Embryonic Stem Cells Repair Spinal Cord

Applied Genetics News, Dec 19, 1999

Scientists led by John W. McDonald, a neurologist from the Washington University School of Medicine, have developed a treatment that improves the locomotion of rats when given more than a week after spinal cord injury. They turned embryonic stem (ES) cells into precursors of nerve cells and transplanted the precursors into the injury site. Inside the animals, some of the cells survived and developed into the three major types of cells needed for spinal cord repair. Their results are reported in the December issue of Nature Medicine.

"Establishing regenerative therapies that promote substantial improvements in locomotion when instituted after the injury process is complete has been a difficult obstacle," says McDonald, "This is a key threshold that has not before been crossed."

The research team treated rats nine days after a thoracic-level spinal cord injury that affected the animals' hind legs. They transplanted about one million nerve cell precursors-derived from mouse embryonic stem cells-into a fluid-filled cavity that had developed at the injury site. To prevent rejection, they also gave the animals the immunosuppressant drug cyclosporine, which is used for organ transplantation in humans.

Two weeks to five weeks later, the researchers looked for the transplanted cells, which they had labeled in various ways, including with genetic markers. They also used specialized techniques to identify any axons that had sprouted from the transplanted cells. The cells had differentiated into some of the appropriate cells for repair -neurons, which transmit information; oligodendrocytes, which wrap the axons of neurons in the fatty sheath needed for efficient conductance; and astrocytes, which maintain an optimal environment for nerve cell function. None of the cells had generated tumors.

Using an open field locomotor test to assess voluntary locomotion, the researchers compared the performance of the transplanted rats with the performance of injured rats that had undergone sham operations. One month after the surgery, the hind limbs of the control rats could move but not in a coordinated fashion. They also were completely unable to support the weight of the body. But the hind limbs of the transplanted rats had partly regained some coordinated movement. They also were able to partly support the body's weight.

"Only a small percentage of the transplanted cells survived," notes McDonald. "If cell survival could be enhanced, it might be possible to restore bowel and bladder control or even walking."

To approach this goal, the researchers plan to generate designer ES cells through genetic manipulation. For example, it should be possible to inactivate apoptosis genes. Yet other genetic modifications might persuade all of the transplanted cells to develop into a particular tissue type, like oligodendrocytes, if re-insulation of intact axons was a priority. The researchers also could turn ES cells into factories that manufacture growth factors known to promote nerve cell survival.