In the beginning (of gestation, that is) a newly baked cluster of embryonic stem cells started dividing and redividing to populate the future fetus with all of the cells and tissues it would need to become a full-fledged human baby.
Besides the no-no notion of cloning whole people, these embryonic stem cells have the pluripotent potential to produce on demand the myriad body parts for repairing or replacing the cells, tissues or complete organs that ailing adults may need. That therapeutic cloning ploy has engendered much political uneasiness, because in the White House and on Capitol Hill, the concept of cultivating embryonic stem cells seems to impinge on the forbidden zone of reproductive cloning.
Not to worry. Riding to the rescue from this worrisome prospect came the adult human stem cells. They’re a step or two down the developmental ladder from the embryonic stem cells, but apparently can be coaxed into behaving like those progenitors for therapeutic purposes.
Now it’s worry time again.
Two adjacent articles in the March 13, 2002, issue of Nature suggest that optimistic reports of alleged versatility in human adult stem cell differentiation may be exaggerated or plain off base. Both papers imply that the same cell-fusion mechanism explains the multicell progeny, instead of the more visionary cloning machinery.
One article is titled: “Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion.” Its senior author is molecular geneticist Edward Scott, who directs the University of Florida’s Stem Cell Program in Gainesville.
The other manuscript bears the heading: “Changing potency by spontaneous fusion.” Its senior author is geneticist Austin Smith at the Center for Genomic Research at the University of Edinburgh in Scotland. Both authors follow closely parallel approaches in making the same perhaps deflationary point.
“Recent reports have suggested that mammalian cells residing in one tissue,” Smith said, “may have the capacity to produce differentiated cell types for other tissues and organs. Here we define a mechanism by which progenitor cells of the central nervous system can give rise to non-neural derivatives. Cells taken from mouse brain,” he continued, “were co-cultured with pluripotent embryonic stem cells. The altered phenotype does not arise by direct conversion of brain to embryonic stem cell, but rather through spontaneous generation of hybrid cells. We propose that [this] could underlie many observations otherwise attributed to an intrinsic plasticity of tissue stem cells.”
“Essentially, what we’ve shown,” Scott told BioWorld Today, “is that under in vitro culture conditions, adult hematopoietic [blood-forming] stem cells or their progeny grown under conditions in which stem cells will start to differentiate can fuse to other cell types. But what’s shown in the paper is fusion to embryonic stem cells, and deeming they’re phenotypes. What we are suggesting from this is that we just need to be more careful when we try to interpret transplantation data. Either have two markers so you can definitely tell donor from recipient, or do it in such a way that you go back and actually check the chromosome number whether or not you’re looking at a tetraploid cell [with four chromosomes].”
Don’t Dismiss Adult Cells; Handle With Care
Scott does not think these two papers pull the rug out from under adult stem cell prospects. “I think it’s a cautionary tale not just for adult stem cells but for all stem cells,” he observed. “In both of our papers, the primary cells that are fusing are embryonic stem cells. So I don’t think adult stem cells will no longer be useful, but before we make some of the large interpretations of transdifferentiation into other cell types, we just need to do a few extra controls.
“I still thoroughly believe that most of the transdifferentiation information is correct,” Scott went on, “particularly when you have robust transdifferentiation, like in the case of the liver. It’s where you have a situation where there’s a few cells here and there that are carrying only one marker of donor origin that you might need to be careful. One of the things that has caught me a little by surprise,” he added, “was the spin that’s being put on both of our papers that this is a major blow to adult stem cells, and therefore we need to expand the embryonic stem cell world. That’s perhaps pushing our data further than we should.”
Scott’s first author, Naohiro Terada, pointed out, “If confirmed by animal studies, the findings could be a reality check for those hoping to use adult stem cells clinically. Fused cells carry double the normal amount of DNA, and may be unhealthy. It might be a precautionary tale for stem cell research.”
Halting ES Research Not Scientific’
Commenting on the implications of his own work, Smith noted, “This suggests a need for caution with regard to the therapeutic use of adult tissue stem cells. If they only make other tissues by fusing with existing cells rather than producing new cells, their utility for tissue repair and regenerative medicine will be greatly restricted. While there is justifiably a great deal of interest in the broader applicability of adult stem cells, our findings illustrate that we are currently very ignorant of their biology. If nothing else,” he concluded,” our study indicates that calls for a halt to embryonic stem cell research are not scientifically justified, and confirms the far-sightedness of the United Kingdom legislature in approving embryonic stem cell derivation and research.”