I am honored to release this interview with Dr. Stefano Pluchino of the highly regarded Pluchino Lab in Cambridge, UK. Dr. Pluchino received his MD and PhD degrees at the University of Siena, Italy, and additional training at Cambridge University, UK.
Dr. Pluchino is an international expert on neuroimmunology-related applications of exosomes, with his lab exploring modalities by which neural progenitor cells (NPCs) engage in cell-to-cell communication. The focus of the laboratory is to explore cellular and molecular mechanisms regulating to the therapeutic plasticity of stem cells in preclinical models of CNS conditions, including multiple sclerosis (MS), stroke, and spinal cord injury. Enjoy!
Interview with Dr. Stefano Pluchino of the Pluchino Lab
Cade Hildreth: What are exosomes?
Dr. Stefano Pluchino: Exosomes are naturally-occurring, small membrane vesicles that originate from the internal (late endocytic) cellular compartments to be secreted into the extracellular space by fusion with the cellular plasma membrane.
Cade Hildreth: What are other terms for exosomes?
Dr. Stefano Pluchino: Other terms for the broad category of extracellular membrane vesicles are:
- Extracellular vesicles
- Membrane particles
- Shedding (or shed) vesicles
- Exosome-like particles
In cancer, they are also called large size oncosomes, among other names.
Cade Hildreth: What types of exosomes has your research group studied?
Dr. Stefano Pluchino: My research group has a long standing interest on extracellular vesicles from stem cells of the brain. In fact, there is substantial evidence that some of the functions of brain stem cells, including their remarkable capacity of modulating immune responses – which we have identified – require sophisticated mechanisms of intercellular communication.
While some of this cell-to-cell signalling is delivered by secreted cytokines or growth factors, our recent work suggests that a key role can be attributed to a novel mechanism of intercellular communication through the transfer of exosomes/membrane vesicles from stem cells to target cells.
Cade Hildreth: What is the ability of NSC-derived EVs to consume and produce metabolites?
Dr. Stefano Pluchino: This is quite remarkable, and refers to our most recent discovery just published this month on the journal Nature Chemical Biology. In this study, combining biochemical assays and mass-spect applied to consumption/release experiments, we found that NSC-EVs harbor L-asparaginase activity, catalyzed by the enzyme asparaginase-like protein 1 (Asrgl1), which confers EVs the capability of working as fully independent metabolic units consuming asparagine and producing aspartate.
This finding is very important as it reveals a new (fully intrinsic) drug delivery capability of EVs, which in principle might be optimised to kill some cancer cells (eg those using asparagine to survive), without depleting essential nutrients required for healthy cell function.
Cade Hildreth: How can neural stem cell exosomes/EVs be used to alter their local microenvironment?
Dr. Stefano Pluchino: We have provided two clear proof-of-concept examples of how exosomes/membrane vesicles can modify the local environment, but I guess there is some more to come. One is by trafficking high affinity functional receptors for ligands of the environment to target cells, which ultimately acquire responsiveness to these ligands (work published in Molecular Cell back in 2014). The other is by consuming and producing key metabolic determinants of the environment (eg asparagine and aspartate, respectively) this recent discovery of trafficking of functionally active enzymes.
Cade Hildreth: What medical applications could result from these findings?
Dr. Stefano Pluchino: The most obvious one is the optimisation and development of stem cell free (acellular) approaches for those conditions where some of the key signalling properties of exosomes/vesicles (e.g. trafficking of proteins, metabolites, enzymes, also ncRNAs) might have a therapeutic role.
In theory, exosomes are naturally occurring nano carriers with very interesting intrinsic drug delivery capabilities. Another application might be to identify a key property in naturally occurring vesicles, and make it more potent, or more selective, upon encapsulation into synthetic nano carriers.
Cade Hildreth: What companies are working the area of exosomes/EVs?
Dr. Stefano Pluchino: There are a few growing, some of which are focusing onto EVs as diagnostic/prognostic markers in the emerging niche of ‘liquid biopsy’ more often in cancer, and others instead moving forward from the development of stem cell therapeutics for clinical applications towards the development of acellular (see above) approaches.
I am serving myself as CSO of a small biotech (CITC Ltd), which is currently pursuing a number of specific activities aimed ad translating some of these EV findings into clinically oriented business programmes and opportunities.
Cade Hildreth: What advantages do exosomes/EVs have over cell-based therapeutics?
Dr. Stefano Pluchino: There are potential advantages and disadvantages. The most obvious advantage is the acellular (no nucleus) nature of the product. However, there is not yet a standard protocol/method to select or purify highly homogeneous fractions of EVs out of tissue culture media; or to make cells producing homogeneous or stable EVs over time in culture. The standards for large scale production and druggability and translation into clinical medications of EVs in general are yet to come either.
Cade Hildreth: What advances do you anticipate will occur in the area of regenerative neuroimmunology over the next 3-5 years?
Dr. Stefano Pluchino: We envisage that EV therapeutics are indeed an additional promise in the emerging field of regenerative neuroimmunology, especially for the remarkable capacities, which are super imposable to those manifested by parental stem cells at least in vitro and in vivo in animal models, of modulating immune responses. As said, we are just a the very beginning of a long and exciting journey which major challenges will be how to translate into clinical medicines some of these seminal experimental findings.
Cade Hildreth: How can people get in touch with you to learn more?
Dr. Stefano Pluchino: We have a very active social media approach to people interested to know more and and my team can be approached either through our laboratory website (www.pluchinolab.org), Facebook or Twitter accounts, or of course by email.