Mapping out the mystery of blood stem cells

November 25, 2020

Princess Margaret scientists have revealed how stem cells are able to generate new blood cells throughout our life by looking at vast, uncharted regions of our genetic material that hold important clues to subtle biological changes in these cells.

The finding, obtained from studying normal blood, can be used to enhance methods for stem cell transplantation, and may also shed light into processes that occur in cancer cells that allow them to survive chemotherapy and relapse into cancer growth many years after treatment.

Using state-of-the art sequencing technology to perform genome-wide profiling of the epigenetic landscape of human stem cells, the research revealed important information about how genes are regulated through the three-dimensional folding of chromatin.

Chromatin is composed of DNA and proteins, the latter which package DNA into compact structures, and is found in the nucleus of cells. Changes in chromatin structure are linked to DNA replication, repair and gene expression (turning genes on or off).

The research by Princess Margaret Cancer Centre Senior Scientists Drs. Mathieu Lupien and John Dick is published in Cell Stem Cell, Wednesday, November 25, 2020.

"We don't have a comprehensive view of what makes a stem cell function in a specific way or what makes it tick," says Dr. Dick, who is also a Professor in the Department of Molecular Genetics, University of Toronto.

"Stem cells are normally dormant but they need to occasionally become activated to keep the blood system going. Understanding this transition into activation is key to be able to harness the power of stem cells for therapy, but also to understand how malignant cells change this balance.

"Stem cells are powerful, potent and rare. But it's a knife's edge as to whether they get activated to replenish new blood cells on demand, or go rogue to divide rapidly and develop mutations, or lie dormant quietly, in a pristine state."

Understanding what turns that knife's edge into these various stem cell states has perplexed scientists for decades. Now, with this research, we have a better understanding of what defines a stem cell and makes it function in a particular way.

"We are exploring uncharted territory," says Dr. Mathieu Lupien, who is also an Associate Professor in the Department of Medical Biophysics, University of Toronto. "We had to look into the origami of the genome of cells to understand why some can self-renew throughout our life while others lose that ability. We had to look beyond what genetics alone can tell us."

In this research, scientists focused on the often overlooked noncoding regions of the genome: vast stretches of DNA that are free of genes (i.e. that do not code for proteins), but nonetheless harbour important regulatory elements that determine if genes are turned on or off.

Hidden amongst this noncoding DNA - which comprise about 98% of the genome - are crucial elements that not only control the activity of thousands of genes, but also play a role in many diseases.

The researchers examined two distinct human hematopoietic stem cells or immature cells that go through several steps in order to develop into different types of blood cells, such as white or red blood cells, or platelets.

They looked at long-term hematopoietic stem cells (HSCs) and short-term HSCs found in the bone marrow of humans. The researchers wanted to map out the cellular machinery involved in the "dormancy" state of long-term cells, with their continuous self-renewing ability, as compared to the more primed, activated and "ready-to-go" short-term cells which can transition quickly into various blood cells.

The researchers found differences in the three-dimensional chromatin structures between the two stem cell types, which is significant since the ways in which chromatin is arranged or folded and looped impacts how genes and other parts of our genome are expressed and regulated.

Using state-of-the-art 3D mapping techniques, the scientists were able to analyze and link the long-term stem cell types with the activity of the chromatin folding protein CTCF and its ability to regulate the expression of 300 genes to control long-term, self-renewal.

"Until now, we have not had a comprehensive view of what makes a stem cell function in a particular way," says Dr. Dick, adding that the 300 genes represent what scientists now think is the "essence" of a long-term stem cell.

He adds that long-term dormant cells are a "protection" against malignancy, because they can survive for long periods and evade treatment, potentially causing relapse many years later.

However, a short-term stem cell that is poised to become active, dividing and reproducing more quickly than a long-term one, can gather up many more mutations, and sometimes these can progress to blood cancers, he adds.

"This research gives us insight into aspects of how cancer starts and how some cancer cells can retain stem-cell like properties that allow them to survive long-term," says Dr. Dick.

He adds that a deeper understanding of stem cells can also help with stem cells transplants for the treatment of blood cancers in the future, by potentially stimulating and growing these cells ex vivo (out of the body) for improved transplantation.
-end-
The research was supported by The Princess Margaret Cancer Foundation, Ontario Institute for Cancer Research, Canadian Institutes for Health Research (CIHR), Medicine by Design, University of Toronto, Canadian Cancer Society Research Institute, and the Terry Fox Research Institute.

Competing Interests

Dr. John Dick served on the SAB at Trillium Therapeutics, and has ownership interest (including patents) in Trillium Therapeutics. He also reports receiving a commercial research grant from Celgene.

About Princess Margaret Cancer Centre

Princess Margaret Cancer Centre has achieved an international reputation as a global leader in the fight against cancer and delivering personalized cancer medicine. The Princess Margaret, one of the top five international cancer research centres, is a member of the University Health Network, which also includes Toronto General Hospital, Toronto Western Hospital, Toronto Rehabilitation Institute and the Michener Institute for Education at UHN. All are research hospitals affiliated with the University of Toronto. For more information: http://www.theprincessmargaret.ca

University Health Network

Related Science Articles from Brightsurf:

75 science societies urge the education department to base Title IX sexual harassment regulations on evidence and science
The American Educational Research Association (AERA) and the American Association for the Advancement of Science (AAAS) today led 75 scientific societies in submitting comments on the US Department of Education's proposed changes to Title IX regulations.

Science/Science Careers' survey ranks top biotech, biopharma, and pharma employers
The Science and Science Careers' 2018 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Science in the palm of your hand: How citizen science transforms passive learners
Citizen science projects can engage even children who previously were not interested in science.

Applied science may yield more translational research publications than basic science
While translational research can happen at any stage of the research process, a recent investigation of behavioral and social science research awards granted by the NIH between 2008 and 2014 revealed that applied science yielded a higher volume of translational research publications than basic science, according to a study published May 9, 2018 in the open-access journal PLOS ONE by Xueying Han from the Science and Technology Policy Institute, USA, and colleagues.

Prominent academics, including Salk's Thomas Albright, call for more science in forensic science
Six scientists who recently served on the National Commission on Forensic Science are calling on the scientific community at large to advocate for increased research and financial support of forensic science as well as the introduction of empirical testing requirements to ensure the validity of outcomes.

World Science Forum 2017 Jordan issues Science for Peace Declaration
On behalf of the coordinating organizations responsible for delivering the World Science Forum Jordan, the concluding Science for Peace Declaration issued at the Dead Sea represents a global call for action to science and society to build a future that promises greater equality, security and opportunity for all, and in which science plays an increasingly prominent role as an enabler of fair and sustainable development.

PETA science group promotes animal-free science at society of toxicology conference
The PETA International Science Consortium Ltd. is presenting two posters on animal-free methods for testing inhalation toxicity at the 56th annual Society of Toxicology (SOT) meeting March 12 to 16, 2017, in Baltimore, Maryland.

Citizen Science in the Digital Age: Rhetoric, Science and Public Engagement
James Wynn's timely investigation highlights scientific studies grounded in publicly gathered data and probes the rhetoric these studies employ.

Science/Science Careers' survey ranks top biotech, pharma, and biopharma employers
The Science and Science Careers' 2016 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Three natural science professors win TJ Park Science Fellowship
Professor Jung-Min Kee (Department of Chemistry, UNIST), Professor Kyudong Choi (Department of Mathematical Sciences, UNIST), and Professor Kwanpyo Kim (Department of Physics, UNIST) are the recipients of the Cheong-Am (TJ Park) Science Fellowship of the year 2016.

Read More: Science News and Science Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.