iPSCs less pliable than ESCs?

Stem cells derived from adult tissues may be less able to differentiate into different tissues than those derived from embryos, because adult cells appear to retain an "epigenetic memory" of the cell type from which they were derived, according to two mouse studies published this week in Nature journals.

An iPSC colony
Image: Jose M. Polo and
Konrad Hochedlinger

The papers show that induced pluripotent stem cells (iPSCs) "are not truly similar to [embryonic stem cells] when examined at a high resolution," cell biologist Mahendra Rao of linkurl:Life Technologies;http://www.lifetechnologies.com/home.html in California, who was not involved in the research, told The Scientist in an email. iPSCs' lack of flexibility appears to stem from differences in how their DNA is methylated. iPSCs are often created by infusing adult tissues with genetic factors that make the cells regress in their development to an embryonic-like state, capable of differentiating into any of the many tissue types in the body. But stem cell biologists have long suspected that iPSCs may not be as truly pliable, or "pluripotent," as embryonic stem cells (ESCs). Sure enough, when stem cell biologist linkurl:George Daley;http://daley.med.harvard.edu/ of the Harvard Medical School and Children's Hospital Boston and his colleagues tried differentiating blood-derived mouse iPSCs into bone tissue and bone-derived mouse iPSCs into blood, they found both types of cells failed to differentiate into a different tissue type as efficiently as either mouse ESCs or iPSCs derived from that tissue. They also found that DNA methylation patterns differed between the different iPSCs and between the adult and embryonic cells, which may explain the differences in their ability to form different tissues. The differences were "detectible to the point where we could literally use the methylation signatures to tell the lineage in the blood where the iPS cells had come from," said Daley, who published the findings in Nature. "When we select for pluripotency, we haven't necessarily erased all of the epigenetic memory." However, mouse cells derived by somatic cell nuclear transfer -- in which the nucleus of an adult cell is implanted into a mature egg cell, which is then grown to an early stage embryo -- appeared to differentiate more easily into various lineages, performing similarly to ESCs. Meanwhile, in an independent laboratory down the hall at Harvard Medical School, linkurl:Konrad Hochedlinger;http://harvardscience.harvard.edu/directory/researchers/konrad-hochedlinger of Harvard and Massachusetts General Hospital and his colleagues were investigating the same question -- and getting the same results. Comparing mouse iPS cells derived from skin, blood, and muscle precursors, the researchers found different gene expression profiles and different patterns of DNA methylation -- both indicative of an epigenetic memory. They further confirmed Daley's functional findings by showing that the tissue of origin influences the iPS cells' ability to develop into different lineages. However, by continuing to culture the iPS cells, the researchers were able to reduce these differences, yielding more embryonic-like stem cells. "The bottom line is that [in young iPS cells], there is memory which affects the differentiation capacity of cells into different lineages," Hochedlinger said. "But on the other hand," he added, "you can simply culture them extensively [to] lose the memory." Their results are published online today (July 19) in Nature Biotechnology. Understanding the mechanisms underlying such epigenetic memory and its consequences is vital to using iPSCs in a clinical setting, researchers agree. Clearly, caution is warranted "if you want to use iPS cells for disease modeling," for example, Hochedlinger warned. "The differences [between the diseased iPS cells and the normal ES cells] may in part not be due to patient-specific abnormalities, as you hope, but rather that there was memory of the cell of origin in your iPS cell." But the memory may not be in and of itself a bad thing. "The fact that iPS cells at early passage retain a memory of their cell of origin could be exploited in a potential therapeutic setting," Hochedlinger said -- iPSCs derived from blood would, in theory, make new blood cells more efficiently than other iPSCs, he noted. Indeed, "in some of the presented experiments, blood-derived iPS cells performed even better than regular ES cells at making new blood in vitro!" stem cell biologist linkurl:Thorsten Schlaeger;http://stemcell.childrenshospital.org/about-us/leadership-faculty-staff/thorsten-m-schlaeger/ of Children's Hospital Boston, who was not involved in the research, noted in an email. Of course, "how to precisely control this would require further substantial investigations," stem cell biologist linkurl:Sheng Ding;http://www.scripps.edu/chem/ding/ of The Scripps Research Institute in California, also not a co-author, wrote in an email. "It's a double-edged sword," agreed Daley. "Depending on your experimental model, this memory is either going to be working in your favor or against you." K. Kim, et al., "Epigenetic memory in induced pluripotent stem cells," Nature AOP, DOI: 10.1038/nature09342, 2010. J.M. Polo, et al., "Cell type of origin influences the molecular and functional properties of mouse induce pluripotent stem cells," Nature Biotechnology AOP, DOI: 10.1038/nbt1667, 2010. Correction: This article has been updated from its original version to note that iPSCs retain an "epigenetic memory," not a "genetic memory." The Scientist regrets the error.
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[23rd July 2009]