Modification of the brain-derived neurotrophic factor gene: a portal to transform mesenchymal stem cells into advantageous engineering cells for neuroregeneration and neuroprotection.
Multipotential mesenchymal stem cells (MSCs) are ideal seed cells for recruiting the loss of neural cells due to their strong proliferative capacity, easy acquisition, and considerable tolerance of genetic modifications. After transduction of brain-derived neurotrophic factor (BDNF) gene via recombinant retroviral vectors into the human MSCs, nearly 100% of cells expressed BDNF (which were therefore transformed into BNDF-MSCs) as detected by immunocytochemistry, and the quantity of BDNF in the culture medium was increased by approximately 20,000-fold. In spite of the genomic integration of an exogenous gene, BDNF-MSCs did not present any structural aberration in the chromosomes. All-trans-retinoic acid (RA) induction caused the BDNF-MSCs to differentiate into neural cells with significantly increased expressions of such neural-specific proteins as nestin, NeuN, O4, and glial fibrillary acidic protein (GFAP). The voltage-dependent K+/Ca2+ currents were recorded from the induced BDNF-MSCs using patch-clamp technique. Compared with the MSCs induced by both RA and BDNF, BDNF-MSCs survived in significantly greater number in the induction medium, and also more cells were induced into neuron-like cells (NeuN, P < 0.01) and oligodendrocyte-like cells (O4, P < 0.05). We suppose that, once engrafted into human central nervous system, the BDNF-MSCs would not only recruit the neuronal losses, but also provide, by way of paracrine, large quantities of BDNF that effectively perform the functions of neuroprotection and neuroregeneration, promoting the activation of endogenous neural stem/progenitor cells and their chemotactic migration. On the other hand, the BDNF-MSCs that can survive in the host environment and differentiate subsequently into functional mature cells may also serve as specifically targeting vectors for ex vivo gene therapy.
Zhao
Lian-Xu
LX
Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, Guangdong, 515031, PR China.
Zhang
Jie
J
Cao
Feng
F
Meng
Ling
L
Wang
Dong-Mei
DM
Li
Yan-Hua
YH
Nan
Xue
X
Jiao
Wen-Cang
WC
Zheng
Min
M
Xu
Xiao-Hu
XH
Pei
Xue-Tao
XT
D000328:Adult; D001854:Bone Marrow Cells / Q000166:cytology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000502:physiology; D008875:Middle Aged; D039902:Multipotent Stem Cells / Q000166:cytology / Q000502:physiology; D009416:Nerve Regeneration / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects; D018408:Patch-Clamp Techniques; D023822:Tissue Engineering / Q000379:methods*; D014161:Transduction, Genetic / Q000379:methods*; D014212:Tretinoin / Q000494:pharmacology
D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; C019277:brain-derived growth factor; D014212:Tretinoin