Activating a pro-survival stress response unique to stem cells protects them through the stress of self-renewal, with significant implications for improving stem cell transplants in the future.
For the first time, research by Dr. John Dick and Dr. Stephanie Xie at Princess Margaret Cancer Centre, identifies a link between lipid metabolism and cellular stress protective programs which are able to shepherd blood stem cells through the stress of multiplying in a cell-culture dish, a process by which cells are grown outside their usual environment, under controlled conditions.
Understanding this protective mechanism can, in turn, help us better understand and harness the unique capacity of a stem cell for self-renewal. Only hematopoietic stem cells (HSC) are able to regenerate the entire blood system upon transplantation and maintain long-term output due to their unique capacity for self-renewal.
The research, "Sphingolipid Modulation Activates Proteostasis Programs to Govern Human Hematopoietic Stem Cell Self-renewal" is published online in
Cell Stem Cell on Oct. 17.
"This finding will advance our knowledge of the basic biology of the human blood system, as well as potentially improve clinical blood stem cell transplantation," says Dr. Xie, Scientific Associate, the Princess Margaret.
"The connection between lipid metabolism and blood stem cell biology is underexplored and has never been described for this class of lipids. These lipids are different in stem cells than in other blood cells, and altering these lipids is sufficient to change blood production."
Currently, 1,200 to 1,400 hematopoietic stem cell transplants are performed each year in Canada, primarily for cancer therapy. However, less than 25 per cent of patients who need stem cell transplants find a compatible donor within their family. The others must rely on stem cells donors, but may not be able to find a match.
That means there's a crucial need to find ways to multiply stem cells in the lab so that they can be used for people urgently requiring a transplant.
"Stem cells are sensitive," explains Dr. Dick, Senior Scientist, the Princess Margaret, and Professor, Department of Molecular Genetics, University of Toronto. "They're also powerful since they're responsible for constantly renewing our blood by producing billions of blood cells each day.
"So they need to be controlled exquisitely because if they do get out of control, they can cause leukemia."
Scientists have been studying self-renewal in blood stem cells for the past 25 years. Self-renewal is the process in which stem cells divide to make more stem cells, creating a stem cell pool for life.
Researchers have had a difficult time trying to grow or maintain stem cells in culture, with labs around the world vying to come up with ways to preserve the property of self-renewal in a stem cell, without it differentiating or becoming other blood cells.
Maintaining self-renewal of a stem cell is important because it could provide an unlimited source of cells for transplantation and potentially targets for other stem cell-based cellular therapies.
One of the questions for Dr. Stephanie Xie to solve was: "What are the triggers that activate the protective portion of the stress response which protects self-renewal of the stem cell?
"Stem cells have a unique way of handling stress, but putting them into a petri dish alters these stress pathways. Often they don't survive. That pro-survival piece is lost in the culture dish. How do we find it?"
Extracting HSCs from 100 human umbilical cords – a rich source of HSCs – Dr. Xie found that when the metabolism of a specific class of lipids called sphingolipids was altered in the blood stem cells during expansion or growth, stem cells improved their function when transplanted into immunodeficient pre-clinical models. Altering lipid metabolism activated stress protective programs which are crucial in protecting blood stem cells from the initial stress and accumulating damage within the cell, thereby keeping them healthy.
Dr. Xie also noted that the initial stress response is protective only for about eight days. The stem cells can no longer protect themselves from the stress if their lipid metabolism was altered for longer periods: their function becomes impaired, severely decreasing blood production.
This work on lipids can lay the groundwork for new therapies for leukemia, she says, adding that because the specific lipid content in leukemia stem cells is likely different from normal blood stem cells, it could be a new therapeutic target which spares normal blood stem cells.
