REPROGRAMMED CELLS GROW IN TO NEW BLOOD VESSELS
By transforming human scar cells into blood vessel cells, scientists at
Houston Methodist may have discovered a new way to repair damaged tissue. The
method, described in an upcoming issue of Circulation, appeared to improve blood flow, oxygenation, and
nutrition to areas in need
Cardiovascular
scientists at Houston Methodist, with colleagues at Stanford University and
Cincinnati Children's Hospital, learned that fibroblasts -- cells that causes
scarring and are plentiful throughout the human body -- can be coaxed into
becoming endothelium, an entirely different type of adult cell that forms the
lining of blood vessels.
"To our
knowledge, this is the first time that trans-differentiation to a therapeutic
cell type has been accomplished with a small molecules and proteins," said
Houston Methodist Research Institute Department of Cardiovascular Sciences
Chair John Cooke, M.D., Ph.D., the study's principal investigator. "In
this particular case, we've found a way to turn fibroblasts into
'shapeshifters' nearly on command."
Cooke said the
regenerative medicine approach provides proof-of-concept for a small molecule
therapy that could one day be used to improve the healing of cardiovascular
damage or other injuries.
Other research groups
have managed to generate endothelial cells cells using infectious virus
particles specially engineered to deliver gene-manipulating DNA to cells. The
DNA encodes proteins called transcription factors to alter gene expression
patterns in such a way that cells behave more like endothelial cells.
"There are
problems with using viruses to transfer genes into cells," Cooke said.
"This gene therapy approach is more complicated, and using viral vectors
means the possibility of causing damage to the patient's chromosomes. We
believe a small-molecule approach to transforming the cells will be far more
feasible and safer for clinical therapies."
The new method
described by Cooke and his coauthors starts with exposing fibroblasts to poly
I:C (polyinosinic:polycytidylic acid), a small segment of double-stranded RNA
that binds to the host cell receptor TLR3 (toll-like receptor 3), tricking the
cells into reacting as if attacked by a virus. Cooke and coauthors reported to
Cell in 2012 that fibroblasts' response to a viral attack -- or, in this case,
a fake viral attack -- appears to be a vital step in diverting fibroblasts
toward a new cell fate. After treatment with poly I:C, the researchers observed
a reorganization of nuclear chromatin, allowing previously blocked-off genes to
be expressed. The fibroblasts were then treated with factors, such as VEGF,
that are known to compel less differentiated cells into becoming endothelial
cells.
Cooke and his
colleagues reported to Circulation that about 2 percent of the fibroblasts were
transformed from fibroblasts into endothelial cells, a rate comparable to what
other research groups have accomplished using viruses and gene therapy. But
Cooke said preliminary, as-yet-unpublished work by his group suggests they may
be able to achieve transformation rates as high as 15 percent.
"That's about
where we think the yield of transformed cells needs to be," Cooke said.
"You don't want all of the fibroblasts to be transformed -- fibroblasts
perform a number of important functions, including making proteins that hold
tissue together. Our approach will transform some of the scar cells into blood
vessel cells that will provide blood flow to heal the injury."
In a second part of
the study, the scientists introduced the transformed human cells into
immune-deficient mice that had poor blood flow to their hind limbs. The human
blood vessel cells increased the number of vessels in the mouse limb, improving
circulation.
"The cells
spontaneously form new blood vessels -- they self assemble," Cooke said.
"Our transformed cells appear to form capillaries in vivo that
join with the existing vessels in the animal, as we saw mouse red blood cells
inside the vessels composed of human cells."
Cooke, who is also the
director of the Houston Methodist Center for Cardiovascular Regeneration, said
that figuring out how to manipulate adult cells of one type into becoming a
completely different type of cell will be an important part of the development
of regenerative medicine as a scientific and clinical field. Humans are
generally unable to regenerate heavily damaged tissue, whereas other animals,
such as some newts and flat worms, can regenerate entire lost limbs -- even
entire heads.
"It is likely
that modifications of this small molecule approach may be used to generate
other body cells of therapeutic interest," Cooke said. "What we are
seeing is evidence of the fluidity of cell fate with the proper stimulation. If
we can understand the underlying pathways and how to manipulate them, we may
very well learn how reawaken primordial mechanisms for regeneration that are
active in lower vertebrates such as newts."
Cooke said more animal
model studies are needed before his group begins clinical trials.
"One of the next
steps will be to see if we can rescue an animal from an injury," Cooke
said. "We want to know if the therapy enhances healing by increasing blood
flow to tissues that may have been damaged by a loss of blood because of ischemia."
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