Altered Cellular Pathway Found to Control Stem Cell Fate

A new study led by researchers at Cedars-Sinai and the University of California, San Francisco (UCSF) has found that altering a specific cellular process can lead to the death or regeneration of stem cells. The findings, published in the journal Cell Stem Cell, may assist in developing new drugs that can manipulate this process to slow or stop cancer from growing and spreading, as well as enable regeneration in the context of other diseases.

Ophir Klein, MD, PhD, executive director of Cedars-Sinai Guerin Children's and the study's senior author, said the findings underscore the body's need to produce just the right amount of new cells. "It's like a Goldilocks situation with cell production," explains Klein. "If you have too much cell division, you end up with tumors. If you have too little, you have poor replacement of old cells."

Various biological pathways regulate the body's cells, typically by creating new molecules or proteins. For this study, investigators at Cedars-Sinai and UCSF observed the effects of a gene called Discs large 1 (Dlg1) on the Wnt signaling pathway. This pathway involves a series of molecular interactions that regulate the growth or death of stem cells.

Although the Wnt pathway has been studied extensively, much is still unknown about how incremental alterations in the frequency of communication signals through the system may affect cell generation. "The signals or instructions can vary over time and under different conditions of health and disease," says Klein, the David and Meredith Kaplan Distinguished Chair in Children's Health.

To investigate the effects of Dlg1 on the Wnt signaling pathway, the researchers studied intestinal tissue samples from laboratory mice. By performing gene expression analysis on the samples, the team looked for changes in genes that typically send signals along the Wnt pathway. Through this process, investigators were able to see how changes in signaling frequency affected the creation of stem cells.

The investigators found that when they inhibited the expression of Dlg1 and then increased signaling along the Wnt pathway by adding a specific molecule, such as a virus or drug, the stem cells died rather than generating new daughter cells.

"By better understanding cell signaling, we can learn how to use a molecule to speed up or slow down this pathway and normalize signaling so that a given organ has the right number of cells," says David Castillo-Azofeifa, PhD, co-first author of the study, originally a postdoctoral fellow in Klein's lab and now a principal scientist at Genentech, Inc.