Mapping replacement of dead cells in the intestine uncovers critical stem cell pool

Aug 14, 2013
Cancer biology: In search of stem cell origins
Normally quiescent Bmi1-positive intestinal stem cells (ISCs) (left) undergo increased division in the event of drug-induced cell death (right). Blue staining indicates successful lineage tracing of new cells arising from ISC proliferation and maturation. Credit: 2013 Elsevier

Stem cells play a critical role in replacing various cells within the intestine, but can also become drivers for colorectal cancer. The composition of these stem cell reservoirs has been debated. New research from Dmitry Bulavin of the A*STAR Institute of Molecular and Cell Biology has now clarified the organization of this tissue, yielding insights that should steer future cancer research.

Bulavin and co-workers had previously identified a population of '+4' cells—denoting their position within the —that appeared to contain intestinal (ISCs)2. They determined that activation of certain oncogenes rapidly kills these cells via a mechanism called apoptosis, a critical safeguard against cancerous growth. Accordingly, mice with a genetic mutation that increased the apoptotic response of these cells were also protected against intestinal tumors. However, subsequent findings from another team identified a different pool of putative ISCs, identifiable by their expression of the marker gene Lgr5.

"We could not explain the tumor-resistant phenotype of our mice using this new model," says Bulavin. "This motivated further analysis of different stem in the intestine." His team employed a technique called 'lineage tracing', which enables selective labeling of cells expressing a marker gene of interest with a fluorescent protein. Descendants of these cells become similarly labeled, allowing researchers to track the point of origin for cell populations or tissues of interest. Bulavin and co-workers then used radiation or chemical trauma to induce apoptosis, and examined the response of different cell populations to identify likely ISCs.

Their experiments revealed that a pool of +4 cells, identifiable by expression of the cellular Bmi1, appear to represent true ISCs. These cells are normally dormant, but sporadically replicate to replace lost to normal wear and tear (see image). They can also be rallied to repair more severe damage. "Massive cell death is a very powerful factor in the stimulation of these +4 ISCs," says Bulavin. "They exit quiescence and enter a proliferative state after high doses of irradiation." The previously identified pool of Lgr5-expressing cells in turn appears to consist of progenitor cells, which develop into ISCs only when Bmi1-positive ISCs are depleted.

Armed with some initial insights into how improper regulation of apoptosis affects these various cell populations, Bulavin's team is now working to understand their relevance in cancer. "We want to see how apoptosis affects the development of polyps when oncogenic mutations occur in different cellular compartments in the mouse intestine," he says.

Explore further: Tracking nanodiamond-tagged stem cells

More information: Zhu, Y., Huang, Y.-F., Kek, C. & Bulavin, D. V. Apoptosis differently affects lineage tracing of Lgr5 and Bmi1 intestinal stem cell populations. Cell Stem Cell 12, 298–303 (2013). dx.doi.org/10.1016/j.stem.2013.01.003

Demidov, O. et al. Wip1 phosphatase regulates p53-dependent apoptosis of stem cells and tumorigenesis in the mouse intestine. Cell Stem Cell 1, 180–190 (2007). www.sciencedirect.com/science/article/pii/S1934590907000641

add to favorites email to friend print save as pdf

Related Stories

Tracking nanodiamond-tagged stem cells

Aug 05, 2013

A method that is used to track the fate of a single stem cell within mouse lung tissue is reported in a study published online this week in Nature Nanotechnology. The method may offer insights into the factors that determ ...

Researchers identify elusive taste stem cells

Feb 04, 2013

Scientists at the Monell Center have identified the location and certain genetic characteristics of taste stem cells on the tongue. The findings will facilitate techniques to grow and manipulate new functional taste cells ...

Recommended for you

Ocean microbes display remarkable genetic diversity

15 hours ago

The smallest, most abundant marine microbe, Prochlorococcus, is a photosynthetic bacteria species essential to the marine ecosystem. An estimated billion billion billion of the single-cell creatures live i ...

Cell resiliency surprises scientists

16 hours ago

New research shows that cells are more resilient in taking care of their DNA than scientists originally thought. Even when missing critical components, cells can adapt and make copies of their DNA in an alternative ...

Cell division speed influences gene architecture

Apr 23, 2014

Speed-reading is a technique used to read quickly. It involves visual searching for clues to meaning and skipping non-essential words and/ or sentences. Similarly to humans, biological systems are sometimes ...

User comments : 0

More news stories

Genetic legacy of rare dwarf trees is widespread

Researchers from Queen Mary University of London have found genetic evidence that one of Britain's native tree species, the dwarf birch found in the Scottish Highlands, was once common in England.

Ocean microbes display remarkable genetic diversity

The smallest, most abundant marine microbe, Prochlorococcus, is a photosynthetic bacteria species essential to the marine ecosystem. An estimated billion billion billion of the single-cell creatures live i ...

Genetic code of the deadly tsetse fly unraveled

Mining the genome of the disease-transmitting tsetse fly, researchers have revealed the genetic adaptions that allow it to have such unique biology and transmit disease to both humans and animals.

Cell resiliency surprises scientists

New research shows that cells are more resilient in taking care of their DNA than scientists originally thought. Even when missing critical components, cells can adapt and make copies of their DNA in an alternative ...

Google+ boss leaving the company

The executive credited with bringing the Google+ social network to life is leaving the Internet colossus after playing a key role there for nearly eight years.