Use of Transdifferentiated Cells in Regenerative Therapy

When creating patient-matched cells for use in regenerative therapies the present approach is to generate pluripotent cells, such as induced pluripotent stem cells, from an easily obtained sample, and then guide those cells to differentiate into the desired cell type. Researchers are finding it is possible in some cases to directly transform one cell type into another, however, a process called transdifferentiation. In theory this might prove more efficient and less costly, but at this point it is very early in the development of regenerative therapies that use transdifferentiated cells:

[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 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. 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.

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. Preliminary, as-yet-unpublished work [suggests] they may be able to achieve transformation rates as high as 15 percent.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. 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."

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. 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. One of the next steps will be to see if we can rescue an animal from an injury. 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."

Link: http://www.houstonmethodist.org/methodist.cfm?&id=495&action=detail&ref=1295

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