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.