September 19, 2009
Induced Stem Cells Retain Some Original Cell Type Memory

A continuing series of improvements in how to make cells revert to pluripotent (highly flexible) state open up the possibility of stem cell therapies for a large assortment of disorders and diseaess. But a group that has developed a new safer method for reverting cells to the pluripotent state finds that the converted cells still show signs of their original differentiated state.

A team of researchers from the University of California, San Diego School of Medicine and the Salk Institute for Biological Studies in La Jolla have developed a safe strategy for reprogramming cells to a pluripotent state without use of viral vectors or genomic insertions. Their studies reveal that these induced pluripotent stem cells (iPSCs) are very similar to human embryonic stem cells, yet maintain a "transcriptional signature." In essence, these cells retain some memory of the donor cells they once were.

This "transcriptional signature" they speak of is the pattern of gene expression into messenger RNAs and other RNA pieces that DNA sections get used to generate. Basically, DNA gets read to create matching RNA and then the RNA gets used to guide the creation of proteins.

That a cell can be induced to become more like embryonic cells and yet still retain characteristics of, say, skin or fat cells is problematic for the desire to create stem cell therapies. Ideally one wants to convert cells back to an embryonic-like state and get them to turn off all genes that are specific to being, for example, a liver or fat or kidney cell. This report suggests that inducing cells to become pluripotent does not, by itself, make them into the ideal starting point for stem cell therapies. The job of resetting cells back to a truly embryonic state is trickier than that and scientists haven't get figured out how to fully manage that trick.

On the bright side, the scientists did identify a single gene that is enough to convert a cell into the pluripotent state.

The study, led by UCSD Stem Cell Program researcher Alysson R. Muotri, assistant professor in the Departments of Pediatrics at UCSD and Rady Children's Hospital and UCSD's Department of Cellular and Molecular Medicine, will be published online in PLoS ONE on September 17.

"Working with neural stem cells, we discovered that a single factor can be used to re-program a human cell into a pluripotent state, one with the ability to differentiate into any type of cell in the body" said Muotri. Traditionally, a combination of four factors was used to create iPSCs, in a technology using viral vectors viruses with the potential to affect the transcriptional profile of cells, sometimes inducing cell death or tumors.

The researchers were using familiar genes for inducing pluripotency: Oct4 and Nanog. (and this link is to the full paper)

Genetic reprogramming of somatic cells to a pluripotent state (induced pluripotent stem cells or iPSCs) by over-expression of specific genes has been accomplished using mouse and human cells. However, it is still unclear how similar human iPSCs are to human Embryonic Stem Cells (hESCs). Here, we describe the transcriptional profile of human iPSCs generated without viral vectors or genomic insertions, revealing that these cells are in general similar to hESCs but with significant differences. For the generation of human iPSCs without viral vectors or genomic insertions, pluripotent factors Oct4 and Nanog were cloned in episomal vectors and transfected into human fetal neural progenitor cells. The transient expression of these two factors, or from Oct4 alone, resulted in efficient generation of human iPSCs. The reprogramming strategy described here revealed a potential transcriptional signature for human iPSCs yet retaining the gene expression of donor cells in human reprogrammed cells free of viral and transgene interference. Moreover, the episomal reprogramming strategy represents a safe way to generate human iPSCs for clinical purposes and basic research.

My guess: We need a far more detailed understanding of genetic regulation in order to create at least some types of cell therapies and for the growth of replacement organs. But for a lot of fatal diseases a cell therapy that is less than perfect might still extend life.

Share |      Randall Parker, 2009 September 19 10:29 PM  Biotech Stem Cells

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