Genetically perpetuated human neural stem cells engraft and differentiate into the adult mammalian brain.
Human neural stem cells (HNSCs) may serve as a cellular vehicle for molecular therapies as well as for cell replacement in the human CNS. The survival, integration, and differentiation of HNSC.100, a multipotent cell line of HNSCs (A. Villa et al. (2000), Exp. Neurol. 161, 67-84), conditionally perpetuated by genetic and epigenetic means, was investigated after transplantation to the striatum and substantia nigra of the adult, intact rat brain. These are two key regions in the mammalian brain involved in the control of voluntary movement and motor coordination, among other functions. Soon after transplantation (1 week), the cells had already integrated in a nondisruptive manner into the surrounding tissue and migrated out of the implantation site to different distances depending on graft location (in the range of 0.5-2.5 mm). Cell migration was markedly more extensive in the striatum, where the cells colonized the whole extent of the caudate-putamen, than in the substantia nigra region. The engrafted cells completely downregulated the stem cell marker nestin and, due to their multipotential nature, differentiated and expressed mature neural markers. As expected from cells grafted into nonneurogenic regions of the intact brain, the majority of differentiated cells expressed GFAP (astroglia), but expression of other markers, like GalC (oligodendroglia) and MAP2, beta-tubulin III, NeuN, and NSE (for mature neurons) could also be detected. These results demonstrate that genetically perpetuated HNSCs, once transplanted, find residence in the host brain, where they differentiate, generating mature neural cells in the host, chimeric, adult mammalian brain. HNSCs cell lines may be a highly useful model for the development of humanized systems for cell replacement and/or gene transfer to the CNS, which will likely be strong candidates for future therapeutic application in human neurodegenerative conditions.
Rubio
F J
FJ
Center of Molecular Biology Severo Ochoa, Autonomous University of Madrid, Campus Cantoblanco, Madrid, 28049-, Spain.
Bueno
C
C
Villa
A
A
Navarro
B
B
Martínez-Serrano
A
A
D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D001345:Autoradiography; D001921:Brain / Q000166:cytology* / Q000378:metabolism / Q000601:surgery; D002454:Cell Differentiation; D002460:Cell Line; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism / Q000601:surgery; D015536:Down-Regulation; D005260:Female; D006085:Graft Survival; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins; D064231:Nestin; D009474:Neurons / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation*; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism / Q000601:surgery; D014183:Transplantation, Heterologous
D000943:Antigens, Differentiation; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577486:Nes protein, rat; D064231:Nestin; D012333:RNA, Messenger