Authors of previous studies have reported that adult transplanted neural progenitor cells (NPCs) are suitable for brain cell replacement or gene delivery. In this study, the authors evaluated survival and integration of adult rat–derived NPCs after transplantation and explored the potential impact on transplant survival of various mechanical and biological factors of clinical importance.
Adult female Fischer 344 rats were used both as a source and recipient of transplanted NPCs. Both 9L and RG2 rat glioma cells were used to generate in vivo brain tumor models. On the 5th day after tumor implantation, NPCs expressing green fluorescent protein (GFP) were administered either intravenously (3.5 × 107 cells) or by stereotactic injection (1 × 104–1 × 106 cells) into normal or tumor-bearing brain. The authors evaluated the effect of delivery method (sharp compared with blunt needles, normal compared with zero-volume needles, phosphate-buffered saline compared with medium as vehicle), delivery sites (intravenous compared with intratumoral compared with intraparenchymal), and pretreatment with an immunosuppressive agent (cyclosporin) or brain irradiation (20–40 Gy) on survival and integration of transplanted NPCs.
Very few cells survived when less than 105 cells were transplanted. When 105 cells or more were transplanted, only previously administered brain irradiation significantly affected survival and integration of NPCs. Although GFP-containing NPCs could be readily detected 1 day after injection, few cells survived 4 days to 1 week unless preceded by whole-brain radiation (20 or 40 Gy in a single fraction), which increased the number of GFP-containing NPCs within the tissue more than fivefold.
he authors' findings indicate that most NPCs, including those from a syngeneic autologous source, do not survive at the site of implantation, but that brain irradiation can facilitate subsequent survival in both normal and tumor-bearing brain. An understanding of the mechanisms of this effect could lead to improved survival and clinical utility of transplanted NPCs.
Abbreviations used in this paper: CNS = central nervous system; GFP = green fluorescent protein; HBSS = Hanks balanced salt solution; MASC = multipotent astrocytic stem cell; NPC = neural progenitor cell; NSC = neural stem cell; PBS = phosphate-buffered saline; SEZ = subependymal zone.
Address reprint requests to: Glenn T. Gobbel, D.V.M., Ph.D., Department of Neurological Surgery, B-400, University of Pittsburgh Medical Center-Presbyterian, 200 Lothrop Street, Pittsburgh, Pennsylvania 15213. email:
BrownABYangWSchmidtNOCarrollRLeishearKKRainovNG: Intravascular delivery of neural stem cell lines to target intracranial and extracranial tumors of neural and non-neural origin. Hum Gene Ther14:1777–17852003
CraigCGTropepeVMorsheadCMReynoldsBAWeissSvan der KooyD: In vivo growth factor expansion of endogenous sub-ependymal neural precursor cell populations in the adult mouse brain. J Neurosci16:2649–26581996
FranklinRJBayleySABlakemoreWF: Transplanted CG4 cells (an oligodendrocyte progenitor cell line) survive, migrate, and contribute to repair of areas of demyelination in X-irradiated and damaged spinal cord but not in normal spinal cord. Exp Neurol137:263–2761996
HinksGLChariDMO'LearyMTZhaoCKeirsteadHSBlakemoreWF: Depletion of endogenous oligodendrocyte progenitors rather than increased availability of survival factors is a likely explanation for enhanced survival of transplanted oligodendrocyte progenitors in X-irradiated compared to normal CNS. Neuropathol Appl Neurobiol27:59–672001
JinKSunYXieLMaoXOChildsJPeelA: Comparison of ischemia-directed migration of neural precursor cells after intrastriatal, intraventricular, or intravenous transplantation in the rat. Neurobiol Dis18:366–3742005
MalhiHGorlaGRIraniANAnnamaneniPGuptaS: Cell transplantation after oxidative hepatic preconditioning with radiation and ischemia-reperfusion leads to extensive liver repopulation. Proc Natl Acad Sci U S A99:13114–131192002
MligilicheNLXuYMatsumotoNIdelC: Survival of neural progenitor cells from the subventricular zone of the adult rat after transplantation into the host spinal cord of the same strain of adult rat. Anat Sci Int80:229–2342005
MuraokaKShingoTYasuharaTKamedaMYuanWHayaseH: The high integration and differentiation potential of autologous neural stem cell transplantation compared with allogeneic transplantation in adult rat hippocampus. Exp Neurol199:311–3272006
ParentJMTadaEFikeJRLowensteinDH: Inhibition of dentate granule cell neurogenesis with brain irradiation does not prevent seizure-induced mossy fiber synaptic reorganization in the rat. J Neurosci19:4508–45191999
SvendsenCNClarkeDJRosserAEDunnettSB: Survival and differentiation of rat and human epidermal growth factor-responsive precursor cells following grafting into the lesioned adult central nervous system. Exp Neurol137:376–3881996