STEM CELLS Young Investigator Award 2023 winner: Dr. Salvatore Fusco

Meet Dr. Salvatore Fusco – winner of the 2023 STEM CELLS Young Investigator Award. The Young Investigator Award is a prize granted annually to an early career scientist publishing a study with STEM CELLS that is deemed to be of global significance.

From Dr. Jan Nolta, Editor-in-Chief of STEM CELLS: “We are delighted to select Dr. Fusco for the Young Investigator Award. His work determining the epigenetic mechanisms that link insulin signalling to neurogenesis are highly interesting and important. The studies assist in our understanding of neural stem/progenitor cell biology and may lead to potential therapeutic intervention for metabolic disorder-related cognitive dysfunction.”

Dr. Fusco recently answered some questions about his research, career so far, and why the STEM CELLS Young Investigator Award is important to him:

1. Why did you choose to publish with STEM CELLS?
   A: STEM CELLS is a high reputation journal with a wide audience of experts about the mechanistic aspects of stem cell biology and the therapeutic potential of different types of stem cells. It was my first choice to publish our manuscript about the therapeutic efficacy of stem cell-derived extracellular vesicles against the insulin resistance-dependent pauperization of hippocampal neurogenic niche.
    

2. What inspired your investigation into Insulin Resistance-Induced Senescence?
   A: We already demonstrated how nutrient availability can modulate the proliferation of hippocampal neural stem cells (1) and that brain insulin resistance impairs brain plasticity via epigenetic mechanisms (2). Our idea was that alteration of the molecular cascade downstream of insulin receptor could affect the balance between proliferation and senescence of neural stem and precursor cells.
    

3. Can you give a brief overview of your hypothesis?
   A: We theorized that neural stem and precursor cells (NSPC) could also develop insulin resistance and that inhibition alteration of FoxO transcription factors could epigenetically dysregulate the expression of genes controlling neural stem cell fate. We also hypothesized that the molecular signals released by the neural stem cells via extracellular vesicles might influence the behaviour of neurogenic niches.
    

4. Did you encounter any methodological difficulties in your work?
   A: In vivo experiments are always challenging but are fundamental to understand whether the identified molecular mechanisms can play a role in both physiology and pathophysiology of a complex organ such as the brain. Documenting the colocalization of markers of both proliferation (i.e., BrdU) and senescence (i.e., p21) in the same neural stem cell was not easy, but the three-dimensional analysis of the subgranular zone of the dentate gyrus of the hippocampus by confocal imaging helped us to achieve the goal.
    

5. Did any of your findings surprise you?
   A: It’s well known that neural stem cells can exchange paracrine signals within the neurogenic niche.
   It was not obvious that the intranasal administration of their extracellular vesicle could deliver them into the hippocampus and that the molecules contained within their cargo were able in themselves to counteract the detrimental effects of insulin resistance on neurogenic niche.
    

6. What are the most important findings of your research? What are the wider implications?
   A: Our findings identified a novel molecular circuit converging on FoxO-mediated transcription of pro-proliferative and pro-senescence genes that underlies the insulin resistance dependent exhaustion of NSPC. The evidence that the cargo of NSPC-derived extracellular vesicles contains biomolecules regulating the NSPC fate opens the way to translational studies aimed to investigate the therapeutic potential of these vesicles in both neurological and metabolic disorders.
   Identifying the senolytic components of stem cell-derived vesicle cargo will be a great challenge for the regenerative medicine in the next years.
    

7. Are there any people that you would like to thank, either relating to your career so far or this study?
   A: First, I’d like to thank Prof. Claudio Grassi, the Head of Department of Neuroscience of Università Cattolica del Sacro Cuore, who introduced me to the field of neural stem cells several years ago and coordinated with me this study. Moreover, I want to thank all authors of the paper and the first one, Dr. Francesca Natale, who faced every experimental challenge with rigor and perseverance.
    

8. Why did you apply for STEM CELLS’ Young Investigator Award?
   A: I read about the award on the website of the journal, and I thought it could be a nice showcase to make our article known to the readers of STEM CELLS. A few years ago, I created my own independent research group, and this award could represent an important recognition for my career.
    

9. What does winning the STEM CELLS Young Investigator award mean to you?
   A: It is a very great honour for me. It represents a reward for the whole research group and confirms that we are going in the right direction.
    

10. Why did you choose Stem Cells as a research field of interest?
    A: Ever since I started to work with Prof. Grassi about the effects of nutrient-dependent signals on the modulation of adult neurogenesis, I have always been fascinated by the hypothesis that some cells within our brain maintain the ability to self-renew and contribute to preserving the brain plasticity. The active role of adult neural stem cells in humans is still debated, but the increasing evidence about the functional effects of molecular signals released by neural stem cells on brain plasticity could reconcile the different theories about the adult neurogenesis and provide novel insight about the role of neurogenic niche on brain aging.
     

11. What does your day-to-day look like in your current position?
    A: I divide myself between the research projects to coordinate, the teaching activity, the PhD students I tutor and other academic commitments, always trying to devote the right time to develop new research projects and to write grant proposals.
     

12. Is there anything else you would like to highlight about your paper?
    A: The identified epigenetic mechanisms linking insulin-related signals and proliferation/senescence balance of neural stem cells may have multifaced implications given the role of stem cells and metabolic stimuli on human physiology and pathophysiology. Finally, our findings open the way to the potential therapeutic application of extracellular vesicles against metabolic disorder-related cognitive dysfunction.
     

You can read the winning paper here: Neural Stem Cell-Derived Extracellular Vesicles Counteract Insulin Resistance-Induced Senescence of Neurogenic Niche

(1) Fusco S, Leone L, Barbati SA, Samengo D, Piacentini R, Maulucci G, Toietta G, Spinelli M, McBurney M, Pani G, Grassi C. A CREB-Sirt1-Hes1 Circuitry Mediates Neural Stem Cell Response to Glucose Availability. Cell Rep. 2016 Feb 9;14(5):1195-1205.
(2) Spinelli M, Fusco S, Mainardi M, Scala F, Natale F, Lapenta R, Mattera A, Rinaudo M, Li Puma DD, Ripoli C, Grassi A, D'Ascenzo M, Grassi C. Brain insulin resistance impairs hippocampal synaptic plasticity and memory by increasing GluA1 palmitoylation through FoxO3a. Nat Commun. 2017 Dec 8;8(1):2009.