A Region-Specific Approach to Regenerative Medicine
During development, coordinated signaling events genetically encode thousands of unique cell types along the body axis which contribute to the precisely organized neural circuits that shape nuanced behaviors. Disruption to these local networks by traumatic spinal cord injury or neurodegenerative diseases cause paralysis and autonomic deficits that are currently incurable. We seek to use human pluripotent stem cells to understand and develop strategies to regenerate region-specific neural circuits with the goal of advancing personalized therapeutics from the bench to the clinic.
Directing Human Pluripotent Stem Cell Fate
Human pluripotent stem cells (hPSCs) represent an unlimited source for deriving therapeutically relevant cell types for human disease modeling and regenerative medicine. We harness microenvironmental signals from development to direct lineage-specific differentiation of hPSCs in order to recapitulate the diversity of CNS and PNS cell types along the body axis. Not only do we gain insight into basic mechanisms of human development, comprehensive transcriptomic analyses provide a deeper understanding of axial diversity and neural circuit organization.
Modeling Region- and Sex-Specific Human Neural Circuits
Local neural circuits along the body axis are precisely wired to meet the sensory-motor requirements of target limbs and organs. We will use region-specific in vitro models and organoids to elucidate the spatiotemporal dynamics of cell migration, cell sorting, and topographical mapping of axonal projections during CNS development in different regions, spanning the hindbrain through sacral spinal cord. We are particularly interested in lumbosacral circuits and sex-specific differences in innervation that may impact bowel, bladder, and sexual (BBS) function or are induced by pregnancy, working to mitigate sex disparities in BBS research and facilitate evidence-based patient management approaches .
Patient-Specific Models of Neurodegenerative Disease
A variety of motor and sensory neuropathies manifest with bulbar (hindbrain) or limb (spinal) onset and/or differential disease progression, requiring personalized patient-management approaches. Using patient iPSCs, we seek to understand the mechanisms behind region-specific pathologies in neurodegenerative diseases including amyotrophic lateral sclerosis, myasthenia gravis, multiple sclerosis, and hereditary sensory neuropathies and to identify and validate promising therapeutic compounds using our engineered in vitro models.
Cell Therapies for Spinal Cord Injury
Traumatic spinal cord injuries vary widely between patients in the location, type, and degree of tissue damage, resulting in unique sensorimotor deficits and recovery goals for each patient. We seek to investigate the role of region- and phenotype-specific neural transplants for successful circuit rewiring. Our long term goal is to engineer region-specific cell therapies as vehicles for anti-inflammatory and growth factor delivery to further promote a pro-regenerative environment.
Biomanufacturing Cell Products
Reproducible, scalable, cost-effective manufacture is the major challenge moving from the bench into thousands of patients, even as cell therapies have become a multibillion dollar industry. As we identify commercially viable cell products in the laboratory, we will aggressively develop clinical-grade processes for cell expansion, cell preservation, and cost reduction.