Johns Hopkins scientists have developed a reliable method to turn the
clock back on blood cells, restoring them to a primitive stem cell state from
which they can then develop into any other type of cell in the body.
The work, described in the Aug. 8
issue of the journal Public Library of Science (PLoS), is "Chapter
Two" in an ongoing effort to efficiently and consistently convert adult
blood cells into stem cells that are highly qualified for clinical and research
use in place of human embryonic stem cells, says Elias Zambidis, M.D., Ph.D.,
assistant professor of oncology and pediatrics at the Johns Hopkins Institute
for Cell Engineering and the Kimmel Cancer Center.
"Taking a cell from an adult
and converting it all the way back to the way it was when that person was a
6-day-old embryo creates a completely new biology toward our understanding of
how cells age and what happens when things go wrong, as in cancer
development," Zambidis says.
"Chapter One," Zambidis
says, was work described last spring in PLoS One in which Zambidis and colleagues
recounted the use of this successful method of safely transforming adult blood
cells into heart cells. In the latest experiments, he and his colleagues now
describe methods for coaxing adult blood cells to become so-called
induced-pluripotent stem cells (iPS) --- adult cells reprogrammed to an
embryonic like state, and with unprecedented efficiencies.
Zambidis says his team has
managed to develop a "super-efficient, virus-free" way to make iPS
cells, overcoming a persistent difficulty for scientists working with these
cells in the laboratory. Generally, out of hundreds of blood cells, only one or
two might turn into iPS cells. Using Zambidis' method, 50 to 60 percent of
blood cells were engineered into iPS cells. Zambidis' team also found a way around
the use of viruses to convert the cells to a stem cell state. Traditionally,
scientists use viruses to deliver a package of genes to cells to turn on
processes that convert the cells from one type (such as skin or blood) back to
stem cell states. However, viruses used in this way can mutate genes and
initiate cancers in newly transformed cells. To insert the genes without using
a virus, Zambidis' team uses plasmids, rings of DNA that replicate briefly
inside cells and then degrade. The blood cells were also given an additional
new step in which they were stimulated with their natural bone-marrow
environment.
For the new study, the Johns
Hopkins team took cord blood cells, treated them with growth factors, and used
plasmids to transfer four genes into them. They then delivered an electrical
pulse to the cells, making tiny holes in the surface through which the plasmids
could slip inside. Once inside, the plasmids triggered the cells to revert to a
more primitive cell state. The scientific team next grew some of the treated
cells in a dish alone, and some together with irradiated bone-marrow cells.
When scientists compared the
cells grown using the blood cell method with iPS cells grown from hair cells
and from skin cells, they found that the most superior iPS cells came from
blood stem cells treated with just four genes and cultured with the bone marrow
cells. These cells converted to a primitive stem cell state within seven to 14
days. Their techniques also were successful in experiments with blood cells
from adult bone marrow and from circulating blood.
In ongoing studies, Zambidis and
colleagues are testing the quality of the newly formed iPS cells and their
ability to convert to other cell types, as compared with iPS cells made by
other methods.
Efficient methods to produce
virus-free iPS cells may speed research to develop stem cell therapies, using
nearly all cell types, and may provide a more accurate picture of cell
development and biology.
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