Low oxygen boosts stem cell survival in muscular dystrophy therapy

August 21, 2012
An image of a muscle implanted shows pre-existing muscle fibers (green cells only), along with fibers created by transplanted stem cells (green fiber with red membrane). Blue areas represent cells' nuclei. (Purdue University image/Weiyi Liu and Shihuan Kuang)

(Medical Xpress) -- Controlling the amount of oxygen that stem cells are exposed to can significantly increase the effectiveness of a procedure meant to combat an often fatal form of muscular dystrophy, according to Purdue University research.

A genetic mutation in patients with Duchenne muscular dystrophy causes the constant breakdown of muscles and gradual depletion of stem cells that are responsible for repairing the damage and progressive muscle wasting. A healthy stem cell tends to duplicate in a regular pattern that creates one copy of itself that continues to function as a stem cell, and a differentiated cell, which performs a specific function. In a healthy person, a torn or damaged muscle would be repaired through this process.

Stem cell therapy - implanting healthy stem cells to combat tissue wasting - has shown promise against muscular dystrophy and other , but few of the implanted stem cells survive the procedure. Shihuan Kuang, a Purdue assistant professor of animal sciences, and Weiyi Liu, a postdoctoral research associate, showed that survival of implanted muscle stem cells could be increased by as much as fivefold in a mouse model if the cells are cultured under similar to those found in .

"Stem cells survive in a microenvironment in the body that has a low oxygen level," Kuang said. "But when we , there is a lot of oxygen around the . We wanted to see if less oxygen could mimic that . When we did that, we saw that more stem cells survived the transplant."

Liu thinks that's because the stem cells grown in higher oxygen levels acclimate to their surroundings. When they're injected into muscles with lower oxygen levels, they essentially suffocate.

"By contrast, in our study the cells become used to the host environment when they are conditioned under low oxygen levels prior to transplantation," Liu said.

In the mouse model, Kuang and Liu saw more stem cells survive the transplants, and those stem cells retained their ability to duplicate themselves.

"When we lower the oxygen level, we can also maintain the self-renewal process," Kuang said. "If these stem cells self-renew, they should never be used up and should continue to repair damaged muscle."

The findings, reported in the journal Development, shows promise for increasing the effectiveness of for patients with Duchenne muscular dystrophy, which affects about one in 3,500 boys starting at about 3-5 years old. The disease, which confines almost all patients to wheelchairs by their 20s, is often fatal as muscles that control the abilities to breathe and eat deteriorate.

Xiaoqi Liu, a Purdue associate professor of biochemistry, and several graduate students contributed to the study.

Kuang's research will now focus on the signaling pathways within stem cells to understand how oxygen levels affect their functions and examining whether human muscle are similarly regulated by environmental oxygen. The National Institutes of Health, the Muscular Dystrophy Association and the U.S. Department of Agriculture funded the research.

Explore further: Stem cell foundation for muscular dystrophy treatment

More information: Hypoxia Promotes Satellite Cell Self-renewal and Enhances the Efficiency of Myoblast Transplantation, Development.

ABSTRACT
Microenvironmental oxygen (O2) regulates stem cell activity, and a hypoxic niche with low oxygen levels has been reported in multiple stem cell types. Satellite cells are muscle-resident stem cells that maintain the homeostasis and mediate the regeneration of skeletal muscles. We demonstrate here that hypoxic culture conditions favor the quiescence of satellite cell-derived primary myoblasts by upregulating Pax7, a key regulator of satellite cell self-renewal, and downregulating MyoD and myogenin. During myoblast division, hypoxia promotes asymmetric self-renewal divisions and inhibits asymmetric differentiation divisions without affecting the overall rate of proliferation. Mechanistic studies reveal that hypoxia activates the Notch signaling pathway, which subsequently represses the expression of miR-1 and miR-206 through canonical Hes/Hey proteins, leading to increased levels of Pax7. More importantly, hypoxia conditioning enhances the efficiency of myoblast transplantation and the self-renewal of implanted cells. Given the robust effects of hypoxia on maintaining the quiescence and promoting the self-renewal of cultured myoblasts, we predict that oxygen levels in the satellite cell niche play a central role in precisely balancing quiescence versus activation, and self-renewal versus differentiation, in muscle stem cells in vivo.

Related Stories

Stem cell foundation for muscular dystrophy treatment

July 14, 2011
Research at the Australian Regenerative Medicine Institute (ARMI) at Monash University could lay the groundwork for new muscular dystrophy treatments.

Successful transplant of patient-derived stem cells into mice with muscular dystrophy

June 27, 2012
Stem cells from patients with a rare form of muscular dystrophy have been successfully transplanted into mice affected by the same form of dystrophy, according to a new study published today in Science Translational Medicine.

Adult stem cells use special pathways to repair damaged muscle (w/ Video)

December 1, 2011
When a muscle is damaged, dormant adult stem cells called satellite cells are signaled to "wake up" and contribute to repairing the muscle. University of Missouri researchers recently found how even distant satellite cells ...

Recommended for you

Engineered protein treatment found to reduce obesity in mice, rats and primates

October 19, 2017
(Medical Xpress)—A team of researchers with pharmaceutical company Amgen Inc. report that an engineered version of a protein naturally found in the body caused test mice, rats and cynomolgus monkeys to lose weight. In their ...

New procedure enables cultivation of human brain sections in the petri dish

October 19, 2017
Researchers at the University of Tübingen have become the first to keep human brain tissue alive outside the body for several weeks. The researchers, headed by Dr. Niklas Schwarz, Dr. Henner Koch and Dr. Thomas Wuttke at ...

Cancer drug found to offer promising results in treating sepsis in test mice

October 19, 2017
(Medical Xpress)—A combined team of researchers from China and the U.S. has found that a drug commonly used to treat lung cancer in humans offers a degree of protection against sepsis in test mice. In their paper published ...

Tracing cell death pathway points to drug targets for brain damage, kidney injury, asthma

October 19, 2017
University of Pittsburgh scientists are unlocking the complexities of a recently discovered cell death process that plays a key role in health and disease, and new findings link their discovery to asthma, kidney injury and ...

Study reveals key molecular link in major cell growth pathway

October 19, 2017
A team of scientists led by Whitehead Institute has uncovered a surprising molecular link that connects how cells regulate growth with how they sense and make available the nutrients required for growth. Their work, which ...

Inflammation trains the skin to heal faster

October 18, 2017
Scars may fade, but the skin remembers. New research from The Rockefeller University reveals that wounds or other harmful, inflammation-provoking experiences impart long-lasting memories to stem cells residing in the skin, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.