Cell distortion enhances understanding of diseases

22 December 2017

New research on human red blood cells has distorted our knowledge of cell regulation.

For the first time, researchers at the University of Sydney have shown that controllable physical distortion of human red blood cells leads to accelerated metabolic processes inside them and thus enhanced energy transduction. The rate enhancements are nearly two-fold. In addition, cation flux across the cell membrane is seen to increase around five-fold.

"This is the first time a quantitative link between cell shape and metabolism has been reported." Said Professor Emeritus Philip Kuchel.

These findings have implications for understanding the pathology of sickle cell anaemia and malaria that involve red blood cells, and more generally in all tissues including cancer.

Anything that affects the shape of red blood cells influences the ease with which they pass through the narrow capillaries in our tissues; and this occurs on average every 30 seconds.

Diseases by definition are derangements of cell function that impinge on cell shape and volume.

In malaria, the red blood cells are distorted by the internal parasite and they become less flexible. The red blood cells become stuck in the capillaries, restricting blood flow to muscles, the brain and, in fact, any tissue. This is the basis of the signs and symptoms of this disease.

The biochemical mechanisms that operate in maintaining shape and volume of cells are therefore amongst the most fundamental of all for living systems.

A biochemical mechanism for the link between the change in cell shape and enhanced metabolism has been proposed.

"The effect is mediated by a recently discovered membrane-embedded protein Piezo1, which senses changes in the tension or curvature of the cell membrane and opens up transport of cations in and out of the cell," said first author of the findings, recently published in Science Advances, Professor Emeritus Philip Kuchel from the School of Life and Environmental Sciences.

So how do you distort red blood cells given that they are so tiny (a million fit into the size of a pinhead)?

Philip explains, "The initial challenge was to create an experimental apparatus that could reproducibly and reversibly distort cells. This was achieved by suspending them in a gel which resides in an elastic tube that in turn sits inside a glass tube. The elastic tube is stretched or compressed in a controlled way in order to distort the cellular contents."

Importantly, this non-invasive technique allowed signals from metabolites and ions to be recorded while the cells were suspended in the gel.

"The concentrations of metabolites and ions were measured using a technique called Nuclear Magnetic Resonance (NMR) Spectroscopy which measures the selective absorption of radio waves, and hence identification of various molecules and ions, in a sample that is placed in an intense magnetic field."

"This a great advance for NMR of cellular systems and is the culmination of 13 years of research into the use of variably stretchable gels to elicit special spectroscopic responses."

"The discovery will be important for understanding how cells in general regulate their shapes and volume, and potentially help with treating diseases involving the distortion of the normal biconcave-disc shape of red blood cells, such as malaria, sickle-cell anaemia, hereditary spherocytosis, and stomatocytosis, and generally for any cell types," Philip said.

These researchers, were funded by an Australian Research Council Discovery Projects grant, and have expressed their gratitude to Professor Iain Young (Head of the School of Life and Environmental Sciences) and Professor Joel Mackay (Biochemistry, Cellular and Molecular Biology Cluster Chair) for their continuing encouragement and support, and Ann Kwan for her efforts in managing the NMR facility.