Transplantation of apoptosis-resistant embryonic stem cells into the injured rat spinal cord.
Murine embryonic stem cells were induced to differentiate into neural lineage cells by exposure to retinoic acid. Approximately one million cells were transplanted into the lesion site in the spinal cords of adult rats which had received moderate contusion injuries 9 days previously. One group received transplants of cells genetically modified to over-express bcl-2, which codes for an anti-apoptotic protein. A second group received transplants of the wild-type ES cells from which the bcl-2 line was developed. In the untransplanted control group, only medium was injected. Locomotor abilities were assessed using the Basso, Beattie and Bresnahan (BBB) rating scale for 6 weeks. There was no incremental locomotor improvement in either transplant group when compared to control over the survival period. Morbidity and mortality were significantly more prevalent in the transplant groups than in controls. At the conclusion of the 6-week survival period, the spinal cords were examined. Two of six cords from the bcl-2 group and one of 12 cords from the wild-type group showed gross evidence of abnormal growths at the site of transplantation. No similar growth was seen in the control. Pathological examination of the abnormal cords showed very large numbers of undifferentiated cells proliferating at the injection site and extending up to 1.5 cm rostrally and caudally. These results suggest that transplanting KD3 ES cells, or apoptosis-resistant cells derived from the KD3 line, into the injured spinal cord does not improve locomotor recovery and can lead to tumor-like growth of cells, accompanied by increased debilitation, morbidity and mortality.
Howard
Michael J
MJ
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA. howardm@neuro.wustl.edu
Liu
Su
S
Schottler
Frank
F
Joy Snider
B
B
Jacquin
Mark F
MF
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D005260:Female; D006085:Graft Survival / Q000502:physiology; D009043:Motor Activity; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051381:Rats; D020318:Rats, Long-Evans; D020127:Recovery of Function; D013116:Spinal Cord / Q000473:pathology / Q000502:physiology; D013119:Spinal Cord Injuries / Q000473:pathology* / Q000628:therapy*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000473:pathology* / Q000502:physiology; D017211:Treatment Failure
D019253:Proto-Oncogene Proteins c-bcl-2