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New Cell Culture Gels Reveal Molecules that Promote Stem Cell Differentiation

Researchers studying stem cell differentiation on gels that imitate the nanofibrous structure and stiffness of biological tissue have discovered the specific molecules that stem cells use when selecting bone and cartilage fates.

Molecular gels with tunable stiffness used to direct stem cell fate. ( Credit: Alakpa et al./Chem 2016)

When used in standard stem cell cultures, these molecules that consist of mainly lipid and cholesterol metabolites acted as a guide to the stem cells to produce desired cell types.

The study has been published in the July 27 edition of Chem - Cell Press’s first physical science journal. The article illustrates how new biomaterials can eliminate the guesswork involved in identifying factors that drive stem cell differentiation.

It is a known fact among researchers that a hydrogel surface’s stiffness can instruct stem cells to differentiate - for instance, the result of a rigid surface would be bone cell formation, whereas the result of soft surfaces would be an increase in neuron-like cells.

Supramolecular chemist Rein Ulijn of the City University of New York and the University of Strathclyde used this data to formulate a method to create gels that are based on integrating small building-block molecules that impulsively form a network of nanosized fibers, the concentration of which could be modified to regulate the stiffness of the resulting gel.

By imitating the stiffness of cartilage (15 kilopascal) or bone (40 kilopascal), the gel makes stem cells applied to its surface to differentiate.

This paper is a great example of how chemistry can help make step changes in biology. As a biologist, I needed simple yet tunable cell-culture gels that would give me a defined system to study metabolites in the laboratory. Rein had developed the chemistry to allow this to happen.

Matthew Dalby, Professor, University of Glasgow

Cell culture gels currently available are mostly animal derived, which can impact the reproducibility of results or, if artificial, would require coupling of cell-adhesive ligands or coatings.

The gel created by Ulijn is made up of two simple synthetic peptide derivatives: (1) a component that sticks to copies of itself with high directional preference, causing spontaneous formation of nanoscale fibers when the molecules are dissolved in water, and (2) a surfactant-like molecule that links with the fiber surface and offers simple, cell-compatible chemical groups. The components are bound together by moderately weak and reversible interactions (e.g., aromatic stacking and hydrogen bonding).

Variants of the gels created during this research are available via a spinout company, Biogelx, Ltd., where Ulijn works as Chief Scientific Officer.

We wanted a platform that provides nanofiber morphology and as-simple-as-possible chemistry and tunable stiffness to serve as a blank-slate background so that we could focus on changes in stem cell metabolism. Matt and his team performed metabolomics analysis to find out how the key metabolites within a stem cell are used up during the differentiation process.

Rein Ulijn, Chemist, City University of New York

Most of the time, scientists use transcription factors as ingredients to induce stem cell fate, but Dalby and Ulijn hypothesize that specific metabolites “fuel” the pathways that result in inconsistent concentrations of transcription factors that coerce these changes.

The research features one specific called cholesterol sulfate, which was discovered to be used up during osteogenesis on a rigid matrix and consecutively could be applied to change stem cells into bone-like cells in a dish. In the study paper, the researchers reveal how it could impact proteins that drive the transcription factors that transcribe key bone-related genes to promote bone formation - thus illustrating a connection between metabolite usage and activation of transcription factors.

A forewarning of the study is that the gel does not accurately imitate the microenvironment within the body, so it is not apparent if stem cells act differently on the designed gel surfaces. Although the complete list of metabolites obtained from the analysis is just beginning, “it could certainly point researchers in the right direction,” Ulijn says.

Our ambition is to simplify drug discovery—by using the cell’s own metabolites as drug candidates. For example, cholesterol sulfate, which our rigid gel revealed as critical to bone cell differentiation, could be a safer solution (e.g., minimal off-target effects) for treating osteoporosis, spinal fusion, and other bone-related conditions. Presently, growth factors are used, but these can lead to unwanted collateral damage, and government agencies in the UK and US have published warnings against their use.

Matthew Dalby, Professor, University of Glasgow

“That you can use simple metabolites like cholesterol sulfate, which is readily available, to induce differentiation is in my view very powerful if you think about this as a potential drug candidate,” Ulijn adds. “These metabolites are inherently biocompatible, so the hurdles to approval are going to be much lower compared to those associated with completely new chemical entities.”

Going forward, the researchers intend to investigate how metabolites could be used as therapeutic compounds by studying their depletion during cellular modification with regard to diseased states. They also aim to develop the chemistry behind the materials so that it could be possible for gels to better imitate  highly complex cellular environments further than the control of stiffness alone, as well as study how dynamic modifications in matrix properties - a trademark of the stem cell niche - can be imitated  in the laboratory.


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