Powerful technique for multiplying
adult stem cells may aid therapies
CAMBRIDGE, Mass. (Jan. 23, 2006) — Adult stem
cells may be free of the ethical concerns that hamper
embryonic stem cell research, but they still pose formidable
scientific challenges. Chief among these is the doggedness
with which adult stem cells differentiate into mature
tissue the moment they're isolated from the body. This
makes it nearly impossible for researchers to multiply
them in the laboratory. And because adult stem cells
are so rare, that makes it difficult to use them for
treating disease.
Now, researchers in the lab of Whitehead Institute
Member and MIT professor of biology Harvey
Lodish have discovered a way to multiply an adult
stem cell 30-fold, an expansion that offers tremendous
promise for treatments such as bone marrow transplants
and perhaps even gene therapy.
"A 30-fold increase is ten times higher than anyone's
achieved before," says Lodish, senior author on
the paper, which will be published January 22 online
in Nature Medicine.
Unlike embryonic stem cells, adult stem cells are generally
tissue-specific, destined to develop into the kind of
tissue from which they originate. Chengcheng Zhang,
a postdoctoral researcher in the Lodish lab, was determined
to develop a way to multiply adult stem cells once they've
been isolated from tissue. Achieving this goal required
some intricate laboratory sleuthing.
Zhang began by studying adult hematopoietic, or blood
forming, stem cells—cells that give rise to both
oxygen-carrying red blood cells and the white blood
cells that comprise the immune system. Offspring of
some of these cells develop into all of the red and
white blood cells, while others form the immune system.
Using fetal tissue from mice as the source of these
cells, Zhang discovered a population of cells that were
not stem cells, yet appeared to interact with stem cells,
preserving and allowing them to multiply in the fetal
environment. When he isolated the stem cells in the
lab and cultured them in a dish by themselves, they
died. When he mixed them with these newly discovered
cells, they thrived. But how did these new cells manage
to sustain the stem cells so dramatically?
Zhang used a microarray platform to search for genes
that were active in these newly discovered cells, but
not active in similar neighboring cells. Some such genes,
he reasoned, might encode secreted proteins that sustained
stem cells. Eventually, he located a number of such
genes.
In the fall of 2003 and early 2005, Zhang reported
in the journal Blood how one of these genes
codes for a growth factor protein called IGF-2. When
Zhang purified IGF-2 and added it in a solution to hematopoietic
stem cells that he had isolated, the stem cells increased
eight-fold in number.
Zhang then discovered that two more growth factor proteins,
Angiopoietin-like 2 and 3, abbreviated as angpt12 and
angpt13, were also abundantly expressed in these stem-cell
supporting cells. When Zhang combined these two proteins
with IGF-2 and added them to hematopoietic stem cells,
the result was a 30-fold increase.
"People have been culturing and working with these
cells for years, and never before have we seen such
an increase," says Zhang.
A 30-fold expansion, if replicated in human cells, could
open up a number of doors for researchers working on
adult stem cells. Currently, patients with certain blood
diseases are treated with stem cells. These stem cells
can be acquired either from a donor's bone marrow, or
even from cord blood (donated cord blood, or the patient's
own). Still, in both these cases, the actual number
of stem cells from a donor often falls short of the
number needed to adequately treat the patient. This
technique could directly address this problem.
Gene therapy is another area where these findings can
be of immediate value, Lodish says.
With gene therapy, a genetic defect is corrected by
administering a healthy version of the gene into a patient.
For example, a physician isolates hematopoietic stem
cells from a patient, introduces a harmless virus into
them that expresses a correct version of the mutated
gene, and then re-administers the stem cells back into
the patients. While many clinical trials have succeeded,
some ended tragically when the virus ended up activating
a cancer-causing gene. Because of this, the Food and
Drug Administration is not currently approving any gene-therapy
clinical trials.
"If, before the stem cells have been re-introduced
into the patients, the physicians could first multiply
them in the lab, they could then run assays determining
if the virus has landed in any undesirable places,"
says Lodish. "They could then discard those bad
cells, and only administer the good ones to the patients."
But most importantly, these findings aid basic research.
"We want to know all sorts of things, like what
genes are active in this stem cell, or how this stem
cell decides to develop into one kind of cell as opposed
to another," says Lodish.
Lodish and his colleagues are collaborating with researchers
at Lund University in Sweden to repeat these results
with human cord blood.
This research was funded by the National Institutes
of Health and the National Science Foundation.
|
