Marie Csete
Photo: D.C. Goings

Oxygen may be good for you, but it’s not so great for your stem cells — says Marie Csete, a cell biologist and anesthesiologist in the U-M Medical School. She maintains that too much oxygen can kill stem cells, slow growth and even trigger an alternate developmental pathway that converts pre-muscle stem cells into fat cells.

Csete began her career as an anesthesiology professor at the University of California-Los Angeles Medical School, where she taught medical students the critical importance of maintaining the correct amount of oxygen in body tissues during surgery. So when she took a sabbatical in 1996 at the California Institute of Technology to study molecular biology, it made sense to Csete that the proper amount of oxygen was just as important to stem cells as it was to her former patients.

“The more primitive the stem cell, the more sen-sitive it is to oxygen,” says Csete, who joined the U-M Medical School faculty in 2000. “The skeletal muscle satellite cells we study grow faster, live longer and develop into muscle cells more consistently when cultured with the amount of oxygen — between two percent and six percent — found in their natural environment inside the body,” she says. “In the body, stem cells never are exposed to the 20 percent levels of oxygen they encounter in a typical biomedical laboratory.”

During the five years she has been studying the effects of oxygen and other gases on stem cells, Csete has encountered more than her share of skeptics. “It was difficult initially to get people to even consider the idea that oxygen matters, because scientists have been culturing cells the same way for decades,” she says.

To control the oxygen exposure of her stem cell cultures, Csete works with them inside a large, custom-designed plastic box with an entry hatch. She programs the device to monitor and maintain a specific mixture of oxygen and other gases within the box.

Nicole Slawny Photo: Gregory Fox

Nicole Slawny, a graduate student in Csete’s laboratory, handles cell cultures using long gloves that fit through sealed entry holes in the side of the box — much like scientists working with radioactive isotopes. Slawny admits it’s a bit clumsy and time-consuming, but says the results are worth it. “When you see the difference in stem cells grown with low oxygen, you can’t deny it. Cultures that took one week to grow in the lab, grow here in two days. I’m a 100 percent believer now.”

In a recently published study, Csete showed that gene expression patterns changed significantly when stem cells were exposed to varying amounts of oxygen, and that these changes altered the basic biologic function of the cells.

Csete’s study focused on adult stem cells from mouse muscle tissue, which develop into muscle cells — providing a continuous source of new cells to replace those damaged during daily wear-and-tear. Under abnormal oxygen conditions, however, Csete discovered they can morph into fat precursor cells called adipocytes instead.

Csete suspects the abnormal behavior of stem cells grown with too much oxygen may mimic the reaction of aging cells exposed to free radicals and oxidative stress. The toxic effects of oxygen may not be limited to just one type of stem cell. In related experiments with Sean Morrison, Csete found that neural crest stem cells from adult mice have similar reactions to too much oxygen.

In the future, Csete hopes to tackle a new area of research — how stem cells regulate what she suspects is a feedback loop between a developing organ’s stem cells and its network of blood vessels. “This is the one area of developmental biology where people are aware of the importance of gases,” she says. “Vascular biologists know that blood vessels grow faster when oxygen levels are low, in order to increase the supply of blood and oxygen to cells in the developing organ system.

“No one has studied this before, because the stem-cell-to-organ developmental process is already so complicated, no one wants to tackle how the vascular system develops at the same time,” she says. “But some day, if I have enough time, I’d really like to know how it works.”

Also:

Unlocking the Secrets of Stem Cells

A Stem Cell Glossary