(4dp) Advanced Biomaterials-Mediated Transcellular Communication for Tissue Engineering Applications and Therapeutics

Summary: In a nutshell, my research aims to modulate vesicle mediated cell-cell communication utilizing biological and engineering techniques to gain insight towards therapeutics of cardiovascular and neuromuscular disorders.

Research Interests: The interplay between engineering and biology has led to potent, sustainable, and accessible therapeutics. Biomaterial scaffolds can modulate the cellular microenvironment, serve as platforms for in vitro drug screening and decouple biological complexities to gain insight into disease modeling. As a chemical engineer working in the interface between materials and bio-engineering, my research focuses on utilizing hydrogel scaffolds and stem cells to create off-the-shelf personalized treatments for neuronal and cardiovascular disorders.

During my Ph.D. (SUNY Buffalo, Andreadis Lab), I shifted away from my undergraduate research directions (computational fluid dynamics on turbulent flow) and focused on harnessing the potential of dormant neuronal stem cells residing in the skin, an abundant cell source, as a treatment for demyelinating disorders. My goal was to modulate YAP/TAZ signaling, by influencing NRG1 ligand-receptor signaling dynamics and create a transplantable, personalized cell therapy from the patient’s own skin cells, differentiated towards myelinating Schwann cells against multiple sclerosis (Tseropoulos G. et al. Adv. Sci. 2024 / IJMS 2022 / BioTM 2018).

As a postdoc (CU Boulder, Anseth Lab), I pivoted back towards my chemical engineering roots and utilized hydrogel scaffolds to influence the secreted extracellular vesicles (EVs) from MSCs by modulating their cellular microenvironment. Moving away from the caveats of cell transplantation but staying the course of the idea of personalized therapeutics, I engineered the EV membrane, protein and miRNA content towards anti-inflammation, with the ultimate goal of enhancing bone regeneration in rat calvarial defects. In parallel, I worked on recapitulating the hallmarks of cardiac fibrosis on valvular interstitial cells (VICs) from porcine heart valves using soft and stiff hydrogels as culture platforms of myofibroblast differentiation. Through the cellular response to the biomaterial scaffold, we gained valuable insight of potential targets for non-invasive pharmacological treatment (PTEN, Tseropoulos G. et al., Nature CVR, submitted), translatable into healthy and fibrotic human heart valves. Furthermore, I assisted in the development of a novel diagnostic method of aortic valve stenosis through a Fourier series-based algorithmical classification of VIC shape into a spectrum of fibrotic phenotypes (Khang A., ..., Tseropoulos G. et al. Nature Comms, under review).

Future Research Plan: As a future faculty member, I plan to study the effects of biomaterials on EV secretion and their potential as a personalized therapeutic for aortic valve stenosis and neurodegenerative disorders. Implementing quantitative biological techniques and engineering innovative biomaterial platforms offers the opportunity to elucidate on the EV driven transcellular communication in healthy and diseased cell states. Specifically taking advantage of the advent of sequencing (proteomic/RNA) tools, I plan to investigate ligand-receptor and miRNA interactions that drive EV mediated cellular responses, as a function of their genetic and protein content, an area that currently remains largely understudied.

Focus I: Modulate the activation of valve myofibroblasts through extracellular vesicles from valvular endothelial cells through in vitro biomaterial scaffolds.

• Identify the effects of EVs from healthy and fibrotic valvular endothelial cells (VEC) on the VIC myofibroblast activation leading to αSMA upregulation.
• Investigate the sex differences of the EV paracrine signaling in male and female human fibrotic heart valves (miRNA in situ hybridization techniques / sequencing).
• Determine miRNA and protein targets for non-invasive therapeutics for aortic valve stenosis.

Focus II: Investigating the effects of aging and cellular senescence on the paracrine signaling between nerve and muscle cells to study neuromuscular degeneration.

• Senescence and progeria as causes of EV secretion and neuromuscular degeneration
• Responsive biomaterial scaffolds as platforms of EV delivery to neuromuscular lesions

Teaching Interests: I have always viewed teaching as one of the most enjoyable and important parts of my academic career. My comprehensive education in Chemical Engineering from UPatras to UHouston, SUNY Buffalo and CU Boulder has equipped me with the skills to teach classes in the core Chemical Engineering curriculum (thermodynamics, transport phenomena, reactor engineering) at both undergraduate and graduate levels. I am particularly familiar with teaching classical and statistical thermodynamics, having TAed the undergraduate and graduate courses and undertaking a 50% of the semester lectures in SUNY Buffalo. I have extensive expertise in teaching biology to engineers and adjusting the class to the field’s specific interests. Furthermore, I have assisted Dr. Anseth during my postdoc in the course structure of 2 graduate level courses on bioengineering techniques, one of which included a laboratory component, where I served as lab assistant and coordinator. Over the course of my career, I have mentored 14 students/postdocs (8 graduate, 3 undergraduate, 3 postdocs by CU peer mentoring program), a process that motivated me to develop strategies for mentoring my future lab. I have performed extensive outreach (7 years) in Buffalo and Boulder taking part in the SUNY outreach program “Science is Elementary” where I built and engaged in lectures and hands-on science and engineering labs in charter schools and underrepresented communities, an eye-opening experience for the necessity of outreach to the US education system. Lastly, I recently applied for the Allen Institute Next Generation Leaders Program, where I was asked about my proudest accomplishments to date. Apart from papers, awards, fellowships and pivotal data, the words of a few undergraduate students holding a box of freshly baked cookies, little before my TA award back in 2015 really stuck with me: “George, if it wasn’t for you 90% of the class would have failed thermodynamics.”

For more updates and news about my research visit tseropoulos.com

Select Publications:

1. Batan D.*, Tseropoulos G.*, Kirkpatrick B. E., Bishop C., Bera K., Khang A., Anseth K. S., “PTEN regulates Myofibroblast Activation in Valvular Interstitial Cells based on Subnuclear Localization” submitted, Nature Cardiovascular Research (June 2024)
2. Khang A., Barmore A. Tseropoulos G., Bera K. Batan, D., Anseth K. S., “Automated Prediction of Fibroblast Phenotypes Using Mathematical Descriptors of Cellular Features”, under review Nature Communications (June 2024), BioRxiv https://www.biorxiv.org/content/10.1101/2024.05.15.594418v1
3. Tseropoulos G., Mehrotra P., Podder K. A., Willson E., Koontz A., Feltri L., Bronner M. E., Andreadis S. T., “Immobilized NRG1 accelerates differentiation towards functional Schwann cells, mediated through YAP/TAZ nuclear translocation” in Press, in Advanced Science (June 2024).
4. Podder A. K.*, Mohamed A. M.*, Tseropoulos G.*, Nasiri B., Andreadis S. T. “Engineering nanofiber scaffolds with biomimetic cues for differentiation of skin derived neural crest-like stem cells to Schwann cells”, (2022), International Journal of Molecular Sciences 23 (18), 10834
5. Tseropoulos G., Moghadasi Boroujeni S., Bajpai V. K., Lei P., Andreadis S. T., “Derivation of neural crest stem cells from human epidermal keratinocytes requires FGF‐2, IGF‐1, and inhibition of TGF‐β1”, (2018), Bioengineering & translational medicine 3 (3), 256-264

*denotes equal contribution