2016 - IPITA - Stem Cell Derived Beta Cells Workshop
Benefits and Hazards of Genetic Modification
7.2 - Strategies for preventing teratoma formation and transplantation of aneuploid cells
Presenter: Uri, Ben-David, , United States
Authors: Uri Ben-David
The promise of human pluripotent stem cells (hPSCs) for regenerative medicine is rapidly getting closer to fulfillment. However, a few concerns must be characterized and overcome to achieve safe stem cell therapies. Of particular concern, the unique abilities of hPSCs to self-renew and to differentiate into any cell type may also enable them to generate tumors when transplanted into patients, and therefore hinder their clinical application. In this talk, I will discuss two of the major safety issues associated with hPSC-based cell therapies: genomic instability and teratoma formation.
Genomic instability is a hallmark of cancer, but also characterizes stem cells in culture. HPSCs acquire genomic changes throughout their culture propagation, varying in size from point mutations to aneuploidy. Some of these events can take over the culture within few passages, suggesting that they confer a strong selection advantage. These events may potentially affect the differentiation capacity of the pluripotent cells, the functional performance of the differentiated cells, and - perhaps most importantly - their tumorigenic potential. Evidence for culture-acquired aneuploidy and chromosomal instability will be presented, and its prevalence, underlying molecular mechanisms and functional consequences will be reviewed. Potential means to alleviate genomic instability in culture will be discussed, as well as techniques to monitor the stability of both undifferentiated and differentiated cells, in order to prevent the transplantation of aneuploid cells.
Importantly, the tumorigenic risk of hPSCs is not limited to aneuploid cells; when differentiated cells are injected into patients, residual undifferentiated cells may form teratomas, even in the absence of genetic changes. It is therefore essential to get rid of residual hPSCs prior to transplanting the final cell product into patients. In recent years, various strategies have been developed to selectively eliminate undifferentiated cells from culture. These methods usually involve either genetic manipulation or cell sorting (or both), and are therefore not applicable to most clinical settings. We have recently proposed a chemical approach to selectively kill undifferentiated cells using small molecules called PluriSIns (Pluripotent-Specific Inhibitors), thus preventing teratoma formation from residual hPSCs. Strategies to prevent teratoma formation will be reviewed, and their strengths and limitations for different clinical contexts will be compared.
You must be logged in to view recordings
By viewing the material on this site you understand and accept that:
- The opinions and statements expressed on this site reflect the views of the author or authors and do not necessarily reflect those of The Transplantation Society and/or its Sections.
- The hosting of material on The Transplantation Society site does not signify endorsement of this material by The Transplantation Society and/or its Sections.
- The material is solely for educational purposes for qualified health care professionals.
- The Transplantation Society and/or its Sections are not liable for any decision made or action taken based on the information contained in the material on this site.
- The information cannot be used as a substitute for professional care.
- The information does not represent a standard of care.
- No physician-patient relationship is being established.