An update on stem cell research related to neuromuscular disease as of July 2009
Stem cells — immature cells with the potential to develop into different tissue types — have been heralded as a major advance for developing treatments for a variety of diseases. That’s true for diseases of the nerves and muscles, where such cells could potentially be transplanted into the body and either support or replace a patient’s ailing cells. Although most experts believe it will be a few years before stem cells are used for this purpose, they say another usage of stem cells already is bearing fruit: studying how a genetic disease evolves by watching it develop as the stem cell matures.
President Barack Obama announced March 9, 2009, that he will lift Bush-era restraints on federal funding for stem cell research involving human embryos. Although federally funded researchers may now move beyond the limited number of embryo-derived cell lines authorized for research under the Bush administration, restrictions remain, the details of which are as yet unclear. (Stem cell research funded by private companies and organizations in the United States has never been subject to these restraints.) Obama asked the National Institutes of Health to develop new guidelines within four months.
Although opening up federal funding for all types of stem cell development likely will speed research in the field, recent developments have shown that stem cells also can be developed from non-embryonic sources. It remains to be seen which types of cells will be best for specific applications.
Umbilical cord blood cells
Stem cells that are isolated from the umbilical cord blood of healthy babies then mixed in a lab dish with early-stage muscle cells (myoblasts) from people with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD), can fuse. The resulting early-stage muscle fibers can produce dystrophin, researchers in Brazil have found. (Dystrophin is the protein that’s missing or deficient in DMD and BMD.)
Mayana Zatz of the Human Genome Research Center in Sao Paulo, Brazil, and colleagues published their findings Jan. 14, 2009, in the Journal of Translational Medicine.
The researchers say these very immature (“undifferentiated”) umbilical cord stem cells, known as CD34-positive stem cells, are extremely flexible. They say the cells probably responded to chemical factors released by the dystrophic muscle cells that invited fusion and formation of muscle fibers.
This spring, MDA grantees Bradley Olwin at the University of Colorado-Boulder and Dawn Cornelison, now at the University of Missouri-Columbia, and colleagues, isolated a new type of skeletal-muscle stem cell in mice that appears to be particularly suited to repairing damaged muscle tissue.
The investigators, who published their findings March 6, 2009, in the journal Cell Stem Cell, say they believe these cells are the precursors of special muscle repair cells called “satellite cells.” Satellite cells reside near muscle fibers and move into them to compensate for damage when necessary.
The newly isolated cells are a subset of previously identified muscle precursors known as muscle SP (“side population”) cells, the researchers note. SP cells are “stemlike” in their ability to give rise to mature muscle fibers. However, in experiments in mice, relatively few of them have engrafted into existing muscle tissue after injection.
When Olwin and colleagues injected satellite SP cells into leg muscles in mice lacking dystrophin, they saw extensive muscle regeneration and replenishment of this protein.
“These cells are presumably poised to conduct repair operations when needed and can replenish the satellite cells as well as repair muscle,” Olwin said. He added that he’s encouraged at the large effect of one injection with a small number of cells.
Both Olwin and Cornelison have MDA support to continue working in this area.
Nerve cells derived from skin cells
Recently, skin cells from a child with spinal muscular atrophy (SMA) and from an 82-year-old woman with amyotrophic lateral sclerosis (ALS) have been “reprogrammed” back to a stemlike state and then coaxed to develop into SMA-affected or ALS-affected nerve cells. (See Research Updates, Spring 2009.)
This type of turning back the clock so that a mature cell can return to its stem cell origins and regain its ability to take a number of developmental paths is known as creating “induced pluripotent stem cells,” or iPS.
The technique has the advantage of not having to use human embryos to create this type of cell, as well as holding out the possibility of creating therapeutic cells from the cells of a patient, thus avoiding an unwanted immune response to donated cells.
So far, no one is sure of the extent to which iPS cells can actually become functioning specialized cells, such as motor neurons, the nerve cells affected in SMA and ALS. But scientists at the University of California-Los Angeles and the University of Rochester (N.Y.) say they’ve taken a step forward.
William Lowry and colleagues at UCLA, who published their findings online Feb. 23, 2009, in Stem Cells Express, say they’ve created fully functional human motor neurons from skin cells converted back to iPS cells. The motor neurons showed the typical electricity-like signaling functions of these nerve cells. In previous experiments, they say, these functions were not assessed.
New way of deriving nerve cells from stem cells
Researchers at the Burnham Institute for Medical Research in La Jolla, Calif., and the University of California at Los Angeles, say they’ve developed immature nerve cells that are flexible enough to become multiple nervous-system cell types but committed enough not to become other types of cells or form tumors.
Alexey Terskikh at the Burnham Institute, with colleagues there and at UCLA, used two different human embryonic stem cell lines previously approved by the National Institutes of Health to produce “committed neural precursor cells” using a procedure they developed. They say the technique was equally successful in both cell lines.
Their procedure for deriving the partially specialized cells is different from that of other research groups in that they omit a “priming step” in which cells are cultured in serum or serum replacement.
With this new method, the investigators say, the embryonic stem cells rapidly developed into committed neural progenitors, generally after 10 to 14 days in culture.
Unlike neural progenitor cells cultured using certain other conditions, Terskikh’s cells appear to have limited proliferation capacity (ability to divide) and instead mature into nerve cells and related cells called glia.
The researchers consider this a good sign, because too much cell division can lead to damaging over-proliferation of cells and even result in tumor formation. Tumors have been a concern when considering transplantation of embryo-derived cells into patients.
When the researchers transplanted these neural precursor cells into the brains of mice, they found they migrated to different parts of the brain and took on the characteristics of cells in their surroundings. Importantly, the transplanted human cells didn’t over proliferate or form tumors.
The investigators say they’ve described the molecular stages and pathways that normally occur as embryonic cells develop into nerve cells and have proposed genes that may play a role in the process but have not been previously recognized.
They say their cells can be best described as committed neural progenitor cells, which are on a path to becoming nerve cells but are still capable of becoming different types of nerve cells and don’t undergo dangerous proliferation or tumor formation.
Stem cells made from skin cells without help from viruses
Two scientific teams describe virus-free methods for “reprogramming” skin cells from mice and humans so that they become stem cells, with the potential to mature into multiple cell types. Until now, most methods for doing this have required the use of viruses.
Andras Nagy at the University of Toronto and colleagues, and Keisuke Kaji at the University of Edinburgh (United Kingdom) and colleagues, each described their work online March 1, 2009, in the journal Nature.
They say the new approach to cellular reprogramming is technically simpler than earlier methods and allows a range of cell types, not just those with limited susceptibility to viral infection, to be used to create stem cells. In addition, it allows the complete and accurate removal of genes inserted to accomplish the reprogramming.
Virus-free delivery of genes that reprogram cells, and an effective way to remove these genes after reprogramming has occurred, have the potential to provide stem cells that could be used to treat disease, as well as study disease development and screen potentially therapeutic compounds, the researchers say.