26 September 2005. One of the great hopes for stem cells is that they might be capable of curing paralysis brought on by trauma (e.g., spinal cord injury) or degenerative illnesses (e.g., multiple sclerosis). Indeed, recent work has shown that glia derived from stem cells can help reinsulate neurons with damaged myelin sheaths and at least partially restore conductivity and some movement (see ARF related news story). However, similar evidence for neurons derived from stem cells has been sadly lacking. No one knew if they could integrate with and restore damaged circuitry. Now, Aileen Anderson and colleagues at the University of California, Irvine, report in last week’s PNAS that they have succeeded in using human neural stem cells to both remyelinate and repair neural connections. The work suggests that scientists are edging closer to the goal of full spinal cord repair.
Working in collaboration with Fred Gage’s lab at The Salk Institute, Anderson and coworkers used human fetal CNS-derived stem cells to repair neural damage in mice. First author Brian Cummings and colleagues grew the stem cells as neurospheres and then injected them into the thoracic vertebrae of mice with spinal cord contusions. For this experiment the authors used immuno-compromised NOD-scid mice but they also tested the stem cells in “shiverer” mice, which harbor a naturally occurring mutation that compromises myelination of neurons in the CNS.
Sixteen weeks after the human stem cells were grafted, the authors found that treated NOD-scid mice moved significantly better than did animals that received human fibroblasts instead. To make sure that the recovery resulted from the human cells, Cummings treated the animals with diphtheria toxin. Mice are apparently 100,000-fold less sensitive to this toxin than are humans, so any contribution to locomotor activity elicited by the human cells would be sensitive to the toxin. Indeed, 1 week after giving the animals the toxin, the authors found that locomotor activity was back to pre-graft levels.
What causes this improvement in movement? The authors present evidence that the answer might lie in myelin repair, circuitry repair, or perhaps both. For example, the human stem cells differentiated into oligodendrocytes in the mice. This is not a direct indication that the human cells remyelinate mouse neurons, but the authors also found that spinal cord axons in treated shiverer mice had thick, robust myelin sheaths as opposed to the thin, largely absent sheaths in untreated animals. Moreover, the sheaths in the treated mice tested positive for an antibody that detects the part of myelin basic protein that shiverer mice fail to express—a clear indication of the human origin of the myelin.
Similarly, Cummings and colleagues report that the second major cell type assumed by the human stem cells was neuronal. This too, is far from proof that the cells form new circuits, or repair old ones. The paper reports one hint in the direction of this future goal. Under the electron microscope, spinal cord from treated mice revealed that neurons testing positive for human cytoplasmic markers sent processes into the mouse parenchyma and even formed what looked like synapses with mouse neurons.—Tom Fagan.
Cummings BJ, Uchida N, Tamaki SJ, Salazar DL, Hooshmand M, Summers R, Gage FH, Anderson AJ. Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice. PNAS September 27 2005;14069-14074. Abstract