Monthly Archives: March 2014

What a nerve! Skin cells taken from people with bipolar disorder have been turned into brain cells. These in turn are offering up clues about the changes in the brain that drive the disorder, and may also provide a way to test new treatments.

About three in every 100 people develop bipolar disorder a mental illness characterised by episodes of depression and euphoria. But the condition remains poorly understood.

That's because it would be too invasive to obtain and study viable nerve cells from the brains of people with the condition.

There are also no good animal models, because bipolar disorder although highly heritable has, for the most part, not been linked to any specific genes that can be studied using animals.

"People say the condition is probably the result of a lot of small contributions by multiple genes," says Sue O'Shea at the University of Michigan in Ann Arbor.

Now O'Shea and her colleagues may have found an ethical way to make a genetic model of the condition. First, they took skin samples from 22 people with bipolar disorder and 10 healthy volunteers. They induced these adult skin cells to return to a stem-cell-like state, creating what are called induced pluripotent stem cells (iPSCs) and then encouraged these cells to mature into neurons.

O'Shea was surprised to find that neurons derived from people with bipolar disorder grew differently from those from people without the condition. "I was expecting it would take decades of careful science before we would find any real differences," she says.

The "bipolar" neurons expressed more genes involved in calcium signalling between cells. Interfering with this cellular communication can disrupt healthy brain activity, and calcium signalling has already been implicated as a likely factor in diseases like bipolar disorder. Treating the cells with lithium a common treatment for bipolar disorder reduced the abnormal signalling to normal levels.

Some of the genes which influenced activity of neurons were not previously known to be involved in bipolar disorder. "Some of the genes misdirect neurons to the wrong area in the brain," says O'Shea.

This could cause some neurons programmed to become part of one brain region the cortex, for example to express genes typical of a different brain region entirely. Such a genetic difference might provide clues as to why certain people are predisposed to developing bipolar disorder in later life, she says. What might trigger the condition is still unclear.

Original post:
Stem cells offer clue to bipolar disorder treatment

A new scaffold material based on a biocompatible silk-alginate hydrogel, which can be made soft or stiff, could provide the just right environment to culture stem cells for regenerative medicine, say researchers.

Stem cells could provide powerful new treatments for intractable autoimmune diseases, cancer, and other conditions. But the use of stem cells in the clinic requires a robust and reliable culture system that mimics the natural microenvironment of the cell. This microenvironment provides crucial direction to the function and viability of stem cells but is tricky to recreate artificially.

The complex make-up of the microenvironment, which includes a network of proteins like collagen or elastins forming an extracellular matrix (ECM), decides the fate of stem cells through a number of different, complementary mechanisms. For example, the stiffness of the matrix, determined by the orientation and elasticity of the fibers making up the ECM, as well as its fluid handling properties, the presence of signaling molecules and the creation of cytokine gradients all have a profound effect on the growing stem cells.

The new silk-alginate biocomposite developed by researchers at Stanford University and Queens University in Canada could provide a simple solution to tackle these complex problems. The hydrogel is formed from a mixture of alginate and silk in solution, which rapidly gels when immersed in CaCl2 [Ziv, et al., Biomaterials 35 (2014) 3736-3743, http://dx.doi.org/10.1016/j.biomaterials.2014.01.029%5D. But crucially, the stable hydrogel can be made soft and flexible or stiff by controlling the silk-alginate ratio and the concentration of crosslinking ions. Varying the silk-alginate ratio during fabrication changes the elasticity of the hydrogel, which can determine the yield of a particular differentiation path. The elasticity can be further fine-tuned in vitro by varying the CaCl2 concentration. Being able to modify the stiffness of the scaffold material to such a degree gives researchers a powerful means of guiding stem cell survival and differentiation.

The ability to change the elasticity [of the silk-alginate hydrogel] helps mimic the natural process that is happening in the stem cell niche and improves the stem cell commitment into desired differentiation paths, explains first author Keren Ziv, of the Molecular Imaging Program at Stanford.

Using the protein laminin to enhance cell adhesion and promote cell growth, the researchers cultured mouse embryonic stem cells in the new scaffold material and transplanted samples into live mice. The silk-alginate hydrogel appears to be better at maintaining the survival of stem cells once transplanted than the best current alternative, matrigel.

But there is a long way to go until the new scaffold material could be used in the clinic for stem cell applications, cautions Ziv. Ideally, such applications would require the injection of the hydrogel in liquid form followed by gelation but this is currently unfeasible in vivo. The long-term stability of the hydrogel also needs to be scrutinized, along with its effect on other cell types. These issues are tractable, however, say the researchers, and are the focus of on-going efforts.

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Adjustable scaffold tunes stem cell growth