Mitochondrial Membrane Potential Identifies Cells with Enhanced Stemness for Cellular Therapy

http://www.sciencedirect.com/science/article/pii/S1550413115005690

Sukumar M, Liu J, Mehta GU, Patel SJ, Roychoudhuri R, Crompton JG, Klebanoff CA, Ji Y, Li P, Yu Z, Whitehill GD, Clever D, Eil RL, Palmer DC, Mitra S, Rao M, Keyvanfar K, Schrump DS, Wang E, Marincola FM, Gattinoni L, Leonard WJ, Muranski P, Finkel T, Restifo NP

Cancer immunotherapy involves using the immune system to target and eradicate tumours. One method is to isolate and transfer immune cells into the patient. There are a number of different kinds of immune cell, one of which is called the T cell. T cells themselves divide into a number of subtypes, two of which are: effector memory (EM) and stem-cell memory (SCM) T cells. It is known that SCM cells are able to persist for longer periods of time, and are more effective in attacking tumour cells than EM cells. It is therefore desirable to be able to enrich for SCM cells, in a mixed population of T cells, to deliver a more potent immunotherapy.

In this study, the authors stain a mixed population of T cells with a chemical which causes cells with a large mitochondrial membrane potential (ΔΨm) to fluoresce more strongly (using TMRM). They find that fractions with low membrane potential are enriched for SCM cells, whereas fractions with high membrane potential are enriched for EM cells. Indeed, the authors show in a variety of cell lines that low ΔΨm is associated with stem-like properties.

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Thoughts:
Curiously, low ΔΨm cells had a lower glycolysis rate, and higher spare respiratory capacity, and lower baseline respiratory rate, compared to high ΔΨm cells. Low ΔΨm cells tend to favour fatty acid oxidation, which provides an alternative substrate to glucose for energy production. However, fatty acid oxidation drives the Krebs cycle, which in turn can drive oxidative phosphorylation. So, given that these cells are not undergoing glycolysis, one might expect ΔΨm low cells to have a higher resting oxygen consumption rate? It would be interesting to know the ATP concentration of the ΔΨm low cells: my guess would be that they have a lower ATP concentration?