adulthood.
Surprisingly, each gene uses a different mechanism to regulate human stem cells: HES-1 activates signals that cause stem cells to divide more often; HLF turns on other signals that prevent stem cells from dying. The effect of each boosts the number and activity of stem cells early in human development.
“Up until now I’d say we were merely testing candidate genes and trying to pinpoint which of these could be responsible for regulating the behavior of human hematopoietic (blood-forming) stem cells,” Dr. Bhatia said. “This study allows us to say: ‘Here’s what genes really impact the stem cells that form the human blood system.’ Now we need to look at what it is that is turning on these two regulatory genes and what genes they in turn regulate.”
Funding and support for this research was provided by the National Cancer Institute of Canada, Canadian Institutes of Health Research, the National Centre of Excellence Program, Stem Cell Network-Stem Cell Genomics/Genome Canada, the London Regional Genomics Centre, the Krembil Foundation, the Canada Research Chair program and a postgraduate scholarship award from the Ontario Graduate Society.