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Our research interests are focused on stem cell biology, with particular emphasis on questions pertaining to differentiation mechanisms of murine pancreatic progenitor cells, both early in development and postnatally. Our aim is to deepen our understanding of how the insulin-producing β cells are generated, and through this process to identify novel ways to induce β-cell regeneration (by differentiation of progenitors, transdifferentiation or activation of proliferation), as a means to combat Type 1 Diabetes. In parallel, we are using organoid-based technologies as a tool to study adult pancreatic stem cells and their role in β-cell regeneration as well as in pancreatic cancer initiation.

Initial phases of our work employed the use of directed differentiation of embryonic stem cells as a tool to model the developmental mechanisms of β-cell specification. These studies, combined with high-throughput gene-expression profiling analyses, have generated significant new knowledge on how β cells are specified in vivo and have provided useful clues for improving the efficiency of stem cell differentiation into functional β cells in vitro. For example, we identified a new signal, sphingosine-1-phosphate, which plays a conserved role in islet cell clustering and showed that the same signaling pathway mediates survival of endocrine progenitors and triggers their differentiation through modulating YAP and Notch signaling.

Another important molecule that has been central to our lab’s research activities is Aldehyde Dehydrogenase 1b1 (Aldh1b1). Aldh genes are increasingly associated with stem / progenitor cell status during development and lately, Aldh enzymatic activity has been used to isolate cells with tumour-initiating properties (cancer stem cells) from adult tissues, however, the exact role of this gene superfamily in the maintenance of pluripotency still remains largely uncertain. We have found that Aldh1b1, encoding a mitochondrial isoform of the Aldh superfamily, regulates the timing of differentiation in the developing pancreas. The gene is expressed in all pancreatic progenitors during development and we showed that its elimination accelerates differentiation and compromises β-cell functionality later in life. We also demonstrated that the centroacinar Aldh1b1 expressing cells of the adult pancreas are adult stem cells necessary and sufficient for the generation of adult pancreatic organoids. More importantly, and consistent with current hypotheses that stem cells may function as tumor initiating cells, we showed that pancreatic cancer is abolished in the absence of Aldh1b1 and that Aldh1b1+ stem cells rapidly expand following exclusive expression of an oncogenic form of Kras.

Understanding the developmental origin of adult pancreatic stem cells, deciphering the molecular mechanisms implicated in the maintenance of multipotency, and identifying signals that trigger the activation of these cells, have now evolved into central themes of our lab’s mission. Additionally, and in parallel to our stem-cell focus, we are exploring alternative ways to stimulate islet regeneration, for example by pharmacological activation of β-cell proliferation. Finally, the potential role of Aldh1b1 activity in pancreatic cancer initiation have sparked a more generalized interest of our lab in adult tissue stem cells, and their role in tumorigenesis. In this context, we are currently exploring the field of cancer stem cell-derived organoids and their use in drug screening and other applications of targeted therapy in Precision Medicine.