Understanding β-cell function
Several avenues can be explored to replenish β-cell function in diabetic patients, ranging from generation of functional cells from stem cells (see below) to regenerating endogenous injured β-cells. To accomplish these goals, efforts need to be undertaken to understand the differentiation state and functional capacities of β-cell population within diabetic patients. To gain insights into β-cell function, we are currently using different models to study the role of specific signaling pathways in mouse and human β-cells (Landsman et al. PNAS 2011, Puri et al. Genes Dev 2013, Puri et al. PLoS One 2013)..
In addition, we are interested in the mechanisms that regulate β-cell regeneration in the mouse, using a model where tamoxifen-mediated induction of c-myc expression leads to β-cell apoptosis followed by recovery (Cano et al. Diabetes 2008). This tool allows us to test the capacity of young and aged β-cell to regenerate and define modulators of this process.
Directing differentiation of human pluripotent stem cells into insulin producing β-cells and thymic epithelial cells
Even though cell replacement therapy using cadaveric islets holds great promise to treat patients suffering from Type 1 Diabetes, its application is severely limited by the shortage of donor material. To circumvent this problem, a lot of effort has been invested towards directing differentiation of human embryonic stem cells (hESCs) into insulin producing β-cells. Previous work by us and others has provided crucial insights into the key roles of embryonic signaling pathways in pancreas organogenesis, therefore giving us essential information on how to improve the differentiation of uncommitted stem cells towards a β-cell phenotype (Guo et al. Diabetes2013).
In addition, since one of our long-term objective is to create a source of β-cells that can be used to treat diabetic patients, part of our current research is also focused on finding ways to protect those cells after transplantation. In order to address that problem, we chose to focus on the thymus, the major organ involved in controlling immune tolerance. In collaboration with another group from UCSF (Mark Anderson), we have developed a novel method to efficiently generate functional thymic epithelial progenitors from human pluripotent stem cells and are now testing their ability to modulate immune tolerance in immune compromised mice (Parent et al. Cell Stem Cell 2013).
Understanding pancreatic cancer initiation and progression
Human pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer death in the US and oncogenic mutations in Kras are a hallmark of this disease. Reprogramming normal pancreatic cells into PDA precursors represents a significant shift in pancreatic plasticity, permitting cells to assume otherwise restricted cell fates that are similar to a transient state observed during pancreatic regeneration.
Part of our work focuses on how pathways critical to establishment and maintenance of pancreatic cell identity and function are tuned to specify this de-differentiated state that appears permissive for the development of PDA precursors (Morris et al. J Clin Invest 2010, Kopp et al. Cancer Cell 2012, von Figura et al. Gut 2013). In addition, we are investigating the role of chromatin regulators in the neoplastic specification of the pancreas (von Figura et al. Nat Cell Bio 2014, Roy et al. Genes Dev 2015).
Studying the mechanisms that underlie pancreas organogenesis
Recent results from us and others have reintroduced the pancreatic mesenchyme as critical support tissue that guides the development of pancreatic epithelial cells. We have developed tools that allow genetic manipulation as well as isolation of mesenchymal cells. Our previous work has shown that the Nkx3.2-Cre transgenic mouse line directs Cre activity to the mesenchyme during pancreas development and can thus be used as a tool to specifically manipulate gene expression in this tissue. For example, this system has been used to demonstrate that embryonic mesenchyme provides critical signals to the epithelium throughout pancreas organogenesis (Landsman et al., PLOS Biology2011).
Investigating the role of the immune system in pancreas injury and regeneration
We are interested in understanding how different immune cells contribute to the process of pancreatic regeneration following injury. One of our goals has been to dissect the interactions between resident tissue cells and infiltrating immune cells during injury, and address how immunological factors can affect cellular plasticity (Folias et al. PLoS One 2014). This issue is particularly relevant for stem cell studies, as well as current transplantation and regenerative medicine therapies. Additionally, de-differentiated acinar cells harboring genetic mutations can develop into pancreatic cancer precursors, highlighting the importance in understanding the initiation event of this potentially carcinogenic cellular transformation.
