Intracellular calcium integrates complex signaling to control stem cell activity

December 02, 2015

Adult stem cells ensure continuous regeneration of tissues throughout our entire life. But the activity of these stem cells has to be carefully controlled in order to support regeneration without cancer. How this balanced control is achieved and maintained as the organism ages remains a critical question in stem cell biology. Publishing in Nature, researchers at the Buck Institute have identified a new mode of stem cell regulation. Working in the fly gut, senior scientist Heinrich Jasper, PhD, and colleagues show that stem cells adjust their proliferative activity in response to a wide variety of signals via intracellular calcium (Ca2+) signaling. Mechanisms that control the intracellular Ca2+ concentration and proteins that respond to intracellular Ca2+ changes thus emerge as master regulators of stem cell activity.

Adult stem cells in the gut exist in a very active environment, they are continually bombarded with signals - from diet, the microbiome, and from invading bacteria and other stressors. Should the cells spring into regenerative action and divide or remain poised for future needs? Jasper says a Ca2+ sensitive gene regulatory system integrates these stimuli to control intestinal proliferation by influencing the oscillation of Ca2+ levels within the cells.

"These findings help explain how stem cells are able to respond to such a wide range of stimuli," said Jasper, who is also the Chief Scientific Officer at the Buck Institute. "The fact that one variable - Ca2+ - is integrating all of these signals was quite an exciting and surprising discovery in stem cell biology with implications for our understanding of various cancers and a range of degenerative diseases."

Postdoctoral fellow Hansong Deng, PhD, determined the wide-ranging significance of Ca2+ signaling after discovering that intestinal stem cells have receptors that sense L-glutamate, and that dietary L-glutamate stimulated stem cell division and gut growth in the flies. Deng teamed up with Buck Research Professor Akos Gerencser, PhD, (co-director of the Institute's imaging core) who was able to image live stem cells in the fly gut. Surprisingly, they discovered that Ca2+ levels oscillate regularly in stem cells and that L-glutamate regulates stem cell activity by triggering a sustained increase of Ca2+ within the cell.

Research showed that this change in Ca2+ levels in stem cells was not limited to the response to L-glutamate, but was also observed when these cells became activated in response to other stimuli, including infection and tissue damage. In addition, the scientists found that elevating Ca2+ by genetically perturbing Ca2+ pumps in the stem cells resulted in a strong, continuous proliferative response.

A sustained elevated intracellular Ca2+ concentration thus emerged as a universal and required characteristic of activated stem cells, and Deng found that the activation of stem cells by Ca2+ was accomplished by Ca2+-sensitive protein phosphates and transcription factors. The researchers say this universal role of Ca2+ in stem cell activation suggests that these cells use the intracellular Ca2+ concentration as a gauge to respond dynamically to the multitude of signals vying for their attention.

Jasper says that in the future, his lab plans to explore the role of this regulatory system in influencing stem cell based diseases and age-related dysfunctions in the gut and other high-turnover tissues, adding that the work has important implications for how environmental challenges influence such diseases. L-glutamate, for example, is the most abundant naturally-occurring amino acid in the body and is involved in many metabolic processes. Dietary sources of L-glutamate include beef, chicken, fish and eggs. Its sodium salt is also known as the flavor enhancer MSG, which was fed to the flies in this study. Jasper says this study provides an interesting new angle to our understanding of the effects of the widely-used ingredient. "We've shown in the fly that supplementing a protein-restricted diet with MSG stimulates the proliferation of stem cells. Supplementing the same diet with high concentrations of MSG, on the other hand, impaired stem cell activity, indicating that at these high concentrations MSG may cause stem cell toxicity. Whether the effect of MSG on stem cell proliferation is a good or bad thing is another story," he said. "Supplementing the diet with low levels of MSG might just be supporting regeneration or it might be causing stem cells to proliferate too much, facilitating the development of gastrointestinal cancers. It's an open question that needs more study, especially in vertebrates."
Citation: Signal integration by Ca2+ regulates intestinal stem cell activity.
DOI: 10.1038/nature16170

This work was supported by the National Institute on Aging (R01 AG028127), the National Institute on General Medical Sciences (R01 GM100196), and by a Glenn Foundation for Medical Research postdoctoral fellowship to Hansong Deng.

About the Buck Institute for Research on Aging

The Buck Institute is the U.S.'s first independent research organization devoted to Geroscience - focused on the connection between normal aging and chronic disease. Based in Novato, CA, The Buck is dedicated to extending "Healthspan", the healthy years of human life and does so utilizing a unique interdisciplinary approach involving laboratories studying the mechanisms of aging and those focused on specific diseases. Buck scientists strive to discover new ways of detecting, preventing and treating age-related diseases such as Alzheimer's and Parkinson's, cancer, cardiovascular disease, macular degeneration, osteoporosis, diabetes and stroke. In their collaborative research, they are supported by the most recent developments in genomics, proteomics, bioinformatics and stem cell technologies. For more information:

Buck Institute for Research on Aging

Related Stem Cells Articles from Brightsurf:

SUTD researchers create heart cells from stem cells using 3D printing
SUTD researchers 3D printed a micro-scaled physical device to demonstrate a new level of control in the directed differentiation of stem cells, enhancing the production of cardiomyocytes.

More selective elimination of leukemia stem cells and blood stem cells
Hematopoietic stem cells from a healthy donor can help patients suffering from acute leukemia.

Computer simulations visualize how DNA is recognized to convert cells into stem cells
Researchers of the Hubrecht Institute (KNAW - The Netherlands) and the Max Planck Institute in Münster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells.

First events in stem cells becoming specialized cells needed for organ development
Cell biologists at the University of Toronto shed light on the very first step stem cells go through to turn into the specialized cells that make up organs.

Surprising research result: All immature cells can develop into stem cells
New sensational study conducted at the University of Copenhagen disproves traditional knowledge of stem cell development.

The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.

Healthy blood stem cells have as many DNA mutations as leukemic cells
Researchers from the Princess Máxima Center for Pediatric Oncology have shown that the number of mutations in healthy and leukemic blood stem cells does not differ.

New method grows brain cells from stem cells quickly and efficiently
Researchers at Lund University in Sweden have developed a faster method to generate functional brain cells, called astrocytes, from embryonic stem cells.

NUS researchers confine mature cells to turn them into stem cells
Recent research led by Professor G.V. Shivashankar of the Mechanobiology Institute at the National University of Singapore and the FIRC Institute of Molecular Oncology in Italy, has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification -- by confining them to a defined geometric space for an extended period of time.

Researchers develop a new method for turning skin cells into pluripotent stem cells
Researchers at the University of Helsinki, Finland, and Karolinska Institutet, Sweden, have for the first time succeeded in converting human skin cells into pluripotent stem cells by activating the cell's own genes.

Read More: Stem Cells News and Stem Cells Current Events 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