Key Molecules Tha Control Stem Cell Fate Identified

Adult stem cells, such as mesenchymal stem cells and blood-vessel-associated pericytes represent patient-specific stem cells that are excellent candidates for regenerative medicine. To that end being able to control the differentiation of these stem cells with drugs or small molecules is extremely desirable for eliciting targeted tissue and organ regeneration.

However, identifying these stem-cell-inducing molecules is time-consuming, expensive, and fraught with dead ends. Is there an easier way to control the behavior of stem cells in culture or in your own body?

Research from the City University of New York (CUNY) suggests that the answer to this question might be “yes.” According to Rein Ulijn from CUNY, “Simple small metabolites present in the body already can dictate cell behavior.”

In collaboration with Matthew Dalby from the University of Glasgow, Ulijn and his colleagues discovered that when they grew stem cells on a gel-like medium, the stiffness of which could be easily adjusted, they found molecules that could direct the differentiation of cultured stem cells. As an added bonus, they could direct the differentiation of cultured stem cells much more cheaply.

Ulijn and Dalby began their collaboration in 2011 after other laboratories had demonstrated that the stiffness of the medium could affect the differentiation of stem cells. “On a stiff gel you might get bone-like differentiation,” Ulijn explained. “On a softer gel differentiation into neurons is more likely.” They wanted to use such a system to identify small molecules that can control stem cell differentiation in culture. Such a finding could also “aid the discovery of natural metabolite-based drugs,” added Ulijn added. Such natural-based drugs could be used to, for example, reinforce bones in osteoporosis.

Dalby was interested in the role metabolites played in this stem cell differentiation. Unfortunately, these metabolites are present in fleetingly low concentrations. To complicate the picture, the different formulations of stiffer and floppier materials can mask subtle changes in metabolite concentration. Ulijn found a way around this problem by turning to the two-component peptide gels made by Biogelx (full disclosure: Ulijn serves as the chief scientific officer for Biogelx). Fine-tuning the concentration of the two different gel components changes the rigidity of the gel without changing any other components of the gel that might mask metabolite variation.

The researchers therefore studied concentration changes of hundreds of metabolites during stiffness-controlled stem cell differentiation of stem cells into bone or cartilage. Several metabolites that seemed to make a significant difference for stem cell differentiation were lysophosphatidic acid, which drove stem cells to form cartilage and cholesterol sulfate, which helped stem cells form bone. When Ulijn and his coworkers fed these metabolites to standard stem cell cultures, they differentiated into the desired cell type.

Helena Azevedo of Queen Mary University of London, said, “We will see, for sure, studies exploiting these metabolites for inducing controlled differentiation of stem cells.” She went on to called this study “highly innovative” and said that it might directly influence future stem cell differentiation experiments; particularly those that involve the formation of cartilage or bone.