The role of cellular metabolism and memory on reprogramming

26 March 2018
Dr Alex Harvey and team are investigating the stability of human induced pluripotent stem cells
A collaborative study, between scientists from the University of Melbourne and CSIRO has revealed more about the stability of human pluripotent stem cells, with important implications for the development of therapies using these cells.

Human pluripotent stem cells have great promise as a source of cells for regenerative medicine because they can be converted into any cell type in the body. Human induced pluripotent stem (iPS) cells, cells that have been transformed from an adult cell into a stem cell (a process known as reprogramming), are of particular interest because they can be used to generate cellular models of disease, and are projected to be used for patient specific cellular replacement therapies. However, scientists are concerned that the process of reprogramming not only leads to genetic and cellular irregularities, but also retains the memory of their adult cell type, which may subsequently compromise the usefulness of iPSC cells for cell therapy.

Work by postdoctoral researcher Alexandra Harvey at the University of Melbourne focuses on defining the nutrient requirements of stem cells in the dish, and how changing the nutrients provided can impact cell identity, function and quality. Accompanying the transformation of adult cells back to a stem cell-like state, is a change in how the iPS cells use nutrients from their surrounding environment. Alex, along with other members of the Gardner lab, was interested in whether iPS cell metabolism was similar to embryonic stem (ES) cells, the ‘gold standard’ of stem cells, and was equally capable of appropriately responding to a change in nutrient availability.
In collaboration with Dr Andrew Laslett at CSIRO, their latest study published in PLOS One analysed the pattern of nutrient use in iPS cells in response to oxygen availability in the surrounding incubator atmosphere. Although human ES cells, and preimplantation embryos, produce a well-characterised metabolic response to oxygen availability, the iPS cells examined failed to elicit these changes. Of the small number of iPS cell lines studied, only one was able to regulate carbohydrate use. Furthermore, other nutrients were variably affected across each of the cell lines. Yet, by all other standard measures of stem cell characterisation, these lines appear normal.
Significantly, the cells displayed a metabolic response to oxygen similar to that elicited by the adult cell type from which they were derived, identifying that these cells harbour a “metabolic memory” of their adult cell past. The team’s data suggest that iPS cell metabolism is wired differently to that of ES cells, and their developmental counterpart, the embryo, and this may mean that these cells are less able to respond to other types of signals. This is particularly important given that they must respond to the prevailing local environment within the body when transplanted.

Abnormalities in cell metabolism have been implicated in many diseases, including cancer, neurological diseases and diabetes. While the data generated are an important step towards understanding the frequency and types of changes that occur in iPS cells, they highlight the importance of evaluating stem cells using physiological analyses, to ensure cells are normal and hence safe for therapeutic applications, and that any changes being described for iPS cell models of disease are inherent to the disease, not to the process of creating the model.

Our understanding around how nutrients can act as signals in their own right, and how they link the environment to (epi)genetic change, is now beginning to gain momentum, an area of research referred to as Metaboloepigenetics. Establishing whether perturbations in nutrient use persist in subsequent cells, whether metabolic memory interferes with differentiating stem cells into adult cell types, and how individual nutrients impact cell function, will help us understand the significance of nutrients in regulating developmental processes. Understanding these factors will enable researchers to better investigate how iPS cells might be used in therapies. 

Professor David Gardner is a Chief Investigator with Stem Cells Australia; Dr Andrew Laslett is an Affiliate Investigator.  

For more information: 
Read the journal article.