Muscles In Muscular Dystrophy Animal Model Improved By Stem-cell Transplantation

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Muscles In Muscular Dystrophy Animal Model Improved By Stem-cell

Transplantation

http://www.medicalnewstoday.com/articles/94617.php

Using embryonic stem cells from mice, UT Southwestern Medical Center

researchers have prompted the growth of healthy - and more

importantly, functioning - muscle cells in mice afflicted with a

human model of Duchenne muscular dystrophy.

The study represents the first time transplanted embryonic stem

cells have been shown to restore function to defective muscles in a

model of muscular dystrophy.

The researchers' newly developed technique, which involves stringent

sorting to preserve all stem cells destined to become muscle, avoids

the risk of tumor formation while improving the overall muscle

strength and coordination of the mice, the researchers found.

The mice used in the study lacked dystrophin, the same protein that

humans with the fatal wasting disease also are missing.

The study, headed by Dr. Rita Perlingeiro, assistant professor of

developmental biology and molecular biology, is available online

today and in the February issue of Nature Medicine.

" We envision eventually developing a stem-cell therapy for humans

with muscular dystrophy, if we are able to successfully combine this

approach with the technology now available to make human embryonic

stem cells from reprogrammed skin cells, " Dr. Perlingeiro

said. " These cells can be transplanted into the muscle, and they

cause muscle regeneration resulting in stronger contractility. "

The study represents a major step in the field, she said, because

the researchers were able to tease out exactly the cells they

wanted.

" The problem had been that embryonic stem cells make everything, "

Dr. Perlingeiro said. " They make a great variety of cells. The trick

is to pull out only the one type you want. "

The UT Southwestern researchers focused on manipulating genes that

are active in the very early stages as embryonic stem cells start to

develop into more specialized cells. At first, they activated a gene

called Pax3, which is involved in creating muscle cells, and then

injected those cells into the animals' muscles. Those cells caused

tumors containing many different types of cells, indicating that

there were still residual undifferentiated embryonic stem cells in

the cultures at the time of implantation.

" Even if there are 10 undesirable cells, that's too many, " Dr.

Perlingeiro said.

The researchers then began using fluorescent dyes to sort cells

depending on whether some surface markers were turned on while

others were turned off. By analogy, it was as if they were dealing

with a crowd of people and wanted to pull out only those with red

hair, green scarves and blue coats, while those with red hair, green

scarves and no coats would be disqualified.

The final selection of cells, containing only one type, was again

injected into the animals' hind-limb muscles. After a month, the

fluorescent dyes showed that the cells had deeply penetrated the

muscle, an indication that they were growing and reproducing as

desired, and many of the muscle fibers also contained dystrophin,

the key protein lacking in muscular dystrophy.

After three months, the mice also showed no signs of tumors.

Tests of isolated muscles showed that the treated muscles were

significantly stronger than untreated mice lacking dystrophin,

although not quite as strong as those of normal mice.

The treated mice also were tested for coordination. Again, their

performance was better than that of untreated mice, but not as good

as that of normal mice.

" The improved coordination is significant because it shows the

embryonic stem cells have benefited the animal's quality of life,

not simply caused an isolated growth with no overall improvement, "

Dr. Perlingeiro said.

The researchers will next investigate whether these transplanted

cells can make " muscle stem cells, " which are partially developed

cells in muscle tissue that serve as a reserve to replenish muscles.

They also are testing their implantation approach in animal models

of other types of muscular dystrophy.