Linheng Li Lab

Linheng Li, Ph.D.

Investigator

Co-leader, Cancer Biology
   The University of Kansas Cancer Center

Professor, Department of Pathology & Laboratory Medicine
   The University of Kansas School of Medicine

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A set of intriguingly titled children's books. That's what sparked Linheng Li's curiosity and started him on a quest for answers to formidable questions.

"When I was growing up, it wasn't like today, when kids can get on the Internet and search for information. But there was a series of books called Ten Thousand Unknown Questions that I really liked to read," says Li. "The books raised so many questions, but offered no answers. That got me thinking about mysteries and how to solve them."

Hematopoietic stem cell niche in the bone marrow.  The resident stem cell is shown in green and niche cells are shown in red. Image: Li lab.

Today, Li's curiosity and his drive to tackle tough problems are helping him unravel some of the most closely guarded secrets of stem cells.

Stem cells are a special class of cells that occur naturally in the body but have amazing qualities that set them apart from other cells. In biological terms, they themselves are "unspecialized," but they can develop into cells with specific functions, such as brain, blood or muscle cells. What's more, they can keep dividing and renewing themselves, which makes them handy for repairing injured tissue and replacing worn out or damaged cells. It's this capacity for repair and regeneration, coupled with their longevity, that makes stem cells potentially useful in medical applications that range from fixing facial deformities to mending diseased hearts to treating neurodegenerative diseases.

One obstacle to those marvelous possibilities is growing enough stem cells in the lab, through a process called expansion, for use in cell-based therapies. Embryonic stem cells, which are present in the body only during very early development, lend themselves well to expansion in the lab but carry the risk of forming tumors. Adult stem cells, which persist into adulthood and reside in specific tissues such as bone marrow, blood and brain, have a restricted capacity for self renewal making them less likely to form tumors but more difficult to expand in culture. Because both embryonic and adult stem cells have potential medical uses, being able to grow both types is desirable.

Li was intrigued by an observation of one type of adult stem cells, blood-forming cells. In the lab, they are characteristically stubborn, but in the body, they can rapidly expand under stressful situations such as extreme blood loss.

In the intestinal epithelium, stem cells reside in crypts. Image: Li lab.

"We wanted to know, why does this happen in the body, but not in the lab?" says Li. Could stem cells' surroundings—their "microenvironment" or "niche"—be the defining factor? Li's group explored this question by defining the hematopoietic (blood-forming) stem cell niche (the first mammalian stem cell niche to be identified at the cellular level). They found that signals from a molecular pathway called BMP control the size of the niche, which in turn controls stem cell expansion.

Subsequent work by Li's group and others identified additional signals that promote self-renewal, including Wnt and PI3K-Akt. Li and his team went on to use molecular mimics of some of those signals to successfully grow blood-forming stem cells they had isolated from mice. "Our next goal is to extend the study to see if we can expand human blood-forming cells," Li says.

Another surprising finding about blood-forming cells challenged the dominant dogma that all the stem cells in that particular pool are alike. Li's group discovered that there are actually two sub-populations of blood forming cells.

"One population is very active, to support blood production, but there's another small population that's normally not active because it's in a sleeping state," says Li. "When you have stresses, such as blood loss, this population can wake up and become active. You hear a lot of talk these days about the strategic oil reserve. Well, this is the same idea: a strategic stem cells reserve."

The finding has implications for cancer treatment, as there's evidence that tumors also contain active stem cells and a reservoir of quiescent backup cells. "This may explain why patients often respond to chemotherapy at first, but then the cancer comes back, and the tumor becomes resistant to treatment," Li says. "At first, you're killing the active, proliferating cells, but then the dormant ones wake up and undergo expansion. These quiescent cancer stem cells may be the reason for cancer relapse. In order to treat cancer effectively, we need to find ways of attacking both the active and the sleeping cells."