Reprogrammed Cells Grow Into New Blood Vessels

Scar cells (left, nuclei stained blue) are coaxed into becoming
 blood vessel cells with a new, small-molecule and protein
therapy. Evidence of the conversion is shown in the second
 panel (right), where red staining indicates the presence of
CD31, a protein made by blood vessel cells. In a new, scientists
report these transformed cells self-assembled into vessels
 that improved blood flow. (Credit: Jack Wong, Houston
Methodist Research Institute)
By transforming human scar cells into blood vessel cells, scientists may have discovered a new way to repair damaged tissue. The method, described in an upcoming issue of Circulation (early online), appeared to improve blood flow, oxygenation, and nutrition to areas in need.

Cardiovascular scientists 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. The researchers 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.

The new method 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. The researchers 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.

The researchers 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 the researchers said preliminary, as-yet-unpublished work by his group suggests they may be able to achieve transformation rates as high as 15 percent.

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.

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.
 
More animal model studies are needed before the group begins clinical trials. The researchers 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.