Tumor tropism of intravenously injected human-induced pluripotent stem cell-derived neural stem cells and their gene therapy application in a metastatic breast cancer model.
Human pluripotent stem cells can serve as an accessible and reliable source for the generation of functional human cells for medical therapies. In this study, we used a conventional lentiviral transduction method to derive human-induced pluripotent stem (iPS) cells from primary human fibroblasts and then generated neural stem cells (NSCs) from the iPS cells. Using a dual-color whole-body imaging technology, we demonstrated that after tail vein injection, these human NSCs displayed a robust migratory capacity outside the central nervous system in both immunodeficient and immunocompetent mice and homed in on established orthotopic 4T1 mouse mammary tumors. To investigate whether the iPS cell-derived NSCs can be used as a cellular delivery vehicle for cancer gene therapy, the cells were transduced with a baculoviral vector containing the herpes simplex virus thymidine kinase suicide gene and injected through tail vein into 4T1 tumor-bearing mice. The transduced NSCs were effective in inhibiting the growth of the orthotopic 4T1 breast tumor and the metastatic spread of the cancer cells in the presence of ganciclovir, leading to prolonged survival of the tumor-bearing mice. The use of iPS cell-derived NSCs for cancer gene therapy bypasses the sensitive ethical issue surrounding the use of cells derived from human fetal tissues or human embryonic stem cells. This approach may also help to overcome problems associated with allogeneic transplantation of other types of human NSCs.
Department of Biological Sciences, National University of Singapore, Singapore.
Jing
J
Yang
Dang Hoang
DH
Lam
Sally Sallee
SS
Goh
Esther Xingwei
EX
Lee
Ying
Y
Zhao
Felix Chang
FC
Tay
Can
C
Chen
Shouhui
S
Du
Ghayathri
G
Balasundaram
Mohammad
M
Shahbazi
Chee Kian
CK
Tham
Wai Hoe
WH
Ng
Han Chong
HC
Toh
Shu
S
Wang
D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D009928:Organ Specificity; D033581:Stem Cell Transplantation; D014183:Transplantation, Heterologous