StratRegen Junior Research Grantees 2020
Patients suffering from esophageal caners are commonly treated by a combination of chemotherapy and esophagectomy, a debilitating surgical procedure. We have identified heterogeneity within the esophageal stem cell population in the normal mouse esophagus, and are now working to understand how this heterogeneity is established and maintained.
We want to functionally characterize distinct stem cell populations and map out how they interact with neighboring stromal cells in the healthy esophagus, in order to then understand how these interactions change during esophageal cancer.
Our goal is to systematically identify and impact alterations in tumor cells and their stromal niche to reduce tumor growth.
Massive cell death and axonal degeneration are activated in the developing mammalian nervous system and represent an essential process in the formation of functional neural circuits. At the opposite, failures in the processes controlling cell death contribute to neurodegenerative disorders and tumorigenesis. In both situations, similar signaling pathways are playing a crucial role in providing a survival advantage or inducing cell death.
In this project, we are aiming at dissecting the dynamic of gene expression within the development of sensory neurons during the cell death period and study both in vitro and in vivo the molecular triggers of their apoptotic death. Newly identified key factors of cell death control in developing neurons will then be exploited for studying new treatment of resistant cancers.
Treating diabetes with the use of genome engineered embryonic stem cells in the eye
Human pancreatic islet transplantation can improve the quality of life of patients with diabetes, but is restricted donor organ scarcity and complications of immune suppressive drugs. With previous support from StratRegen we have established a clinically compliant hESC line, KARO1.
With this additional support we will now engineer KARO1 to avoid transplantation rejection. In parallel we have established a protocol to generate glucose responsive islet-like structures from hESCs and will focus on adopting a clinical manufacturing strategy. Finally, together with our collaborators we will optimize the procedure to best utilize our preferred site of transplantation, the anterior chamber of the eye.
The liver has a remarkable regenerative potential. While mature hepatocytes generally do not divide, upon liver injury, they rapidly dedifferentiate into bipotent, proliferative progenitor cells and regenerate the injured tissue. However, for end-stage or congenital liver diseases, orthotopic liver transplantation is the only therapeutic option. Importantly though, the paucity of donor organs results in long waiting lists and high mortality rates while waiting. Regenerative medicine aims to tap into the regenerative potential of the intact liver to palliate the need for donor organs.
In this project we will investigate the molecular dynamics of human liver regeneration using a novel protocol that allows for the first time to stimulate proliferation of primary human hepatocytes in vitro. Using 3D cultures of primary human liver cells, we can dedifferentiate these mature cells into hepatic progenitors rendering them susceptible to the induction of proliferation. Importantly, liver and pancreas share a common origin and structure connected to the ductal tree, as well as exhibit similarities in their transcriptional regulation signatures in mice where pancreatic cells proliferate readily after partial pancreatectomy, analogous to the process of liver regeneration. However, in humans this regenerative response is blunted. We will investigate the effects of the proliferation cocktail we developed on the proliferation of primary pancreatic islets from mice and humans and comprehensively analyze their species-specific differences in transcriptional regulators to identify, and eventually target, factors that explain the absence of human pancreas regeneration.
Regenerative treatment of gastrointestinal neuropathy by applying developmental mechanisms
Neuropathy within the enteric nervous system (ENS) contribute to congenital, degenerative and inflammatory gastrointestinal disorders that lack satisfactory treatment. Recent progress in enteric stem cell research has incited hope for cell-based therapies, but challenges remain for their implementation.
To achieve functional recovery, a balanced cellular constitution needs to be re-created, which stresses the importance of defining enteric neuron types and their developmental generation. We have overcome the vast and heterogenous structure of the ENS by applying novel transcriptional analysis and will now couple information from our expression resources with viral gene-editing technologies in murine disease models to develop regenerative strategies aimed at treating neural deficits in the gut.
It is a central, unaddressed question in human cardiogenesis how the formation of the muscular ventricular chamber is coordinated with the overlying large vessels and how the fundamental cellular defects and molecular cues lead to congenital heart disease (CHD).
The central hypothesis of the current proposal is that a novel subset of human cardiac outflow tract-specific cono-ventricular progenitors and their downstream progeny would play a critical role in guiding human outflow tract formation and that defects within this specific subset and its functional molecular pathway may play a major causative role in the pathogenesis of human CHD.
The identification of a novel subset of human cono-ventricular progenitors and their paracrine cues may uncover new approaches to mitigate the severe forms of the disease.
Identification of novel cellular and molecular mechanisms promoting intestinal stem cell-mediated tissue regeneration following injury
Adult intestinal stem cells (ISC) are responsible for the efficient and constant regeneration of the intestinal epithelium throughout life. Breakdown in ISC-mediated tissue homeostasis and epithelial barrier integrity may lead to the pathogenesis of chronic inflammatory bowel diseases (IBD).
After inflammation has begun, harnessing the power of mucosal healing to accelerate and promote resolution is a promising approach. Thus, due to the lack of targets for induction of mucosal regeneration, the main goal of my research proposal is to identify and validate novel genetic and cellular therapeutic targets for ISC-mediated regenerative medicine.