will play important roles in the functioning of an organ. Other cells, like pancreatic islet cells, or hematopoietic cells, will require less complex incorporation.

Also, the large-scale propagation of human ESCs in culture will require that they can be grown without feeder cells (Odorico et al., 2001). Research is needed to elucidate the mechanisms of feeder cells in repressing differentiation and to find alternatives to them, at the same time eliminating the potential that an animal virus from the feeder cells might be transferred to the ESCs.

Finally, it was noted earlier that the chromosomes of human ESCs have been shown to be stable in tissue culture. This does not mean however, that ESC lines will not be subject to the random mutations that affect all cell lines as they age. In cells from humans and other animals, approximately one mutation occurs every time a cell divides. A cell that has divided 200 times in culture therefore can be expected to harbor approximately 200 different mutations (Kunkel and Bebeneck, 2000). So far, there have been no studies published about the changes that may have occurred in existing stem cell lines. Vigilant monitoring of the integrity of existing cell lines is essential to allow understanding of the impact of long-term culture, and new stem cell lines may need to be developed in the future.

Obstacles and Risks Associated with the Use of ESCs

In addition to demonstrating the functional effectiveness of ESC transplants, it is necessary to identify and minimize, or eliminate, the risks that ESCs might pose. Two identifiable risks are tumor formation and immune rejection. As noted earlier, human ESCs injected into mice can produce a benign tumor made up of diverse tissues; this response is believed to be related to the multipotency of the undifferentiated cells in an in vivo environment. However, in a small number of short-term studies in mice, human ESCs that have been allowed to begin the process of differentiation before transplantation have not resulted in



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