(4i) Neural Engineering for Restoring Vision: Stem Cell Therapies and Microphysiological Systems

My passion lies in developing our fundamental understanding of neural sensory perception and plasticity and using this basic knowledge to repair the neurocircuitry of the visual system. Ultimately, I aim to establish new approaches to restore vision loss and nervous system dysfunction using tissue engineering and stem cell therapies.

Before focusing on vision research, I immersed myself in the pharmaceutical sciences as an undergraduate. I worked on developing drug delivery vehicles, designing affinity peptides, and engineering antibody therapeutics through academic research and industry internships. My work in these areas revealed that drug molecules might be ineffective for neurological disorders and tissue damage. Inspired to begin research in neural tissue engineering, I pursued a doctoral degree at Northeastern University, where I developed novel biomaterials for nerve regeneration and engineered microphysiological systems (MPS) for investigating the neurocardiac axis.

At Northeastern, in Dr. Ryan Koppes’ lab, I designed and engineered photocrosslinkable materials with both neurophobic and neruosupportive domains to direct regeneration and support anastomosis of peripheral nerve injuries (Soucy et al., Tissue Engineering Part A, 2018). In parallel, I established microphysiological models of the cardiac sympathetic nervous system and was awarded the American Heart Association Predoctoral Fellowship. Using this MPS approach, I demonstrated that cardiac innervation is increased due to increased heart rate – a previously unknown mechanism of cardiac nervous system remolding (Soucy et al., Advanced Biosystems, 2020). As a cell critical for peripheral nerve regeneration, I also studied the role of Schwann cells in the heart using a combination of 3D cell culture and in silico modeling and, for the first time, demonstrated the role and importance of glial cells in modifying the electrophysiological properties of the cardiomyocytes (Soucy et al., Biofabrication, 2019). Lastly, I developed the first MPS of the sympathetic adrenomedullary axis and confirmed that adrenomedullary innervation and exposure to nicotine or opioids inhibit prenatal oxygen tension-mediated catecholamine release (Soucy et al., Organs-on-a-Chip, 2021). Altogether these studies demonstrated that altered activity in electrically excitable cells affects cardiac permittivity, neurite innervation, and catecholamine exocytosis.

As I neared the completion of my PhD, I learned that my poor vision was caused by a neurodevelopmental disorder (deprivation amblyopia) rather than a refractive error. Consequently, I wanted to expand my engineering background to focus my postdoctoral training on studying the visual system to better understand my vision problems. When I was three, doctors removed a congenital cataract from my left eye and implanted an interocular lens. When cataract surgery is performed in newborns and adults, vision is often completely restored; however, my delay in treatment resulted in an irreversible and uncorrectable loss of visual acuity in that eye. Despite advances in vision research, there remains no effective strategy to restore vision, as is the case with glaucoma.

Instead of joining a tissue engineering lab for my postdoctoral training, I joined Dr. Petr Baranov’s lab at Mass Eye and Ear/Harvard Medical School to advance the transplantation of retinal ganglion cells (RGCs) lost in glaucoma. Since joining the lab, I was awarded the Molecular Bases of Eye Disease Fellowship (NEI T32), the Kirschstein-NRSA Postdoctoral Fellowship (NEI F32), and the NIH Loan Repayment Program (NEI LRP-REACH) award based on my ideas to improve stem cell-derived RGC transplantation by controlling the intrinsic donor cell state and the host retinal microenvironment.

I established a framework to identify, select, and apply neurotrophic factors and chemokines to control donor neuron behavior in vivo within the retina (Soucy et al., PNAS, 2023). I used available single-cell transcriptome data of the developing human retina to determine which systems we could exploit to support RGC survival and control RGC migration. I improved donor cell survival and transplantation success by formulating donor RGCs with slow-release neurotrophic factors (Soucy et al., in review, 2024). Furthermore, establishing an exogenous SDF1 gradient and blocking Down Syndrome Cell Adhesion Molecule interactions improves the structural integration of RGCs following transplantation. Finally, by altering the migratory profile of donor RGCs toward multipolar migration, I improved overall migration in mature retinal tissues. However, despite this recent progress in enhancing donor RGC survival and structural integration, we have yet to observe any functional vision rescue.

For my next career stage as a Principal Investigator, I aim to build on my graduate and current postdoctoral work to study neural plasticity in the visual system towards improving the functional integration of donor RGCs. Specifically, I will modulate neural activity to study neurocircuit formation, remodeling, and degeneration using transplantation in the visual pathway (brain and retina) and in vitro and ex vivo models of visual neural circuits. This will form the basis of my Neural Engineering for Restoring Vision (NERV) lab.

With a vested interest in visual neurodevelopment, and my strong research background in neural tissue engineering, neuromodulation, organ-on-chip models, electrophysiology, and regenerative ophthalmology, I am well-positioned to launch an independent research career and found the NERV lab. From my previous experiences, I believe that the level of control afforded and ease of imaging within in vitro systems enables more rapid discovery of fundamental principles of neural system organization. Furthermore, establishing human models in vitro using stem cell technologies would improve the relevance and translatability of these findings. By developing human visual neural circuits in vitro, I will have unprecedented control over neurocircuit formation to study the fundamentals of neuroplasticity. Much like the discoveries I made within the neurocardiac axis, an in vitro model of the retina and optic pathway will lead to a better understanding of neural plasticity and new principles and approaches to promote remolding and repair within the visual and central nervous systems.

Teaching Interest

My approach to teaching and mentoring is to ExCITE learning through Experience-based, Collaborative, Inclusive, Transparent, and Engaging learning environments. To provide transformational experiences and inspire students to become lifetime learners, I aim to prepare students not only to master the material conceptually but also to understand and engage with practical examples (i.e., chemical synthesis of pharmaceutics/biomaterials) and relevant scholarly research. As an educator, I will teach students to innovate in the face of complex challenges while collaborating with peers of diverse backgrounds. Furthermore, I will establish a culture of equality and transparency so that students feel welcomed, valued, and supported in their learning and community. With the ever-changing landscape of education in and out of the classroom, technology, including artificial intelligence, will play a central role in learning and allow the opportunity to engage with a more diverse group of previously underserved students. In addition to providing access through technology, I will use online and social media tools to evolve my teaching by providing transparency in grading, asking for constant feedback, and building a flexible and collaborative learning environment. As a future professor, I will focus on current and classical concepts in engineering while also challenging my students to apply interdisciplinary approaches to addressing the most pressing societal needs.

In line with my teaching philosophy, as a graduate student, I supported STEM education by mentoring two female high school students, supervising thirteen undergraduate researchers, and speaking at a regional high school about academic research. Several of these students’ work has been highlighted in my research manuscripts as co-authors. Furthermore, one student received a provost award under my mentorship. I also served as a teaching assistant for a unit operations lab course and as a lab equipment manager to facilitate training on proper usage.

As a postdoctoral trainee, I have continued my role as a mentor in the lab, but as an engineer in an ophthalmology department, I have also spoken about increasing representation, as having outside perspectives will lead to novel and creative hypotheses. To further contribute to increasing representation in ophthalmology, I got involved in a program to build a more diverse talent pipeline by mentoring students interested in ophthalmology earlier in their careers. In this program, I established a series of interactive workshops to teach academic reading, writing, and communication skills. I have also taken an active role as a member of the research community by volunteering as a theme and session chair at the 2021 AIChE Annual Meeting and serving as an ad hoc peer reviewer for several journals. Within my institute, I have been serving as a scientific voting member of the IACUC. Lastly, I have been participating as an Emerging Vision Scientist at the RGC Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) consortium and led the writing of a whitepaper to advance the translational development of vision restoration therapies (Soucy et al., Molecular Neurodegeneration, 2023). As a future faculty, I will leverage all these experiences that have shaped my social and scientific outlooks to continue learning and promoting diversity in higher education.