In the publication “Large-Scale Analysis Reveals Acquisition of Lineage-Specific Chromosomal Aberrations in Human Adult Stem Cells” by Uri Ben-David, Yoav Mayshar, and Nissim Benvenisty, published in the August 5, 2011 issue of Cell Stem Cell (Ben-David et al., 2011), the statement is made that human adult mesenchymal stromal cells (MSC) present a 4% risk of chromosomal abnormalities acquisition. Moreover, the authors propose in their concluding remarks that transplantation of adult stem cells may result in tumor formation, an assertion that call into question the safety of MSC-based cell therapy. This work is based on a comprehensive evaluation of chromosomal aberrations performed using gene expression profiles for a large series of human stem cells from different origins (neural stem cells, mesenchymal stem cells, and pluripotent stem cells). However, some misinterpretations, outright errors, and mistakes or omission undermine the conclusions, particularly for adult MSCs that are widely used in clinical trials for immunoregulation and tissue repair purposes. Overall, MSC genetic instability was identified in 4 studies out of 22. In one of them (GSE18934_GSM469130; supplemental table 1), MSC presenting chromosomal aberrations are not of adult origin but were obtained from fetal liver, and cannot thus be considered as adult stem cells. In another (GSE9520; supplemental table 1), the authors report of 3 different MSCs, displaying the same monosomy 6q- appearing at the beginning of the second passage at day 2 but later disappearing at D7. These results are not commented but are clearly at odds with the general interpretation that “in MSCs chromosomal aberrations can take over the culture in as few as seven passages” and that "multipotent stem cells are prone to acquire advantageous chromosomal aberrations, which enable them to rapidly outgrow the normal cell population”. Finally, in a third example, genetic abnormalities were detected in a technical replicate of MSCs studied after 28 passages, whereas there is a general consensus to estimate the maximal cumulative population doublings of MSCs below 40-50. Importantly, the authors do not reference and analyze a pivotal paper reporting a large and longitudinal study of 20 clinical grade cultured MSCs obtained using two distinct and well defined culture conditions (Tarte et al., Blood 2010) showing that some chromosomal abnormalities, i.e. trisomies of chromosomes 5, 8, and/or 20, could be detected using conventional karyotype and FISH analysis, but without any selective advantage in vitro, disappearing rapidly after the second or the third passages. In our study, all MSC lots reached senescence without recurrence of these chromosomal abnormalities and no cell transformation could be documented either in vitro or in immunocompromised mice. These previously reported results undermine the statement of the acquisition of lineage-specific chromosomal aberrations conferring growth advantage in human adult stem cells. Moreover, the authors studied many cultured MSCs, but little is known about the methods of culture utilized and it seems these methods did not fulfill the standards required for clinical use of MSCs. Finally, there are meaningful misdirections related to the references. The referenced article of Rosland (Rosland et al., 2009) was retracted in 2010 (Torsvik et al., 2010), the genetic abnormalities being related to cross-contaminations by various cancer cell lines. The same trouble occurred in the study of Rubio et al performed on adipose tissue-derived MSCs (Rubio et al., 2005, retracted in Garcia et al., 2010) underlying the absolute requirement to validate, prior to scientific publications, that the cells analyzed at the end of the culture actually derive from the cells initially set in culture. It is also surprising to state that “Transplantation of human adult stem cells may result in tumor formation” referencing an article in which cells used were fetal neural cells and not adult cells (Amariglio et al., 2009), and another article showing tumor formation only in immune-compromised mice injected with NSCs derived from an olfactory bulb adjacent to meningioma or after a very special culture process (Casalbore et al., 2009). Due to all these specific points, a more balanced view of the fundamental issue of genetic stability of adult stem cells should be given to all the actors of the field, researchers, physicians, and regulatory authorities. In conclusion, we would argue that genomic stability of cultured adult stem cells, MSCs in particular, is robust and does not support the synthesis of Uri Ben-David, Yoav Mayshar, and Nissim Benvenisty.

Limited acquisition of chromosomal aberrations in human adult mesenchymal stromal cells.

KRAMPERA, Mauro;
2012-01-01

Abstract

In the publication “Large-Scale Analysis Reveals Acquisition of Lineage-Specific Chromosomal Aberrations in Human Adult Stem Cells” by Uri Ben-David, Yoav Mayshar, and Nissim Benvenisty, published in the August 5, 2011 issue of Cell Stem Cell (Ben-David et al., 2011), the statement is made that human adult mesenchymal stromal cells (MSC) present a 4% risk of chromosomal abnormalities acquisition. Moreover, the authors propose in their concluding remarks that transplantation of adult stem cells may result in tumor formation, an assertion that call into question the safety of MSC-based cell therapy. This work is based on a comprehensive evaluation of chromosomal aberrations performed using gene expression profiles for a large series of human stem cells from different origins (neural stem cells, mesenchymal stem cells, and pluripotent stem cells). However, some misinterpretations, outright errors, and mistakes or omission undermine the conclusions, particularly for adult MSCs that are widely used in clinical trials for immunoregulation and tissue repair purposes. Overall, MSC genetic instability was identified in 4 studies out of 22. In one of them (GSE18934_GSM469130; supplemental table 1), MSC presenting chromosomal aberrations are not of adult origin but were obtained from fetal liver, and cannot thus be considered as adult stem cells. In another (GSE9520; supplemental table 1), the authors report of 3 different MSCs, displaying the same monosomy 6q- appearing at the beginning of the second passage at day 2 but later disappearing at D7. These results are not commented but are clearly at odds with the general interpretation that “in MSCs chromosomal aberrations can take over the culture in as few as seven passages” and that "multipotent stem cells are prone to acquire advantageous chromosomal aberrations, which enable them to rapidly outgrow the normal cell population”. Finally, in a third example, genetic abnormalities were detected in a technical replicate of MSCs studied after 28 passages, whereas there is a general consensus to estimate the maximal cumulative population doublings of MSCs below 40-50. Importantly, the authors do not reference and analyze a pivotal paper reporting a large and longitudinal study of 20 clinical grade cultured MSCs obtained using two distinct and well defined culture conditions (Tarte et al., Blood 2010) showing that some chromosomal abnormalities, i.e. trisomies of chromosomes 5, 8, and/or 20, could be detected using conventional karyotype and FISH analysis, but without any selective advantage in vitro, disappearing rapidly after the second or the third passages. In our study, all MSC lots reached senescence without recurrence of these chromosomal abnormalities and no cell transformation could be documented either in vitro or in immunocompromised mice. These previously reported results undermine the statement of the acquisition of lineage-specific chromosomal aberrations conferring growth advantage in human adult stem cells. Moreover, the authors studied many cultured MSCs, but little is known about the methods of culture utilized and it seems these methods did not fulfill the standards required for clinical use of MSCs. Finally, there are meaningful misdirections related to the references. The referenced article of Rosland (Rosland et al., 2009) was retracted in 2010 (Torsvik et al., 2010), the genetic abnormalities being related to cross-contaminations by various cancer cell lines. The same trouble occurred in the study of Rubio et al performed on adipose tissue-derived MSCs (Rubio et al., 2005, retracted in Garcia et al., 2010) underlying the absolute requirement to validate, prior to scientific publications, that the cells analyzed at the end of the culture actually derive from the cells initially set in culture. It is also surprising to state that “Transplantation of human adult stem cells may result in tumor formation” referencing an article in which cells used were fetal neural cells and not adult cells (Amariglio et al., 2009), and another article showing tumor formation only in immune-compromised mice injected with NSCs derived from an olfactory bulb adjacent to meningioma or after a very special culture process (Casalbore et al., 2009). Due to all these specific points, a more balanced view of the fundamental issue of genetic stability of adult stem cells should be given to all the actors of the field, researchers, physicians, and regulatory authorities. In conclusion, we would argue that genomic stability of cultured adult stem cells, MSCs in particular, is robust and does not support the synthesis of Uri Ben-David, Yoav Mayshar, and Nissim Benvenisty.
2012
mesenchymal stem cells; transformation
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/391892
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