A Setback for
Stem Cell Therapy?
Evan David Rosen, M.D., Ph.D.
Assistant Professor of Medicine,
Harvard Medical School
Beta-cell
replacement in diabetes is a red hot area of research, and no
approach is getting more attention than stem cell therapy. Currently,
islet transplantation from human donors is the only available
option for curative therapy of type 1 diabetes, but limitations
on transplant survival and the number of donor pancreata prevent
this technique from being widely adopted. Gene therapy is very
cool, and might ultimately be the way things are done, but the
process is simply not technically feasible yet. Stem cells provide
(in theory at least) a renewable pool of material that can be
differentiated into insulin-secreting cells in culture and then
implanted into diabetic recipients. While the technology is
not yet ready-for-prime-time, there have been a series of exciting
advances that have held out the promise that real people will
benefit from stem cells in the not so distant future.
A new study, however, has given
stem cell researchers something to chew on, and may indicate
that we are not quite as far along as we had thought.
First, however, a little background.
Several groups around the world have presented evidence that
human and rodent stem cells can be tweaked and prodded using
a variety of cell culture conditions to turn into beta-cells.
These stem cells have been derived from both embryonic and adult
tissues, and from liver cells in addition to pancreas. Bone
marrow is another possible source of cells that is being investigated.
There is extra excitement surrounding the use of adult tissues
as a source of stem cells, because of the ongoing ethical and
political debate concerning the use of embryonic tissue in this
country.
Each of the half dozen or so
published studies has used different criteria to support their
claims, but all of them have shown that the cells can be made
to stain positive for insulin, which is of course the hallmark
of a beta-cell. Some authors have gone farther, and have shown
that implantation of their cells into mice with type 1 diabetes
rescues blood sugar levels to normal.
In the new study, a different
group of researchers tried to copy the protocol used by another
successful group, using embryonic stem cells from mice and humans.
Like the first group, they were able to show that 10-30% of
the cells in the dish stained positive with an antibody to insulin.
However, the second group did some additional control experiments,
such as expressing a marker gene from the stretch of DNA that
normally directs insulin expression in beta-cells. If the stem
cells were truly turning into beta-cells, then the marker gene
would turn on as well (in this case, turning the cells blue
when a special stain is added). To their surprise, only one
in every 100,000 cells turned blue.
So why did so many cells stain
positive for insulin? Cells are grown in nutrients which include
serum from cattle; this serum contains growth factors, including
insulin, that help cells to survive in a dish. The stem cells,
it appears, were merely collecting and storing the insulin from
the serum, rather than producing it themselves. To add to the
ruse, the cells are capable of releasing this stored insulin
slowly over time. Theoretically at least, transplantation of
these cells could thus “cure” diabetes in mice,
as some groups have shown.
The new findings point to the
need for strict and uniform criteria for deciding when beta-cell
differentiation has been achieved. At a minimum, investigators
will now need to show that cells are producing their own insulin,
and releasing it in response to normal stimuli like glucose.
Transplantation experiments will also have to be prolonged for
more than a month to show that any reduction in blood sugar
in diabetic mice can be sustained.
Ultimately, stem cells may still
be our best bet for beta-cell replacement. Even the authors
of the new study remain optimistic about the long-term chances
for success; it’s just going to take a little longer to
get there than everyone hoped.
To review the original article
Potential Problem with Using Embryonic Stem Cells to Cure Diabetes.
Go to http://www.diabetesincontrol.com/features/i140.shtml
References:
1. Jayaraj Rajagopal, William
J. Anderson, Shoen Kume, Olga I. Martinez, and Douglas A. Melton.
Insulin Staining of ES Cell Progeny from Insulin Uptake. Science
Jan 17 2003: 363.
2. Andreas Lechner and Joel F.
Habener. Stem/progenitor cells derived from adult tissues: potential
for the treatment of diabetes mellitus. American Journal of
Physiology – Endocrinology & Metabolism 284: E259-E266,
2003. 10.1152/ajpendo.00393.2002
Written by Evan D. Rosen, M.D.,
Ph.D.
Content created 2/6/03
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