Lipidomics Opens Doors to Understanding Stem Cell Differentiation

It has long been known that the fats we consume in our diet can have an impact on our health. However, their implications on differentiation of our cells has not previously been understood. With the help of lipidomics, scientists from The University of Texas have shown that dietary fat composition influenced mesenchymal stem cell fate, providing insight into how to improve “healthy aging”. This work was recently featured in our news items.

We spoke to Professor Ilya Levental (IL), the paper's last author and assistant professor of integrative biology and pharmacology at McGovern Medical School at UTHealth, to learn more about his group’s exciting work on cellular lipidomics and where it is taking his future investigations.

KS How did you come to be working in this field? Is lipidomics an area that you have previously explored?

IL Actually this project started from the most basic of questions combined with serendipitous access to a neat model system. I was always curious whether the membranes of different cell types were different, but it was hard to test this question using cultured cell lines because there are so many potentially confounding variables (culture conditions, tissue / organism of origin, isolation conditions, etc). However, my wife (who is now the co-PI of my lab and is the first author on our recent paper) was working at the time in a biomaterials lab that used Mesenchymal Stem Cells.  We realized that these cells were perfect for testing whether plasma membranes change during controlled in vitro differentiation.

Our entry into lipidomics was the result of this original observation. Once we discovered that the plasma membranes of different cells had different biophysical properties, the immediate question was “Why?”.  And the obvious answer for us seemed to be that they must be made of different lipids. Coincidentally, my former postdoc advisor (Dr Kai Simons of the Max Planck Institute of Cell Biology and Genetics in Dresden, Germany) and his collaborators had spent two decades developing a robust and quantitative platform for doing high precision, comprehensive lipidomics.  So we teamed up with his team and found these surprising differences in the lipids of bone-depositing cells (osteoblasts) versus other types (fat cells and stem cells).

The link to dietary fats came directly from our observations.  We found that the osteoblasts tended to accumulate polyunsaturated fatty acids in the lipids of their membranes, so we reasoned that we could induce their membrane phenotype by ‘feeding’ them with such fats.  And to our surprise, it actually worked!!

KS Spectroscopy, chromatography and mass spectrometry are key techniques utilized in your paper. How have technical advances in analytical techniques and equipment facilitated your work?

IL This is an easy one…  this project would not have existed without the lipidomics facilitated by the new generation of mass spectrometry equipment and techniques.  We would have been stuck at the observation that different cells membranes have different biophysical properties, without any way to show the detailed lipid changes that produce those properties.  With the technologies that are now commercially available (including through Lipotype GmbH, our partners in this work), it was quite easy to do what just a few years ago would have been extremely time- and resource-intensive, and probably untenable for us.

KS What have the major challenges been to this project?

IL The most significant challenge to this project was defining the molecular mechanism by which a broad effect like remodeling of the membrane phenotype in a cell is actually transduced into a cellular response.  First, by changing the membrane, we potentially affect dozens, if not hundreds, of cellular processes. Second, the dietary fats that we use to modulate membrane phenotypes have a variety of potential side-effects unrelated to their role as lipid components.  So, these complications made it very difficult to define the “how” behind our observations.  Ultimately, we were able to identify the important pathways using transcriptomics and proteomics approaches, but I should say that we do not fully understand the paradigm for how complex inputs like wholesale remodeling of cellular membranes are sensed by the cell.  It seems unlikely to us that there is a single protein or pathway that is affected by such large-scale changes.

KS Research often throws up as many questions as it answers. Have there been questions generated by this research that you wish to explore further?

IL Very much so!!  One of these is mentioned above…  how is a broad, non-specific input like different membrane composition and fluidity sensed and transduced by the known cellular signaling machinery?  We also discovered a related dilemma:  if the membrane context is so important to protein function, how is it possible that dramatically changing the membrane does not completely disrupt normal cellular function?  We find that even large changes in membrane phenotypes are not toxic to cells, so there must be some really robust homeostatic mechanisms that allow cells to survive despite major disruptions to their core architectural components.  The final question is the most related to human health and disease: what are the effects of changing membrane phenotypes in other cell types?  Obviously dietary lipids do not only affect the cells we study here, but also most cells in the body.  How do those cells respond to membrane perturbations?  And are there connections between those responses and the deleterious or beneficial effects associated with various dietary lipids?  These are all questions we are excitedly pursuing now.

KS What do you think are the major impacts of your findings? You mention the role of dietary fats and possible implications for clinical conditions, how do you think they may affect healthcare in the future?

IL The links between diet and clinical outcomes are some of the strongest correlations in biomedicine. Replacement of dietary saturated fats by polyunsaturated fats is beneficial in a variety of contexts, most notably cardiovascular disease. But in many cases, these remain correlations without clear explanations.  Our observations suggest that remodeling of cell membranes by dietary lipids, while often-overlooked, is a key mechanism by which our diet affects our physiology. If true, this conclusion may offer a variety of potential interventions for some of today’s most prevalent diseases. First, changes to lipids are easy and cheap to affect – supplements and dietary changes are accessible to almost anyone. Second, lipid biochemistry and metabolism are classic fields that are relatively well understood, with a rich pharmacology of available interventions. Thus, we believe that modulation of cellular membranes represents a somewhat overlooked area of significant biomedical potential.

Prof. Ilya Levental was speaking to Dr Karen Steward, Science Writer for Technology Networks.