Long-term fate of neural precursor cells following transplantation into developing and adult CNS.
Successful strategies for transplantation of neural precursor cells for replacement of lost or dysfunctional CNS cells require long-term survival of grafted cells and integration with the host system, potentially for the life of the recipient. It is also important to demonstrate that transplants do not result in adverse outcomes. Few studies have examined the long-term properties of transplanted neural precursor cells in the CNS, particularly in non-neurogenic regions of the adult. The aim of the present study was to extensively characterize the fate of defined populations of neural precursor cells following transplantation into the developing and adult CNS (brain and spinal cord) for up to 15 months, including integration of graft-derived neurons with the host. Specifically, we employed neuronal-restricted precursors and glial-restricted precursors, which represent neural precursor cells with lineage restrictions for neuronal and glial fate, respectively. Transplanted cells were prepared from embryonic day-13.5 fetal spinal cord of transgenic donor rats that express the marker gene human placental alkaline phosphatase to achieve stable and reliable graft tracking. We found that in both developing and adult CNS grafted cells showed long-term survival, morphological maturation, extensive distribution and differentiation into all mature CNS cell types (neurons, astrocytes and oligodendrocytes). Graft-derived neurons also formed synapses, as identified by electron microscopy, suggesting that transplanted neural precursor cells integrated with adult CNS. Furthermore, grafts did not result in any apparent deleterious outcomes. We did not detect tumor formation, cells did not localize to unwanted locations and no pronounced immune response was present at the graft sites. The long-term stability of neuronal-restricted precursors and glial-restricted precursors and the lack of adverse effects suggest that transplantation of lineage-restricted neural precursor cells can serve as an effective and safe replacement therapy for CNS injury and degeneration.
Lepore
A C
AC
Department of Neurobiology and Anatomy, 2900 Queen Lane, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
Neuhuber
B
B
Connors
T M
TM
Han
S S W
SS
Liu
Y
Y
Daniels
M P
MP
Rao
M S
MS
Fischer
I
I
D000367:Age Factors; D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D017690:Cell Transplantation / Q000379:methods*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000254:growth & development / Q000502:physiology* / Q000648:ultrastructure; D018920:Coculture Techniques / Q000379:methods; D004622:Embryo, Mammalian; D005260:Female; D005732:Gangliosides / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007381:Intermediate Filament Proteins / Q000378:metabolism; D016253:Microscopy, Immunoelectron / Q000379:methods; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013234:Stem Cells / Q000502:physiology*; D013997:Time Factors; D019737:Transplants
D005732:Gangliosides; D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577486:Nes protein, rat; D064231:Nestin; D019006:Neural Cell Adhesion Molecules; D012333:RNA, Messenger; C062875:ganglioside A2B5; D000469:Alkaline Phosphatase; D010751:Phosphopyruvate Hydratase