Reprogrammed cells grow into 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 (early online), 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 accomplish.