Nav: Home

Single gene encourages growth of intestinal stem cells, supporting 'niche' cells -- and cancer

April 28, 2017

A gene previously identified as critical for tumor growth in many human cancers also maintains intestinal stem cells and encourages the growth of cells that support them, according to results of a study led by Johns Hopkins researchers. The finding, reported in the Apr. 28 issue of Nature Communications, adds to evidence for the intimate link between stem cells and cancer, and advances prospects for regenerative medicine and cancer treatments.

Study leader Linda M. S. Resar, M.D., professor of medicine, oncology and pathology at the Institute for Cellular Engineering at the Johns Hopkins University School of Medicine, has been studying genes in the high-mobility group (HMG) family for over two decades. Several years ago, while creating a genetically engineered mouse that expresses high levels of the mouse HMGA1 gene to investigate its role in leukemia, Resar and her colleagues made the chance finding that the intestines of these animals were much larger and heavier than those of "wild-type" animals (or control mice that were not genetically modified). The mouse intestines were also riddled with polyps, abnormal growths projecting from the intestinal lining that can be precursors of cancer. In fact, polyps in humans frequently progress to colon cancer, which is why they are removed during screening colonoscopies in people over 50 and others at risk for colon cancer.

To better understand how HMGA1 affected the rodents' intestines, Resar and Lingling Xian, M.D., Ph.D., research associate at the Johns Hopkins University School of Medicine, and their colleagues examined the transgenic animals' intestinal cells to determine which ones were expressing this gene. Several different experiments localized the active gene and its protein to stem cells buried within the crypts, or deep grooves in the intestinal lining.

After isolating these stem cells from both transgenic and wild-type mice, the researchers found that those carrying the HMGA1 transgene multiplied far more rapidly, forming identical daughter cells in a process called self-renewal, which is a defining property of all stem cells. These transgenic stem cells also readily created intestinal tissues called "organoids" in laboratory dishes. These organoids had more stem cells than those isolated from wild-type mice.

Further investigation, says Resar, showed that these unusual properties arise from the ability of HMGA1 to turn on several genes involved in the Wnt pathway, a network of proteins necessary for embryonic development and stem cell activity.

Stem cells do not function in isolation, explains Resar. They need a "niche" to survive and maintain an undifferentiated state. From the French word nicher, which means to build a nest, a niche is a nest-like compartment comprised of cells that secrete growth factors and other proteins that help stem cells survive. The niche also prevents stem cells from morphing into mature intestinal cells until new intestinal cells are needed. Intestinal stem cells are particularly important because a new intestinal lining is generated about every 4-5 days.

Looking further into the intestinal crypts of both the transgenic and wild-type mice, the research team made what they consider a surprising finding: Not only was HMGA1 causing the stem cells themselves to self-renew or proliferate more rapidly in the transgenic animals, but it was also increasing the number of Paneth cells, a type of niche cell known to support intestinal stem cells. Additional experiments showed that the protein produced by HMGA1 activates another gene called Sox9, which is directly responsible for turning stem cells into Paneth cells.

"We suspected that HMGA1 might generate new stem cells, but we were extremely surprised that it also helps support these cells by building a niche," Resar says. "We believe that our experiments provide the first example of a factor that both expands the intestinal stem cell compartment and builds a niche."

Many genes that are involved in the growth and development of embryos or adult stem cells also play roles in cancer, Resar adds. After scanning the Cancer Genome Atlas, a database of genes expressed in human cancers, the research team discovered that the activity of both HMGA1 and SOX9 genes are tightly correlated in normal colon tissue, and both genes become highly overexpressed in colon cancer. "This tells us that the pathway turned on by HMGA1 in normal intestinal stem cells becomes disrupted and hyperactive in colon cancer," Resar says.

Resar says the team plans to continue investigating the function of HMGA1 and SOX9 in intestinal and other cancers as well as their role in stem cells. Both avenues of investigation could eventually lead to clinical applications, she adds. For example, if scientists can find a way to turn down overexpression of these genes in cancer, we could disrupt cancer growth and prevent tumor progression. On the flip side, turning up expression of these genes or their pathways could help researchers grow new intestinal tissue to replace tissue destroyed by diseases such as inflammatory bowel disease or radiation treatment for cancer. "What we discovered is something referred to as the Goldilocks paradox," she says. "Too little of this protein disrupts normal stem cell function, but too much can promote abnormal growth and lead to cancer. For our work to help patients, we will need to find ways to get the amount just right and in the appropriate cell context."

To view the video that accompanies this release please click here.
-end-
Other Johns Hopkins researchers who participated in this research include Dan Georgess, Tait Huso, Leslie Cope, Amy Belton, Yu-Ting Chang, Wenyong Kuang, Qihua Gu, Xiaoyan Zhang, David L. Huso and Andrew J. Ewald. This work also included Alessio Fasano and Stefania Senger from Massachusetts General Hospital for Children.

This work was supported by grants from the National Cancer Institute (grant numbers CA182679, CA164677, and CA149550) and the Maryland Stem Cell Research Fund (grant numbers 2011-MSCRFE-0102 and 2015-MSCRFE-1759).

Johns Hopkins Medicine

Related Stem Cells Articles:

A protein that stem cells require could be a target in killing breast cancer cells
Researchers have identified a protein that must be present in order for mammary stem cells to perform their normal functions.
Approaching a decades-old goal: Making blood stem cells from patients' own cells
Researchers at Boston Children's Hospital have, for the first time, generated blood-forming stem cells in the lab using pluripotent stem cells, which can make virtually every cell type in the body.
New research finds novel method for generating airway cells from stem cells
Researchers have developed a new approach for growing and studying cells they hope one day will lead to curing lung diseases such as cystic fibrosis through 'personalized medicine.'
Mature heart muscle cells created in the laboratory from stem cells
Generating mature and viable heart muscle cells from human or other animal stem cells has proven difficult for biologists.
Mutations in bone cells can drive leukemia in neighboring stem cells
DNA mutations in bone cells that support blood development can drive leukemia formation in nearby blood stem cells.
Scientists take aging cardiac stem cells out of semiretirement to improve stem cell therapy
With age, the chromosomes of our cardiac stem cells compress as they move into a state of safe, semiretirement.
Purest yet liver-like cells generated from induced pluripotent stem cells
A team of researchers from the Medical University of South Carolina and elsewhere has found a better way to purify liver cells made from induced pluripotent stem cells.
Stem cell scientists discover genetic switch to increase supply of stem cells from cord blood
International stem cell scientists, co-led in Canada by Dr. John Dick and in the Netherlands by Dr.
Stem cells from diabetic patients coaxed to become insulin-secreting cells
Signaling a potential new approach to treating diabetes, researchers at Washington University School of Medicine in St.

Related Stem Cells Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Changing The World
What does it take to change the world for the better? This hour, TED speakers explore ideas on activism—what motivates it, why it matters, and how each of us can make a difference. Guests include civil rights activist Ruby Sales, labor leader and civil rights activist Dolores Huerta, author Jeremy Heimans, "craftivist" Sarah Corbett, and designer and futurist Angela Oguntala.
Now Playing: Science for the People

#521 The Curious Life of Krill
Krill may be one of the most abundant forms of life on our planet... but it turns out we don't know that much about them. For a create that underpins a massive ocean ecosystem and lives in our oceans in massive numbers, they're surprisingly difficult to study. We sit down and shine some light on these underappreciated crustaceans with Stephen Nicol, Adjunct Professor at the University of Tasmania, Scientific Advisor to the Association of Responsible Krill Harvesting Companies, and author of the book "The Curious Life of Krill: A Conservation Story from the Bottom of the World".