Some people are born football players, others are made for basketball: Yi Zhang, PhD, reaches often for this metaphor as he explains his research with stem cell differentiation, recently published in Stem Cell Reports.
Stem cells are well-known for their ability to differentiate, or transform, into different types of cells. Two types of stem cells—embryonic stem cells and induced pluripotent stem cells—are able to ultimately change into any human cell. But that doesn’t mean all stem cells in these groups are equal: They have certain molecular features that bias them toward transforming into particular cell types. The ability to predict a stem cell’s differentiation bias would enable scientists to select a specific embryonic or induced pluripotent cell line to create cells for different applications—like grooming some youth athletes for football, others for basketball.
Zhang’s lab has identified a gene that acts as a powerful biomarker—physical or chemical characteristic whose appearance heralds a particular process—predicting a pluripotent stem cell’s tendency to differentiate into endoderm, cells on the inner layer of an embryo that become lung, digestive tract, pancreas and liver cells. It could be the first of a family of genetic biomarkers that guide scientists trying to create different cells and tissues for regenerative medicine.
“If you want to differentiate stem cells into pancreas cells, for instance, you want to start with a line with a high differentiation potential for endoderm,” explains Zhang, an investigator at Boston Children’s Program in Cellular and Molecular Medicine, in a press release. “Every cell line has its own strengths, and the challenge is knowing what those strengths are.”
Currently, to find the right cell line for the job, scientists have to test their chosen differentiation process on several different lines, at the cost of time and materials that could be focused on the experiment itself. Having a biomarker to predict the differentiation potential for a particular lineage would mean not having to go through this process.
The biomarker’s discovery was serendipitous: Wei Jiang, PhD, a postdoctoral fellow in Zhang’s lab, had been testing different cell lines to find the best ones for cultivating endoderm. He noticed that the cells that differentiated most efficiently also strongly expressed a gene called WNT3. The gene didn’t seem to be functionally necessary for the cells, so Jiang became curious about what the increased level of WNT3 meant.
Jiang and his colleagues got to work measuring the lab’s stem cell lines. As Jiang describes, “We saw that WNT3 showed perfect correlation with endoderm differentiation efficiency. So we then questioned whether the link was functional, what the role of WNT3 was and how stable the correlation was if we looked at different protocols or even cells from different labs.”
Jiang and Zhang borrowed several untested cell lines from other laboratories and found that they could use WNT3 levels to predict each line’s differentiation habits: Those that had a lot of WNT3 activity preferred to turn into endoderm, while those that did not more readily turned into mesoderm or ectoderm (the other two major tissue lineages).
Though they aren’t quite sure why it works yet, Zhang hypothesizes that WNT3 acts to help prime cells’ differentiation by triggering other genes—like an “on your mark” for a race. It doesn’t start the process, but it prepares them for that particular transformation. Case in point: By turning up a given cell line’s expression of WNT3, Jiang and Zhang increased its preference for developing into endoderm, while cutting back WNT3 expression reduced it.
Zhang and Jiang hope that researchers will find molecules that work similarly to push cell development in other directions, perhaps creating a scoring system for cells’ potential.
“Previously, people realized that different pluripotent stem cell lines showed huge variation in terms of lineage differentiation, but they didn’t know whether this difference could be predicted using simple biomarkers,” says Jiang. “Our study clearly showed the answer is ‘Yes.’ Also, our study suggests that ‘bad’ cell lines could be converted into ‘good’ cell lines with higher endoderm differentiation efficiency by manipulating WNT3 level.”
Knowing this trick, labs could ensure access to efficient cell lines and a quick way to identify a cell line’s strengths without going through the whole differentiation process. Ultimately, Zhang and Jiang hope that researchers will find molecules that work similarly to push cell development in other directions, perhaps creating a scoring system for cells’ potential.
“We hope other labs will be inspired to test different cell lines and find other markers for other lineages,” Zhang says. Then scientists will be able to find more “football players” or steer more athletes in that direction.
Wei Jiang, Donghui Zhang, Nenad Bursac and Yi Zhang (2014). WNT3 Is a Biomarker Capable of Predicting the Definitive Endoderm Differentiation Potential of hESCs Stem Cell Reports DOI: 10.1016/j.stemcr.2013.03.003