Yesterday I wrote about how difficult it is to tell different cell lines apart, including normal stem cells and cancer stem cells, especially since some accumulate accumulate oncogenic mutations that may make them seem more similar.
A new paper is coming out that makes this case on a genomic level.
Tomorrow’s Cell Stem Cell edition includes a paper by a team of researchers led by Jeanne Loring that has identified relatively small genomic abnormalities in ESC and iPS cells. While both ESC and iPS cells share a subset of these genomic changes, iPS cells had a particularly high rate of changes.
Two factors make these genomic changes particularly worrisome. First, they are undetectable by conventional karyotyping. Thus, they are relatively difficult to routinely detect by the hundreds of labs working on highly pluripotent stem cells. Second, pretty much all the changes make cells more likely to cause cancer and would be of serious concern in terms of potential clinic use.
The changes included duplications involving pluripotency and cancer-causing genes as well as deletions of tumor suppressor genes, making for an especially cancerous one-two punch.
Loring’s team points out the critical importance of producing iPS cells and perhaps also deriving hESC under conditions that promote genomic integrity. However, a key open question is whether that is even possible as perhaps genomic instability such as duplications of pluripotency genes and deletions of tumor suppressors makes iPS cell formation dramatically more efficient. They could also make hESC easier to establish from blastocysts and grow longer term.
A key second point that Loring makes is that as a field we need to be more aware of these changes and ideally monitor cells for such changes.
JJ’, you asked what else might preserve iPS cell genomic integrity during their production? To get at this, perhaps another question is what the mechanism by which these genomic lesions occur? If we know that then we can try to prevent them better.
PA84,
The most important thing is indeed whether or how these changes might lead to disease.
In terms of wouldn’t it already have shown up in preclinical studies, maybe or maybe not. We also do not know what genomic changes the specific hESC lines that were used in Geron’s and ACT’s preclinical studies might have relative to those examined in the Loring study.
It would be worthwhile to know whether those abnormalities do actually translate into disease in vivo. I’m guessing that, at least as far as the ones in hESCs are concerned, wouldn’t it have shown already in the preclinical trials done by Geron and ACT for their respective products?
What else could be done during the IPSC production process and/or the establishment of ESC cultures to reduce genomic instability? I think Paul’s question about whether genomic instability actually helps make iPS cells in the first place is spot on. I bet it does.
Nick Forsyth discussed this at the ISSCR –
Physiologic oxygen enhances human embryonic stem cell clonal recovery and reduces chromosomal abnormalities.
http://www.ncbi.nlm.nih.gov/pubmed/16571074
Thanks for the comment and link, Ken. While that paper you mentioned looked at relatively huge chromosomal changes, the paper I blogged about specifically ID’d small changes not detectable by karyotyping. Even so, it would be interesting to see if physiologic oxygen reduces these small, but potential powerfully oncogenic chromosomal lesions. Cool idea!