Neural progenitors in the adult human brain

Once in a while a result comes along that I know to be false. Not the result of error or fabrication, mind you, but a finding that stands in direct contradiction to a host of facts — facts on which I have built my understanding of the field in question.

Here’s one such fact: “It is impossible to clone a whole animal from the cells of an adult.” This is self-evident, since differentiation is unidirectional. In college I’d even answered an essay question on an exam in which the correct answer involved elaborating on just how impossible it would be.

Except that in 1996, as I was dropping a friend off at his house, he commented off-handedly that scientists somewhere had cloned a sheep. Since I knew that somatic cloning from the cells of an adult animal was impossible for any number of reasons, I shook my head and explained to him that scientists sometimes introduce a gene into an animal and say that we “cloned it in,” and that this is likely what he’d read.

“I don’t think that’s what they said,” he insisted.
“Where did you read it?” I asked.
“The New York Times,” he said.
“Which section?”
“Front page, above the fold.”

I headed for the nearest newsstand so fast that I forgot to let my friend out of the car. The rest is now ancient history: Ten years ago, the jolly Scots at the Roslin Institute gave us Dolly*. My appreciation for the potential of differentiated cells to be reprogrammed was changed forever.

Here’s another fact: “Brain cells don’t regenerate.” Everyone knows this: brains are virtually entirely made of postmitotic, highly specialized cells that don’t grow back after you lose them. One would assume that the cells themselves have lost the ability to replenish themselves.

As with my 1996 certainty about the impossibility of cloning, this turns out not to be true. It’s part of an old paradigm about tissues, in which we consider a tissue consisting of terminally differentiated cells that perform the tissue’s work, but ignore the tiny minority of cells that comprise the stem cell niche within the tissue. And brains have a stem cell niche, too.

In the upcoming issue of Development, Walton et al. have the scoop:

The isolation and expansion of human neural cell types has become increasingly relevant in restorative neurobiology. Although embryonic and fetal tissue are frequently envisaged as providing sufficiently primordial cells for such applications, the developmental plasticity of endogenous adult neural cells remains largely unclear. To examine the developmental potential of adult human brain cells, we applied conditions favoring the growth of neural stem cells to multiple cortical regions, resulting in the identification and selection of a population of adult human neural progenitors (AHNPs). These nestin+ progenitors may be derived from multiple forebrain regions, are maintainable in adherent conditions, co-express multiple glial and immature markers, and are highly expandable, allowing a single progenitor to theoretically form sufficient cells for ~4×107 adult brains [emphasis mine]. AHNPs longitudinally maintain the ability to generate both glial and neuronal cell types in vivo and in vitro, and are amenable to genetic modification and transplantation. These findings suggest an unprecedented degree of inducible plasticity is retained by cells of the adult central nervous system.

The authors went on to show that these cells can be transplanted successfully into a mouse model, where they do all the things that they’re supposed to do in terms of morphology and marker expression.

Once one is past the mind-blowing (sorry) result, the obvious question is: Why don’t neural progenitors do this in their native context? Why do they have to be taken out of the brain in order to start growing and dividing and repopulating? I’m not a neuroscientist, so I’ll refrain from the wild speculation that usually follows my own rhetorical questions. Instead, I’ll conservatively point the reader to two papers that have shaped my thinking on the subject — last year’s McGee et al. and the recent Syken et al., each of which discusses a gene that limits plasticity in the visual cortex — and suggest that plasticity of all kinds might be present as a potential but actively inhibited in the adult, rather than lost as a consequence of maturation and/or aging.

Back to the matter at hand: Not only do these findings hold obvious clinical relevance of these findings re: the neurodegenerative diseases, but they also hold promise for the repair of routine cell loss. One fervently hopes that the system passes the next few hurdles. Along those lines, I’ll close with a quote from Stanford’s Ben Barres, who was interviewed for the press release:

“That these cells were able to integrate into tissue in an animal model and actually survive — it was extremely important to show that. Now the question is what will these cells do in a human brain? Will they be able to survive for the long term and rebuild circuitry? This work is a first step toward that end.”

* Any budding Wikipedians out there, feel free to stop by the Dolly entry and continue the job of fixing it. It’s a catastrophe; I spent a little while on it last night, e.g. removing a line asserting that telomerase is found in bacteria.