Research Focus

Pancreatic beta cell biology and regeneration

Our research goal is to understand the molecular and cellular events required for pancreatic beta cell regeneration, and apply this knowledge towards the development of cell replacement therapies for diabetes. To this end, we are focusing on two aspects of beta cell regeneration: enhancing beta cell proliferation in vivo and stimulating the differentiation of new beta cells from endogenous progenitors in the pancreas. We use the zebrafish model to study beta cell development due to the small size and optical transparency of its embryos/larvae, as well as the ease of the genetic and chemical-genetic manipulations.

1. Beta cell proliferation
a) Drug discovery for beta cell proliferation


A promising approach for beta cell regeneration is to screen for drugs that can increase the number of beta cell cells. For this purpose, we have generated transgenic lines that monitor in vivo and in real-time the proliferation of beta ells using the FUCCI (Fluorescent Ubiquitination-based Cell Cycle Indicator) system. In this system, the proliferating beta-cells “shine” green light whereas the non-proliferating ones are illuminated in red. Using these tools, we screen for drugs that can increase the number of proliferating beta cells in the islet. We will validate the candidate drugs for their beneficial action on mammalian beta cells.

b) Control of beta cell quiescence and proliferation


The more nutrients we intake, the more beta cells we need in order to cope with the increasing glucose levels produced from these nutrients. Hence, there is a tight correlation between nutrient intake and beta cell number in nondiabetic obese individuals and experimental models of over-nutrition. Likewise, we have found that in zebrafish, beta cells transition rapidly from quiescence to proliferation in response to high nutrient intake. Taking advantage of this knowledge, we have established the gene expression profiles of quiescent and proliferative beta cells. We will use these data to characterize novel genes that regulate the quiescent and proliferative states of beta cells.

2. Beta cell differentiation
a) Notch signaling fine-tunes pancreatic beta cell progenitors


Genetic studies have implicated Notch signaling in the maintenance of beta cell progenitors in the pancreas. However, how Notch signaling regulates the quiescent, proliferative or differentiation behaviors of these progenitors at the single-cell level remained unclear. We found that these beta cell progenitors experience different levels of Notch signaling, which in turn regulate distinct cellular outcomes. High levels of Notch signaling induce quiescence; lower levels promote progenitor amplification, whereas endocrine differentiation requires strong and sustained Notch signaling downregulation. An important goal is therefore to identify the mechanisms by which Notch signaling exerts specific and distinct outcomes at different activity levels, in order to develop means to enhance the renewal and differentiation capacities of beta cell progenitors in the pancreas.

b) Regeneration of beta cells from a defined progenitor population

We found that permanent loss of beta cells in zebrafish recapitulates aspects of human beta cell deficiency, including increased glucose levels. Importantly, we showed that a high demand for beta cells activates a progenitor niche within the pancreatic duct for rapid beta cell regeneration. We will employ this model to better understand how progenitors sense and respond to beta cell loss, as in Diabetes. Our goal is to identify means to enhance beta cell neogenesis from these progenitors, also present in mammals, as a cell replacement therapy for diabetes.

 

 

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