Can a human adult stem cell spontaneously transform?

ヒト細胞に関する、培養過程での癌化の可能性について言及しました。下の文章には、多少間違い（染色体異常の出現率）がありますが、基本的な考え方は問題ありません。




Can a human adult stem cell spontaneously transform?

Correspondence re: Rubio, D., et al., Spontaneous human adult cell transformation. Cancer Res., 65: 3035-3039, 2005.


In vitro "Human adult stem cell transformation" is a major concern for those working on regenerative medicine or cell-based therapy. An article by Rubio et al. provides a caution that human mesenchymal stem cells undergo spontaneous transformation following long-term in vitro culture, i.e., 4 to 5 months. We agree that this was the first report of in vitro spontaneous transformation of human adult stem cells. Theoretically, normal human cells including mesenchymal stem cells have been shown to undergo a limited number of divisions in culture and then enter a non-dividing state referred to as "senescence" and do not spontaneously transform during culture period.

We have performed a similar experiment to determine if such chromosomal abnormality is detected after long-term in vitro culture of human mesenchymal stem cells or mesenchymal cells derived from bone marrow, umbilical cord, planceta, endometrium, and menstrual blood. Karyotypic analysis (G-banding and SKY) revealed that no genomic abnormalities except were found in the mesenchymal cells employed in this study. These abnormalities included translocations, a deletion, other rearrangements, and polyploidy. Our study raised some different points concerning chromosomal abnormality after long-term culture except for clonally inherited minor abnormalities. In addition, no telomerase activity was detected by the TRAP assay in the mesenchymal cells at all of the PDs tested, unlike in the case of multipotent adult progenitor cells (Verfaillie, et al.). Likewise, the telomere length of the mesenchymal cells decreased with the number of PDs.

We also monitored for in vivo malignant transformation of the mesenchymal cells for 3 months after inoculation and then sacrificed by cervical location. The cells did not undergo malignant transformation. They stopped dividing after reaching confluence, and they did not form any foci after confluence in vitro. Nor did the cells grafted into the subcutaneous and muscle tissue of nude mice or immunodeficient NOD/SCID/IL-2 receptor gamma-/- mice produce tumors, at least during the monitoring period (more than 100 days). Immunohistochemical analysis using an antibody against human specific vimentin revealed that injected mesenchymal cells survived but did not proliferate at the injection sites.

In the light that biosafety of mesenchymal stem cells as a source of cell-based therapy is very important, we, off course, should keep in mind that even a unlikely possiblity of human cell transformation during ex vivo expansion cannot be neglected and the human cell transformation may depend on culture condition employed in each laboratory or cell processing center. However, it should not escaped from our idea, i.e. almost zero expectation of spontaneous transformation of human adult stem cells after long-term ex vivo cultivation, obtained from our own results using cells derived from bone marrow, umbilical cord, planceta, endometrium, and menstrual blood.

We would not say the zero risk of spontaneous transformation during cultivation of mesenchymal stem cells and even one litterature (ref. 1) often win the title in this type of discussion to the controversy. However, we here emphasize that possiblity of spontaneous transformation in cultured human mesenchymal stem cell without treatment of storng mutagen or transfection of oncogenes is extremely low or considered to be nearly zero from the scientific viewpoint and tons of literature.