Stem Cell Research

Muscular Dystrophy Shown Definitively To Be Stem Cell Based Disorder

For years, scientists have tried to understand why children with Duchenne muscular dystrophy experience severe muscle wasting and eventual death. After all, laboratory mice with the same mutation that causes the disease in humans display only a slight weakness. Now a new animal model of the disease points a finger squarely at the inability of human muscle stem cells to keep up with the ongoing damage caused by the disorder.

There are at least nine types of muscular dystrophy, the most well known of which is Duchenne's. Each causes a pattern of weakness and disability and is inherited. Weakness and disability are most severe in Duchenne's.

“Patients with muscular dystrophy experience chronic muscle damage, which initiates a never-ending cycle of repair and wasting,” said Helen Blau, PhD, Donald E. and Delia B. Baxter Professor at the Stanford School of Medicine and member of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine. “We found that in mice the muscle stem cells can keep up with the demands on them to cycle.”

Duchenne muscular dystrophy is the most prevalent form of the muscular dystrophies. It is caused by a mutation in the dystrophin gene, which connects the interior cytoskeleton of the muscle fiber to the extracellular matrix. Its absence leads to death of the muscle tissue and progressive weakness, which eventually affects a patient’s ability to breathe; 10-year-olds are often wheelchair-bound. Death usually occurs by the second or third decade as a result of respiratory and heart problems. The disorder affects about one of every 3,500 boys in the United States, whereas girls are generally spared because the gene lies on the X chromosome.

Stem Cell Transplants in Mice Produce Lifelong Enhancement of Muscle Mass

New research has shown that when young host mice with limb muscle injuries were injected with muscle stem cells from young donor mice, the cells not only repaired the injury within days, they caused the treated muscle to double in mass and sustain itself through the lifetime of the transplanted mice.

Muscle stem cells are found within populations of "satellite" cells located between muscle fibers and surrounding connective tissue and are responsible for the repair and maintenance of skeletal muscles, said Olwin. The researchers transplanted between 10 and 50 stem cells along with attached myofibers -- which are individual skeletal muscle cells -- from the donor mice into the host mice.

"We found that the transplanted stem cells are permanently altered and reduce the aging of the transplanted muscle, maintaining strength and mass," said Professor Bradley Olwin of Colorado University at Boulder's molecular, cellular and developmental biology department. Other researchers on the team included John K. Hall of the University of Washington Medical School in Seattle, as well as Glen Banks and Jeffrey Chamberlain of the University of Washington Medical School.

New Means Of Growing Adult Stem Cells In Culture Found

Researchers have found that growing muscle stem cells on a specially developed synthetic matrix that mimics the elasticity of real muscle allows the adult stem cells to maintain their self-renewing properties.

Adult stem cells already exist in the body. They are important in regenerating tissues like blood, muscles and neurons in the brain. But scientists have struggled to produce them in quantities needed for therapies because the cells differentiate and lose their “stemness” as soon as they’re placed in a tissue culture dish.

Now, researchers at Stanford University have found a new method of growing the cells that will allow the behavior of many types of adult stem cells to be studied in culture. 

“Cells don’t normally exist in contact with a rigid cell culture dish,” said Helen Blau, PhD, Professor and member of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine. “They sit on soft tissue. By mimicking this environment we can really influence their function and allow them to self-renew in ways we’ve never been able to achieve before.”

Self-renewal, or the ability to become both another stem cell and a differentiating daughter cell, is a defining trait of stem cells. This ability is necessary for a small number of cells to, for example, fully reconstitute the pantheon of blood cell types necessary to regenerate a patient’s immune system after chemotherapy or to successfully contribute to the long-term generation of new, healthy muscle tissue. Until now, however, all attempts to grow these and some other adult stem cells, like blood stem cells, in culture have resulted in the cells differentiating into more specialized — but less therapeutically useful — progenitor cells. This differentiation constitutes a major obstacle to treating muscle-wasting diseases, for using cord blood or for treating blood cancers.

The researchers wondered if the way the cells are normally grown in culture could be the problem. After all, as Blau pointed out, cells are used to rubbing shoulders comfortably with their neighbors on all sides rather than being splayed out and anchored on a rigid plastic culture dish that is 100,000-fold less elastic than true muscle.

Stem Cells Treat Muscular Dystrophy In Mice

Skeletal muscle precursor cells are adult stem cells located among muscle fibers. Proliferation, migration, and subsequent differentiation of these cells are critical steps in the repair of muscle injury.

In the Harvard/Joslin Diabetes Center study, healthy stem cells were transplanted into the muscles of the mice with muscular dystrophy.  Results show that the healthy stem cells provide an effective source of immediately available muscle regenerative cells as well as a reserve pool that can maintain muscle regenerative activity in response to future challenges.

“This work demonstrates, in concept, that stem cell therapy could be beneficial for degenerative muscle diseases," said Amy Wagers, member of the HSCI Principal Faculty and an assistant professor in Harvard's new Department of Stem Cell and Regenerative Biology.

Muscular Dystrophy: Stem Cell Research Takes Early Step Toward Treatment

 "A new way to manipulate embryonic stem cells (ESCs) offers hope for an eventual cell-based therapy to treat muscular dystrophies."  All muscle cells have a similar embryonic origin.  MD is caused by a loss of Dystrophin, a first team protein in muscle cells that loses the ability to do its job when a certain genetic mutation exists.  An inability to grow new muscle is the result.  Replacing defective cells with embryonic cells might solve the problem. But previous attempts to do this have resulted in too few new muscle cells being created within an acceptable time frame.