The Scientist 14[23]:20, Nov. 27, 2000
http://www.thescientist.com/yr2000/nov/research_001127.html
Heart
Goal: To replace cardiomyocytes that have died during heart attacks.
Several years ago, the lab of Loren J. Field, a professor of medicine and
pediatrics at Indiana University School of Medicine in Indianapolis,
derived relatively pure cardiomyocyte cultures from transfected mouse
ESCs.18 The cardiomyocytes weren't identical to their adult counterparts.
But according to Field, experimental data suggest that under appropriate
humoral and neuronal stimulation, a cardiomyocyte derived from ESCs
"will adapt the characteristics typical for the adult cell."
The number of heart muscle cells in a mouse is several orders of magnitude
lower than the number in a human. Now that his lab has refined its methods,
Field is optimistic that "with bio-processing and growth factors, we can
produce sufficient cells for therapeutic applications." To address the low
efficiency at which the cardiomyocytes seed into recipient hearts, he is
testing such strategies as blocking apoptosis, making the cells more
resistant to ischemia, and boosting their capacity to divide.
Geron Corp., based in Menlo Park, Calif., and a few academic labs have
already shown that cultured human ESCs can give rise to cardiomyocytes.
Meanwhile, the presence of ASCs in the heart itself still hasn't been proven.
"If they exist, they aren't doing their job," Field says, noting the heart's
limited capacity to heal after injury. Other researchers have reported
finding ASCs for cardiomyocytes in other parts of the body such as
the bone marrow, but no such claim has yet won wide acceptance.
Transdifferentiation
Researchers will have to understand transdifferentiation better before they
can deploy adult stem cells (ASCs) as broadly and effectively as possible.
Transdifferentiation is the phenomenon whereby a muscle ASC, say, can
give rise to a blood cell.
Margaret A. Goodell, who studies stem cells at Baylor College of Medicine's
Center for Cell & Gene Therapy, foresees that once biologists begin to
"rationalize" the recent spate of observations of this phenomenon,
"it won't turn out to be just this wild free-for-all where anything can
differentiate into anything." Rules discovered over the last 20 years,
she adds, "must have some meaning because otherwise you wouldn't
get the development of a very highly organized animal."
Richard C. Mulligan, a professor of genetics at Harvard Medical School,
has proposed alternative hypotheses that could help explain transdifferentiation.
One theory is that ASCs in various organs all originate from ASCs in bone
marrow; these ASCs then adopt organ-specific traits after being seeded in
local environments. The other theory is that ASCs arise independently in
various organs but share phenotypic and functional characteristics. Thus,
ASCs from one organ can generate mature cells of another organ because
the ASCs of both organs have a common origin and/or exhibit certain
common features.
In a 1999 Nature paper, a team headed by Mulligan and his Harvard colleague,
Louis M. Kunkel, reported that injecting muscle-derived ASCs into irradiated
mice led to reconstitution of the recipients' hematopoietic compartment.1
ASCs with this capability were designated muscle SP ("side population") cells.
Like hematopoietic SP cells, muscle SP cells resisted staining by a Hoechst dye.
The two SP cell types weren't identical, however.
In unpublished work since then, "we've marched from organ to organ and
tissue to tissue, looking for these SP cells in the heart, the liver, the kidney,
the CNS [central nervous system]," recalls Mulligan. "From each of these
tissues, it appears you can isolate a putative SP population that bears
many of the surface characteristics of both the bone-marrow and muscle
SP population." He contends that the sheer quantity of these cells means
they aren't blood contaminants. Mulligan's lab is now looking for the origin
of SP cells, the notion being that they might be recent offshoots of a
common bone-marrow ASC. The lab is also trying to define what's common
about their surface phenotypes. He hopes his work will guide decisions on
"the practical utility of bone-marrow SP versus organ SP cells for
transplantation purposes."
Another of Mulligan's new findings is that bone-marrow ASCs give rise
to endothelial cells only if the recipient is injured, for example, by an induced
heart attack or by receiving an organ transplant. His 1999 Nature paper
reported that bone-marrow ASCs generated muscle in a murine model of
Duchenne's muscular dystrophy, arguably a form of injury. As a result,
Mulligan is betting that injury is also a prerequisite for hematopoietic-to-muscle
transdifferentiation.
-- Douglas Steinberg
1. E. Gussoni et al., "Dystrophin expression in the mdx mouse restored by
stem cell transplantation," Nature, 401:390-4, 1999.
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