New Findings in the Control of Stem Cell Differentiation

Nodal Activin Pathways Image Source
Researchers from the Genome Institute of Singapore have helped to untangle how stem cells might be controlled with a single signaling pathway -- the nodal activin pathway.

Morphogens are secreted signaling molecules that orchestrate the spatial distribution and sequence of cellular differentiation events throughout embryonic development. The specific cell types, their localization and order of induction from recipient stem cell populations are determined by the concentration gradient of morphogens diffusing from the source of secretion. Previous studies have proposed some of the models by which morphogen gradients are initiated, established and stabilized including the level of receptor occupancy, positive/negative feedback and feed forward mechanisms [1]–[3]. However, little is understood about the transcriptional mechanisms responding to variable receptor activation and how they permit pluripotent stem cells to interpret signaling levels and direct the appropriate differentiation programs during mammalian development....

Nodal and Activin are morphogens of the TGFbeta superfamily of signaling molecules that direct differential cell fate decisions in a dose- and distance-dependent manner. During early embryonic development the Nodal/Activin pathway is responsible for the specification of mesoderm, endoderm, node, and mesendoderm. In contradiction to this drive towards cellular differentiation, the pathway also plays important roles in the maintenance of self-renewal and pluripotency in embryonic and epiblast stem cells. The molecular basis behind stem cell interpretation of Nodal/Activin signaling gradients and the undertaking of disparate cell fate decisions remains poorly understood. Here, we show that any perturbation of endogenous signaling levels in mouse embryonic stem cells leads to their exit from self-renewal towards divergent differentiation programs. Increasing Nodal signals above basal levels by direct stimulation with Activin promotes differentiation towards the mesendodermal lineages while repression of signaling with the specific Nodal/Activin receptor inhibitor SB431542 induces trophectodermal differentiation. To address how quantitative Nodal/Activin signals are translated qualitatively into distinct cell fates decisions, we performed chromatin immunoprecipitation of phospho-Smad2, the primary downstream transcriptional factor of the Nodal/Activin pathway, followed by massively parallel sequencing, and show that phospho-Smad2 binds to and regulates distinct subsets of target genes in a dose-dependent manner. Crucially, Nodal/Activin signaling directly controls the Oct4 master regulator of pluripotency by graded phospho-Smad2 binding in the promoter region. Hence stem cells interpret and carry out differential Nodal/Activin signaling instructions via a corresponding gradient of Smad2 phosphorylation that selectively titrates self-renewal against alternative differentiation programs by direct regulation of distinct target gene subsets and Oct4 expression. _PLoS Genetics

This finding has profound implications for experimental approaches to guided stem cell differentiation and / or stem cell self renewal. The ability to control multiple distinct sets of genes by titrating the dose of signaling molecules is likely to prove a very powerful tool for geneticists, stem cell researchers, and bio-developmental scientists.

In other longevity news, a team of scientists from multiple universities has helped elucidate how cryoprotectant molecules protect proteins from freezing. Future research should enlarge the scope of study to discover optimal cryoprotectants for cells, tissues, organs -- and eventually for entire organisms.

It is quite possible that different types and levels of cryoprotectant will prove optimal for different organs and tissues, so that in order to viably freeze and thaw an entire organism -- say, a human being -- a complex process of multiple simultaneous organ infusion with several cryoprotectants would be necessary.

Restoring Lost Memories: Hope for Long-Lived Brains?

Our brains were not really meant to last for 80, 90, 100 years. Metabolic debris accumulates, DNA repair mechanisms break down, and function tends to degenerate at variable rates -- depending upon the individual's lifestyle and genetic complement. Now scientists at USC in Los Angeles are learning how to restore lost memories -- at least in rats.

Theodore Berger at the University of Southern California in Los Angeles, and colleagues, used electrodes implanted within the hippocampus to record patterns of brain activity while rats learned how to operate a sequence of levers to gain a reward.

Next, the team obliterated the memory of the task by injecting chemicals into the hippocampus that block the signalling between neurons needed to access long-term memories. When tested, the rats could no longer perform the task.

However, when the team used the electrodes to stimulate the brain with the same pattern of activity recorded when the rats first learned the task, their ability to operate the levers in the correct sequence was restored. The rats could temporarily access the original memory, even though the chemical blockade was still in place. When fed scrambled versions of the code, the rats could no longer perform the task.

Ultimately, the researchers hope to create implants that contain codes for 20 to 30 simple tasks, enabling people with brain damage to recover basic abilities that have been lost, such as speaking or dressing themselves.

Berger says that encoding these tasks will be very difficult. "These are very basic capabilities that we are investigating, and it has taken us a lot of effort to get this far," he says. _NewScientist

It is unlikely that the USC team actually encoded rat brain activity with any accuracy. Rather, the team was able to encode a sufficient "hint" so as to allow the rats to internally re-assemble or approximate their former memories. Even in a rat's brain, mental codes are more difficult than even the best scientists understand.

But it is a promising beginning that provides hope for the long-lived brains of the future.

Article Abstract from Jnl of Neural Engineering