MEGA CELLS CONTROL GROWTH OF BLOOD PRODUCING CELLS
While megakaryocytes
are best known for producing platelets that heal wounds, these "mega"
cells found in bone marrow also play a critical role in regulating stem cells
according to new research from the Stowers Institute for Medical Research. In
fact, hematopoietic stem cells differentiate to generate megakaryocytes in bone
marrow. The Stowers study is the first to show that hematopoietic stem cells
(the parent cells) can be directly controlled by their own progeny
(megakaryocytes).
The findings from
the lab of Stowers Investigator Linheng Li, Ph.D., described in the Oct. 19
issue of the journal Nature Medicine, could
cause researchers to rethink what they know about the workings of
megakaryocytes and potentially lead to new treatments for patients recovering
from chemotherapy or organ transplantation.
"Our results
suggest that megakaryocytes might be used clinically to facilitate adult stem
cell regeneration and to expand cultured cells for adult stem cell
transplants," says Meng Zhao, Ph.D., a postdoctoral fellow at Stowers and
lead author on the study. Stowers researchers discovered that megakaryocytes directly
regulate the function of murine hematopoietic stem cells -- adult stem cells
that form blood and immune cells and that constantly renew the body's blood
supply. These cells can also develop into all types of blood cells, including
white blood cells, red blood cells, and platelets.
Because of their
remarkable ability to renew themselves and differentiate into other cells,
hematopoietic stems cells are the focus of intense research and have been used
to treat many diseases and conditions. The transplantation of isolated human
hematopoietic stem cells is used in the treatment of anemia, immune
deficiencies and other diseases, including cancer.
Basic research has
centered on identifying and characterizing hematopoietic stem cells, however,
it is still not clear how hematopoietic stem cells actually work, and how they
are regulated because of the complexity of the bone marrow microenvironment. Zhao
and his colleagues discovered that as a terminally differentiated progeny,
megakaryocytes regulate hematopoietic stem cells by performing two previously
unknown functions.
"Megakaryocytes
can directly regulate the amount of hematopoietic stem cells by telling the
cells when they need to keep in the quiescent stage, and when they need to
start proliferating to meet increased demand." Maintaining that delicate
balance is important, he adds. "You don't want to have too many or too few
hematopoietic stem cells."
These findings are
supported by similar research from the laboratory of Paul S. Frenette, Ph.D.,
at the Albert Einstein College of Medicine, also reported in the Oct. 19 issue
of Nature Medicine.
Employing the
advanced technology of the Institute's Cytometry, Imaging and Histology
centers, the researchers examined the relationship between megakaryocytes and
hematopoietic stem cells in mouse bone marrow. In the course of their research,
they found that the protein transforming growth factor B1 (TGF-B1), contained
in megakaryocytes, signaled quiescence of hematopoietic stem cells. They also
found that when under stress from chemotherapy, megakaryocytes signaled
fibroblast growth factor 1 (FGF1), to stimulate the proliferation of
hematopoietic stem cells.
"Our findings
suggest that megakaryocytes are required for the recovery of hematopoietic stem
cells post chemotherapy," explains Li. The discovery could provide insight
for using megakaryocyte-derived factors, such as TGF-B1 and FGF1, clinically to
facilitate regeneration of hematopoietic stem cells, he adds.
Engineering a
megakaryocyte niche (a special environment in which stem cells live and renew)
that supports the growth of hematopoietic stem cells in culture, is the next
step for the researchers. Zhao and his colleagues are also investigating
whether a megakaryocyte niche can be used to help expand human hematopoietic
stem cells in vitro and stem cell transplantation for
patients.
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