Tuesday, March 04, 2008

Studying stem cells in vivo via inter-species chimeras?   posted by p-ter @ 3/04/2008 08:32:00 PM

One of the most fascinating questions in biology is how a single cell becomes an entire organism--that is, how an amalgamation of largely genetically identical cells manages to act as a complex of vastly different tissues and organs. It's a simple question, but obviously not one with a simple answer, nor is there an experimental approach that immediately comes to mind for how to answer it.

Clearly, if one is interested in, say, the development of the human brain, one approach would be to start with that initial fertilized egg, and follow it as it differentiates into the various neuronal cell types, knocking out different genes to see how development proceeds. It's also just as clear that's simply unethical in just about any culture on earth. For that reason, all studies of stem cells take place in vitro. But what if you were to grow a human brain in a mouse? This might bypass the ethical problems, yet give a fascinating glimpse into not only stem cell biology, but also the evolution of genetic pathways and morphology.

A new paper from Bruce Lahn's group takes the first step towards that possibility. This is a proof-of-principle sort of study-- they take blastocysts from your average lab mouse, and inject stem cells from the wood mouse (these two species are highly diverged--the split time is probably something like 12 Mya). Perhaps surprisingly, these chimeras were viable, and the wood mouse ES cells were simply incorporated into all the organs of the adult.

This seems to be the first step of a much larger research programme, and the authors hint at their next moves:
Owing to various practical and ethical constraints, however, it is impossible to introduce ES cells of certain species into blastocysts of the same species.
We next performed immunofluorescence (IF) staining to examine the identity of Apodemus-derived cells in a wide range of tissues (Fig. 4). We first examined the three major types of neural cells: neurons, oligodendrocytes and astrocytes.
Further genetic manipulation of either the ES cells or the host blastocysts could in theory increase or decrease the degree to which ES cells contribute to a particular tissue or organ. For example, if the host blastocysts are engineered to carry genetic defects that block the development of a particular tissue (e.g. Pdx-1 mutation which leads to the agenesis of the pancreas), the percentage contribution of the ES cells to the affected tissue may increase dramatically.
The implication is clear: this sort of approach could lead to a full in vivo analysis of the development of tissues from "certain" species where research is currently considered unethical. It's worth noting that this work was largely done in China; my guess is that will continue to be the case.