Researchers at the Houston Methodist Research Institute report that their success in transforming human scar cells into blood vessel cells may lead to a new way to repair damaged tissue. The study (“Transdifferentiation of Human Fibroblasts to Endothelial Cells: Role of Innate Immunity”), published in an upcoming issue of Circulation (early online), describes a technique that 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 cause 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 transdifferentiation to a therapeutic cell type has been accomplished with small molecules and proteins,” said John Cooke, M.D., Ph.D., chair of Houston Methodist’s department of cardiovascular sciences. “In this particular case, we've found a way to turn fibroblasts into 'shapeshifters' nearly on command.”

Dr. 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 using infectious virus particles specially engineered to deliver gene-manipulating DNA to cells. The DNA encodes 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,” explained Dr. 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. Dr. Cooke and colleagues previously had reported 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.

In the current study the team reported that about two 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 Dr. Cooke said preliminary, as-yet-unpublished work by his group suggests they may be able to achieve transformation rates as high as fifteen percent.

“This study suggests that manipulation of innate immune signaling may be generally used to modify cell fate,” the researchers said. “As similar signaling pathways are activated by damage-associated molecular patterns, epigenetic plasticity induced by innate immunity may play a fundamental role in transdifferentiation during wound healing and regeneration. Finally, this study is a first step toward development of a small molecule strategy for therapeutic transdifferentiation for vascular disease.”

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