Image by Arek Socha from Pixabay
Humans use various ways to communicate with each other. Through different body gestures, verbal vocalisation, and written text. Internally, however, communication gets a lot more complicated – our organs, tissues, and cells communicate through multidirectional interactions between the nervous system, circulatory, and endocrine systems. Supporting these systems are the extracellular vesicles (EV) – nanoparticles derived from our cells that can deliver materials such as proteins and minuscule nucleic acids, within and between cells, acting very much like messengers.
This characteristic makes these cell-released particles an attractive therapeutic target, especially for the treatment of metabolic diseases such as obesity and type-2 diabetes mellitus (T2DM), where cell-to-cell communication plays a significant role in disease progression. However, despite its intriguing status, the current understanding of extracellular vesicles – when and how it is regulated – is still very lacking.
Tan Chee Fan (left) and Assoc. Prof Sze Siu Kwan Newman (right)
Excitingly, a recent study by Associate Professor Sze Siu Kwan Newman and Ph.D. student Tan Chee Fan, from the School of Biological Sciences (SBS) has revealed new insights in this field. Through an array of bioinformatics and proteomics analysis techniques, Assoc Prof Sze and his team of scientists have managed to identify a group of Cathepsin proteins that could potentially be the key to regulate the production of extracellular vesicles, thus opening the doors for new therapeutic targets for metabolic diseases.
“The field of EV biology has offered a new paradigm on how our body communicates at a cellular level in a targeted manner. In this study, we discovered Cathepsin’s role in regulating EV biogenesis,” commented first author and Ph.D student Tan Chee Fan.
Deciphering more by looking into
the rate of protein production
In the study, the team designed a novel methodology that was adapted from SILAC mass spectrometry, a technique commonly used for protein identification and quantification. The modified technique enabled the team to not only quantify the proteins found in the cells, organelles, and extracellular vesicles but could also study the rate of production of the proteins.
Assoc. Prof Sze
“As metabolic disorders, obesity and T2DM become the biggest epidemic of this century, we developed a new pulse/trace method to study how hypothalamic cells sort cellular proteins into exosomal cargo for secretion to control distal organs’ metabolisms,” shared Associate Professor Sze.
Since extracellular vesicles are responsible for transporting materials within and between cells, a change in the rate of production of transported proteins and proteins required to generate the extracellular vesicles could suggest a relationship between the proteins and the regulation of extracellular vesicle biogenesis as well as the functional roles of the extracellular vesicles.
Relationship between
hypothalamic EVs & Cathepsin proteins
Believing that targeting dysregulated extracellular vesicles from the hypothalamus is the key to treating metabolic disorders, the team studied the hypothalamic extracellular vesicles’ protein turnover in hypothalamic cell lines and found, in particular, Cathepsin D (CTSD) to be a promising regulator of extracellular vesicle production.
“The hypothalamus is the ‘master regulating center’ and decoding the messages from this command center will enable us to develop novel interventions to regulate energy metabolisms in other organs over the whole body. To this end, we found numerous de-novo synthesized proteins that were preferentially sorted into the EVs in the hypothalamic cells,” explained Assoc. Prof Sze.
When CTSD was chemically inhibited, results suggested an increase in extracellular vesicle production and a change of material composition within the extracellular vesicles. Additionally, CTSD is a lysosomal protein. These proteins are highly related to lysosomes which are organelles found within the cells. These organelles are often involved in important cellular processes and hold a role in digesting excess or cellular wastes. And, when there is an inhibition of lysosome activity, many studies have shown that extracellular vesicle production will increase. Taken together, this makes CTSD a highly relevant protein in extracellular vesicle biogenesis.
Looking ahead…
While these findings are exciting, there is still more work to be done. The study helmed by Prof Sze was performed in vitro with a neuronal cell line. This means, experimental conditions are unlikely to wholly represent a human body and therefore, more research still needs to be done in physiological and pathological settings to confirm the important regulatory proteins in extracellular vesicle biogenesis. With that said, this study, however, has narrowed down the list and created a closer starting point to the end.
Tan Chee Fan
“As the hypothalamus is the master regulator of energy metabolism, our work laid the foundation towards the understanding of an alternative communication mechanism by the hypothalamus. The future aim of this project is to mitigate the global epidemics of metabolic syndrome by modulating the function of these hypothalamus EVs,” concluded Chee Fan.
The research article on this study can be found at Exploring Extracellular Vesicles Biogenesis in Hypothalamic Cells through a Heavy Isotope Pulse/Trace Proteomic Approach.
More about Assoc. Prof Sze
Associate Professor Sze Siu Kwan Newman from the School of Biological Sciences
Assoc. Prof Sze joined SBS in 2006 where he is currently leading a Proteomics lab. He focuses on developing mass spectrometry-based technology for biological research with aims to identify novel disease targets and therapeutics to help with human diseases. With his team, he has attained many successful discoveries including a highly cited 2010 research on tumour progression where the lab found that a hypoxic environment was a stimulant that caused hypersecretion of extracellular vesicles in tumor cells.