Correspondence

Tracking Neural Stem Cells in Patients with Brain Trauma

N Engl J Med 2006; 355:2376-2378November 30, 2006

Article

To the Editor:

Regeneration of damaged brain tissue with neural stem cells is a promising strategy for reversing neurologic deficits.1 Superparamagnetic iron oxide nanoparticles have been used to label and track dendritic cells in the experimental treatment of melanoma2 and in experiments in animals.3 We report the feasibility of labeling neural stem cells from humans (two patients for whom written informed consent was provided by next of kin) with superparamagnetic iron oxide nanoparticles and tracking them with the use of magnetic resonance imaging (MRI).

A 34-year-old man had brain trauma in the left temporal lobe in February 2004. During an emergency operation, exposed neural tissue from his brain was collected and cultured in a medium previously shown to select for neural stem cells (for more details, see the Supplementary Appendix, available with the full text of this letter at www.nejm.org). The day before implantation of the cultured neural stem cells, we incubated them in Feridex I.V.4 (a contrast agent containing superparamagnetic iron oxide nanoparticles that is approved by the Food and Drug Administration5) and Effectene (a lipofection reagent) in medium for 60 minutes to allow the Feridex I.V. to infuse into the cells and thereby label them (Figure 1Figure 1Photomicrograph (Panel A) and Transmission Electron Photomicrograph (Panel B) of Neural Stem Cells Labeled with Iron Oxide Nanoparticles.). These autologous cultured neural stem cells were then implanted stereotactically around the region of brain damage. We performed MRI with a 3.0-T system (Signa, General Electric) and gradient reflection echo with a recovery time of 200 msec, an echo time of 20 msec, and a flip angle of 20 degrees at 24 hours and then every 7 days after transplantation for 10 weeks.

We observed marked signal dampening on T₂-weighted MRI images. Pronounced hypointense signals were not found at the injection sites before implantation (Figure 2AFigure 2MRI Scans from the Patient Who Received Neural Stem Cells Labeled with Iron Oxide Nanoparticles (Panels A through F) and the Patient Who Received Unlabeled Cells (Panels G through L).). The injection sites were visible as circular areas of dark tissue on the first day after implantation (Figure 2B). The hypointense signal at each injection site faded thereafter (Figure 2C through 2F). One week after implantation, the change in signal was consistent with cell accumulation and proliferation around the lesion (Figure 2D). The signal at the periphery of the lesion intensified during the second and third weeks (Figure 2E and 2F), suggesting that the neural stem cells had migrated from the primary sites of injection to the border of the damaged tissue. We did not observe a hypointense signal after 7 weeks, which we attribute to a dilution of signal due to cell proliferation.

The control patient was a 42-year-old man who had brain trauma in the right temporal lobe. We cultured neural stem cells from this patient without labeling them with superparamagnetic iron oxide nanoparticles and then implanted them. We did not observe a pronounced change in signal around his lesion after implantation, but we did observe a slightly hypointense signal around the injection sites (Figure 2G through 2L), which showed no significant change during the observation period.

To explore the possibility that the magnetic signal was generated by macrophages that engulfed the labeled neural stem cells, we implanted neural stem cells that had been double-labeled (with green fluorescent protein and superparamagnetic iron oxide nanoparticles) in a rat model of traumatic brain injury. Three weeks after implantation, the regions containing the cells labeled with superparamagnetic iron oxide nanoparticles were identical to those containing cells labeled with green fluorescent protein. This finding suggests that the hypointense signals were not generated by engulfment of the implanted cells by macrophages (for more details, see the Supplementary Appendix). Our pilot clinical study shows that stem-cell engraftment and migration after implantation can be detected noninvasively with the use of MRI.

Jianhong Zhu, M.D., Ph.D.
Liangfu Zhou, M.D.
Fudan University Huashan Hospital, Shanghai 200040, China
jzhu@fudan.edu.cn

FengGe XingWu, M.D.
Shanghai National Key Laboratory for Medical Neurobiology, Shanghai 200032, China

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