Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Primate cell – per se
Reexamination Certificate
2001-10-12
2003-11-11
Reynolds, Deborah J. (Department: 1632)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Primate cell, per se
C435S320100, C435S455000, C435S363000, C435S472000, C435S372000, C435S325000
Reexamination Certificate
active
06645763
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to an immortalized bone marrow mesenchymal stem cell obtained by transferring a cell proliferation factor gene into a bone marrow mesenchymal stem cell.
It has been reported by various researchers that bone marrow mesenchymal stem cells differentiate into bone cells, chondrocytes, adipocytes, myocytes, tendon cells, cardiomyocytes. Therefore, it has been expected that if the bone marrow mesenchymal stem cells can be propagated in large numbers in vitro with the pluripotency kept, the resulting bone marrow mesenchymal stem cells will be a very valuable means for regenerative medicine.
As an example other than a bone marrow mesenchymal stem cell, it is known that a cell-line which maintains appropriate functions for differentiation can be produced by transferring an oncogene to BSMC, MDHF or RKC to immortalize each of the cells (K. A. Westerman, et al., Proc. Natl. Acad. Sci., USA., vol 93, 8971, (1996)). If the method is used, it is possible to obtain those immortalized cells in large numbers. However, when each of the immortalized cell-lines is infused into a living body, there is the problem of a possibility that the patient is exposed to unexpected risk of malignant transformation. Therefore, it is difficult to obtain highly safe bone marrow mesenchymal stem cells which can solve such a problem, in large numbers.
The object of the present invention is to provide immortalized bone marrow mesenchymal stem cells which can proliferate indefinitely and have a means to avoid a possibility of malignant transformation.
SUMMARY OF THE INVENTION
As a result of making an intensive study in view of the above situation, the present inventors have found the followings and completed the present invention. The present inventors have found that bone marrow mesenchymal stem cells, which have a means to avoid risk of malignant transformation and can proliferate in large numbers, can be obtained by transferring to bone marrow mesenchymal stem cells a cell proliferation factor gene which is derived from a normal cell and inserted between a pair of site-specific recombination sequences.
Therefore, the present invention provides an immortalized bone marrow mesenchymal stem cell obtained by transferring a cell proliferation factor gene inserted between a pair of site-specific recombination sequences to a bone marrow mesenchymal stem cell.
In the immortalized bone marrow mesenchymal stem cell, the bone marrow mesenchymal stem cell is preferably a human bone marrow mesenchymal stem cell.
In the immortalized bone marrow mesenchymal stem cell, the cell proliferation factor gene is preferably hTERT (human telomerase reverse transcriptase) gene.
In the immortalized bone marrow mesenchymal stem cell, the pair of site-specific recombination sequences is preferably LoxP sequence.
Further, it is preferable that the cell proliferation factor gene is transferred using a retroviral vector.
This file contains color photos.
REFERENCES:
patent: 5629159 (1997-05-01), Anderson
patent: 2002/0022268 (2002-02-01), Xu et al.
patent: WO 00/18239 (2000-04-01), None
J. Cai et al.; “Construction of a non-tumorigenic rat hepatocyte cell line for transplantation: reversal of hepatocyte cell line for transplantation: reversal of hepatocyte immortalization by site-specific excision of the SV40 T antigen”, Journal of Hepatology 2000; vol. 33; pp. 701-708.
K. Westerman et al.; “Reversible immortalization of mammalian cell mediated by retroiral transfer and site-specific recombination”; Pro. Natl. Acad. Sci.; vol. 93, pp. 8971-8976; 1996.
Shi et al.; “Bone Formation by Human Postnatal Bone Marrow Stromal Stem Cells is Enhanced by Telomerase Expression”; Nature Biotechnology, vol. 20, Jun. 2002; pp. 587-591.
J.L. Simonsen et al.; “Telomerase Expression Extends the Proliferative Life-Span and Maintains the Osteogenic Potential of Human Bone Marow Stromal Cells”; Nature Biotechnology, vol. 20, Jun. 2002, pp. 592-596.
Ray, F. A. et al.; “Iterative Chromosome Mutation and Selection as a Mechanism of Complete Transformation of Human Diploid Fibroblasts by SV40 T Antigen”; Carcinogenesis, vol. 14, No. 8, pp. 1511-1516, 1993.
Fujiwara Toshiyoshi
Kobayashi Naoya
Leboulch Philippe
Tanaka Noriaki
Armstrong Westerman & Hattori, LLP
Bertoglio Valarie
Reynolds Deborah J.
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