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DOI: 10.1055/s-0028-1088228
Tumor Formation Following Murine Neural Precursor Cell Transplantation in a Rat Peripheral Nerve Injury Model
Publication History
Publication Date:
25 September 2008 (online)
ABSTRACT
Neural stem cells show a remarkable aptitude for integration and appropriate differentiation at sites of cellular injury in central nervous system (CNS) disease models. In contrast, reports of neural stem cell applications in peripheral nerve injury models are sparse. In this study we sought to determine if the C17.2 cell line would respond to cues in the microenvironment of the injured peripheral nerve and enhance neuronal regeneration in rodent sciatic nerve injury models. We transplanted C17.2 into several sciatic nerve injury models in 45 nude rats, including nerve transection, nerve crush, and nerve gap models. Twelve of the animals in this study developed large tumors at the site of neural stem cell transplants. Histologically, the tumors resembled neuroblastomas. The tumors were confirmed to be of transplanted cell origin by positive β-galactosidase staining. Tumors occurred only in models where the nerve remained intact or where continuity of the nerve was restored. We concluded that C17.2 transplantation into peripheral nerve injury models resulted in a high rate of tumor formation. This study demonstrates that the success of neural precursor transplants in the CNS cannot necessarily be extrapolated to the peripheral nervous system.
KEYWORDS
Stem cells - neural precursors - peripheral nerve injury - tumorigenesis
REFERENCES
- 1 Meek M F, Coert J, Robinson P. Poor results after nerve grafting in the upper extremity: quo vadis. Microsurgery. 2005; 25 396-402
-
2 Winograd J, Mackinnon S.
Peripheral Nerve Injuries: Repair and Reconstruction . In: Mathes S Plastic Surgery. Vol 7. 2nd ed. New York; WB Saunders 2005: 471-514 - 3 Lundborg G. A 25-year prospective o f peripheral nerve surgery: evolving neuroscientific concepts and clinical significance. J Hand Surg [Am]. 2000; 25A(3) 391-414
- 4 Pfister L A, Papaloizos M, Merkle H P, Gander B. Nerve conduits and growth factor delivery in peripheral nerve repair. J Peripher Nerv Syst. 2007; 12(2) 65-82
- 5 Singec I, Jandial R, Crain A, Nikkhah G, Snyder E Y. The leading edge of stem cell therapeutics. Annu Rev Med. 2007; 58 313-328
- 6 Frostick S P, Yin Q, Kemp G J. Schwann cells, neurotrophic factors and peripheral nerve regeneration. Microsurgery. 1998; 18 397-405
- 7 Snyder E Y, Daley G Q, Goodell M. Taking stock and planning for the next decade: realistic prospects for stem cell therapies for the nervous system. J Neurosci Res. 2004; 76(2) 157-168
- 8 Flax J D, Aurora S, Yang C et al.. Engraftable human neural stem cells respond to developmental cues, replace neurons, and express foreign genes. Nat Biotechnol. 1998; 16(11) 1033-1039
- 9 Park K I, Teng Y D, Snyder E Y. The injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue. Nat Biotechnol. 2002; 20(11) 1111-1117
- 10 Richards L J, Kilpatrick T J, Bartlett P F. De novo generation of neuronal cells from the adult mouse brain. Proc Natl Acad Sci U S A. 1992; 89(18) 8591-8595
- 11 Rosario C M, Yandava B D, Kosaras B, Zurakowski D, Sidman R L, Snyder E Y. Differentiation of engrafted multipotent neural progenitors towards replacement of missing granule neurons in meander tail cerebellum may help determine the locus of mutant gene action. Development. 1997; 124(21) 4213-4224
- 12 Ourednik J, Ourednik V, Lynch W P, Schachner M, Snyder E Y. Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons. Nat Biotechnol. 2002; 20(11) 1103-1110
- 13 Wichterle H, Lieberam I, Porter J A, Jessell T M. Directed differentiation of embryonic stem cells into motor neurons. Cell. 2002; 110(3) 385-397
- 14 Heine W, Conant K, Griffin J W, Hoke A. Transplanted neural stem cells promote axonal regeneration through chronically denervated peripheral nerves. Exp Neurol. 2004; 189(2) 231-240
- 15 Murakami T, Fujimoto Y, Yasunaga Y et al.. Transplanted neuronal progenitor cells in a peripheral nerve gap promote nerve repair. Brain Res. 2003; 974(1–2) 17-24
- 16 Ryder E F, Snyder E Y, Cepko C L. Establishment and characterization of multipotent neural cell lines using retrovirus vector-mediated oncogene transfer. J Neurobiol. 1990; 21(2) 356-375
- 17 Reubinoff B E, Pera M F, Fong C Y, Trounson A, Bongso A. Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat Biotechnol. 2000; 18(4) 399-404
- 18 Thomson J A, Itskovitz-Eldor J, Shapiro S S et al.. Embryonic stem cell lines derived from human blastocysts. Science. 1998; 282(5391) 1145-1147
- 19 Wakitani S, Takaoka K, Hattori T et al.. Embryonic stem cells injected into the mouse knee joint form teratomas and subsequently destroy the joint. Rheumatology (Oxford). 2003; 42(1) 162-165
- 20 Reubinoff B E, Itsykson P, Turetsky T et al.. Neural progenitors from human embryonic stem cells. Nat Biotechnol. 2001; 19(12) 1134-1140
- 21 Zhang F, Inserra M, Richards L, Terris D J, Lineaweaver W C. Quantification of nerve tension after nerve repair: correlations with nerve defects and nerve regeneration. J Reconstr Microsurg. 2001; 17(6) 445-451
- 22 Erdo F, Buhrle C, Blunk J et al.. Host-dependent tumorigenesis of embryonic stem cell transplantation in experimental stroke. J Cereb Blood Flow Metab. 2003; 23(7) 780-785
- 23 Arnhold S, Klein H, Semkova I, Addicks K, Schraermeyer U. Neurally selected embryonic stem cells induce tumor formation after long-term survival following engraftment into the subretinal space. Invest Ophthalmol Vis Sci. 2004; 45(12) 4251-4255
- 24 Niles L P, Armstrong K J, Rincon Castro L M et al.. Neural stem cells express melatonin receptors and neurotrophic factors: colocalization of the MT1 receptor with neuronal and glial markers. BMC Neurosci. 2004; 5(1) 41
Jonathan M WinogradM.D.
Plastic Surgery Research Laboratory, Massachusetts General Hospital, Harvard Medical School
55 Fruit Street, Boston, MA 02114
Email: jmwinograd@partners.org