A recent paper in Cell Stem Cell provides some interesting new information about the origin of hematopoietic stem cells (HSCs), arguably the best characterized population of stem cells in the organism, and the one population that has been successfully used in regenerative medicine for some time.

We already knew that, in the mouse, the placenta acts as a very early reservoir for HSCs. But do they come from the circulation or are they born there? In the new study, Katrin Rhodes and her colleagues looked in mouse embryos that lack a functional heart and have therefore no circulation, and found that bona fide, multipotential HSCs develop in the placental vasculature in the absence of blood flow.

The authors admit that there were fewer HSCs in the placentas of mutant mice than in the placentas of wild-type controls, indicating that blood circulation may after all make a contribution to the total number of HSCs, but these observations do provide good evidence that the placenta is more than a mere reservoir of stem cells, simply waiting for the liver to become the first true hematopoietic organ.

Modeling Parkinson disease in animals has been very hard. The chemical models (6-OHDA and MPTP) are good to study cell replacement therapies, but not so great for pathogenesis. And the genetic models have failed to give the mouse something like true Parkinson disease — there may be alpha-synuclein aggregates or structures akin to Lewy bodies, but no cell death, or vice versa. To add to the debate, Silke Nuber and her colleagues just published in J. Neurosci. a conditional model of Parkinson in which alpha-synuclein expression can be switched off by feeding the animals doxycyclin. This is an image from the paper, showing the expression of the transgene in the two divisions of the substantia nigra of the mice.

Their key finding was that turning alpha-synuclein expression off in mice that started to show neurodegeneration and behavioral symptoms halted disease progression but did not reverse it. This is quite different to what Jose Lucas and his colleagues showed years ago in Huntington disease. In that case, turning the expression of huntingtin off did reverse the motor symptoms in mice.

Albeit interesting, one wonders about the relevance of the findings of Nuber and colleagues to true Parkinson disease. Similar to previous attempts to reproduce the disease in mice, their model was not perfect — there was neurodegeneration, but no Lewy bodies.

Gout is an inflammatory disease that results from the deposition of uric acid crystals in the joints. It tends to be somewhat common in people with high levels of uric acid in the blood, which is, in turn, often the result of reduced renal excretion of the acid. How does this chain of events come about? Two papers in Nature Genetics give us a clue: Veronique Vitart and her colleagues and Angela Doring and her colleagues independently identified variants in the gene SLC2A9 that are linked to variability in uric acid concentrations.

SLC2A9 encodes a fructose transporter, but Vitart and colleagues found that the protein can also transport uric acid when expressed in Xenopus oocytes. Moreover, the transporter was already known to be expressed in the kidney. So, this molecule could very well turn out to be a therapeutic target for gout. The image below, from Ed Euthman, shows uric acid crystals in a human joint.

Speaking of mammals (see the end of my previous entry), not even rats and mice always cut it when it comes to providing good models of human disease. Take, for example, cystic fibrosis. There are a couple of mouse models of the disease (we have published at least one of them), but the community does not seem to be satisfied with them. It is therefore great to see a pair of papers in the JCI reporting on two new attempts at generating the ideal model of cystic fibrosis.

The two of studies are very similar. In the first one, Xingshen Sun and colleagues report the first description of genetically engineered ferrets. They started by targetting the CFTR gene (the gene affected in the disease) in fibroblasts using an adeno-associated viral (AAV) construct, and then used a nuclear transfer protocol to obtain cloned ferrets heterozygous for the CFTR mutation. In the second one, Christopher Rogers and colleagues employed a similar strategy in pigs to obtain heterozygous piglets carrying the CFTR mutation.

The next steps will be to establish how much these models truly recapitulate human disease, and then use them to learn new biology about the disease and/or for preclinical drug-discovery work.

The figures, taken from the papers, show the cloned CFTR ferrets and a non-cloned albino at different ages, and the first CFTR heterozygous pig at one day of age.

People with acne will find this JCI paper of interest. 13-cis retinoic acid can be used to treat acne, as it can kill human sebaceous-gland cells by apoptosis. The molecule is teratogenic, though, making it necessary to look for alternatives. As the mechanism of action of 13-cis retinoic acid is unknown, Amanda Nelson and her colleagues tried to elucidate it, hoping to identify new targets for the treatment of the bothersome skin condition. Using transcriptional profiling of skin cells from people with acne and cultured sebaceous glands, they found that lipocalin-2 was distinctively upregulated by treatment with 13-cis retinoic acid. They also found that the apoptotic effect of 13-cis retinoic acid indeed depended on the expression of neutrophil gelatinase–associated lipocalin (NGAL), the protein encoded by lipocalin-2; by using siRNA to lipocalin-2, they blocked the apoptotic effect, and by adding recombinant NGAL, they promoted it. It is therefore conceivable that manipulating NGAL expression could lead to a new way to fight acne.

A more serious pathology with a connection to retinoids is Matthew-Wood syndrome, a fatal disease characterized by multisystem developmental malformations that has been linked to mutations in STRA6. STRA6 interacts with retinol-binding protein 4 (RBP4), which is, in turn, a carrier of retinoids (vitamin A and its derivatives). A paper published in Cell Metabolism establishes that the biochemical interaction between STRA6 and RBP4 is indeed functionally relevant. Studying zebrafish embryos, Andrea Isken and colleagues found that Stra6 deficiency allows more Rbp4 to remain free and to carry an excess amount of retinoids to several embryonic tissues, including bone, heart and eye. In fact, reducing the levels of Rbp4 prevented these effects. The findings provide a nice molecular account of Matthew-Wood syndrome, although I cannot help but wish that the authors had done the in vivo experiments in a mammal. I must confess that, when we evaluate papers at Nature Medicine, we’re seldom enthused by data from zebrafish, Drosophila or C. elegans, as the relevance of these models to human physiology tends to be harder to ascertain. Nothing personal against the fish or the invertebrates, though.