Stem Cells Derived from Adult Testes Produce Wide Range of Tissue
Types for Therapeutic Organ Regeneration
September 20, 2007
After a decade of research, Howard Hughes Medical Institute
scientists have succeeded in reprogramming adult stem cells from the
testes of male mice into functional blood vessels and contractile
cardiac tissue. The research offers a promising new source of stem
cells for use in organ regeneration studies.
Some scientists think that organ-specific adult stem cells may offer
the same therapeutic potential as embryonic stem cells, without the
ethical concerns or the risk of immune rejection that are associated
with embryonic stem cell therapies. However, adult stem cells may
lack the plasticity and pluripotency of embryonic stem cells'
capacity to generate any cell type. The study of adult stem cells has
also been limited by their relative scarcity in various organs and
the attendant difficulties in identifying and harvesting them, as
well as differentiating them in large quantities into functional
vascularized tissues.
"It appears that these specialized GPR125-positive spermatogonial
cells could be an easily obtained and manipulated source of stem
cells with a similar capability to form new tissues that we see in
embryonic stem cells."
Shahin Rafii
HHMI investigator Shahin Rafii and his colleagues at Weill Cornell
Medical College appear to have solved some of these problems in male
mice. Using spermatogonial progenitor cells obtained from the mouse's
testes, the researchers reprogrammed the cells to form multipotent
adult spermatogonial-
human cells, they say, adult stem cells may be a promising source of
new therapies for men, for diseases such as vascular diseases, heart
disease, Alzheimer's, Parkinson's, stroke, diabetes, and even cancer.
Scientists have had good success in deriving pluripotent stem cell
lines—those with the ability to develop into multiple cell types—from
adult testes cells. But only a small subset of cells from the testes
has the potential to become pluripotent, and until now, investigators
have lacked a means to identify and isolate them.
In a paper published in the September 20, 2007, issue of the journal
Nature, Rafii and colleagues at Weill Cornell Medical College and
Memorial Sloan-Kettering Cancer Center report that they have
identified a novel cell surface marker that is expressed on a unique
set of cells within adult testes known as the spermatogonial stem and
progenitor cells (SPCs). The marker, GPR125, enabled the scientists
to identify and harvest a large number of SPCs from adult mouse
testes, then propagate and reprogram them in the lab to become stem
cells that could differentiate into many cell types.
The researchers demonstrated that these multipotent adult
spermatogonial-
working blood vessel (endothelial) cells and tissue, as well as
contractile cardiac tissue, brain cells, and a host of other cell
types. They also injected MASCs from culture into mouse blastocysts—
embryonic cells—that they implanted in mature female mice. When the
blastocysts developed into mice, the researchers could see that the
MASCs had differentiated into many kinds of tissue. These data
suggested that the MASCs are truly multipotent: reprogrammable to
differentiate into functional tissues.
Ten years ago, Rafii observed that human testicular cancer cells
share many characteristics with adult stem cells. As an oncologist,
he also noticed that a large number of patients with testicular
cancer develop tumors called teratomas, which contain different types
of tissue. Based on these observations, he reasoned that
spermatogonia, whose sole function is to generate the precursors to
sperm, have the potential to readily give rise to pluripotent cells.
As such, he thought, they might prove more amenable to reprogramming
than other adult stem cells.
Using gene screening studies, Rafii and colleagues discovered a
potential specific surface marker on SPCs. Comparison of all cells in
the adult testis showed that this G-protein coupled receptor, known
as GPR125, was expressed on SPCs, but not other mature germ cells.
With GPR125 in hand, Rafii could isolate large numbers of SPCs from
adult mouse testes. They also established a highly sophisticated
culture system in which the progenitor cells rapidly grow and divide,
creating a large population of cells that can be converted into
MASCs.
"It appears that these specialized GPR125-positive spermatogonial
cells could be an easily obtained and manipulated source of stem
cells with a similar capability to form new tissues that we see in
embryonic stem cells," said Rafii. For male patients, he
believes, "It could someday mean a readily available source of stem
cells that gets around ethical issues linked to embryonic stem cells.
It also avoids issues linked to tissue transplant rejection, since
these autologous cells come from the patient's own body."
Rafii's team is currently pursuing a similar study of human testes to
determine whether stem cells derived from their spermatogonial
progenitor cells share the pluripotency of the mouse MASCs. "We
believe this to be an easily obtainable goal in the near future," he
said.
If they succeed, several steps remain before such stem cells could be
applicable to humans. "We still have to learn the exact biochemical
and epigenetic `switch' that tells GPR125-positive SPCs to convert
into MASCs," said Marco Seandel, a senior post-doctoral fellow in
Rafii's laboratory who is the first author of the Nature
paper. "Discovering that switch will be crucial to our being able to
create MASCs on demand,"
There is a chance that implanted cells derived from MASCs may trigger
cancer in the recipient. This is an area that requires further
investigation, Rafii said. However, he noted, "So far, we haven't
seen any cancer or evidence of pro-cancerous activity in adult mice
that are implanted with differentiated MASC cell tissue derivatives.
Rafii and his team have worked out the growing conditions that coax
spermatogonial progenitor cells to develop into MASC germ lines—
genetically stable stem cells that continue reproducing indefinitely.
Stem cell studies have been limited to date by the scarcity of germ
cell lines. "None of these GPR125-positive germ cell lines was
previously readily available for genetic, biochemical, and cellular
analysis by other laboratories,
with other researchers.
Rafii's lab is now investigating whether GPR125 can be used to
isolate cells from other adult tissues that can be converted into
multipotent stem cells. His group has also begun pursuing a similar
effort in ovaries. "It's much more difficult," he said. "However, it
is possible that reprogrammable stem cells with similar properties to
GPR125-positive SPCs may also exist, although at very low numbers, in
adult mouse or human ovaries." His lab is actively investigating this
intriguing possibility, Rafii said.
http://www.hhmi.
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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