Defining the role of Hippo signaling in β-cell development, maintenance, and regeneration.
By restoring the numbers and functionality of β-cells, an anticipated therapy for Type-1 and Type-2 diabetes is on the horizon. The survival and functionality of islets after transplantation decreases significantly over time and does not provide a definitive long-term solution for patient treatment. However, the fact that diabetic recipients become insulin-independent over an initial period of time suggests that replenishment with functional β-cells may offer a more sufficient therapy for those suffering with diabetes. Nonetheless, the lack of a reliable and functional source of β-cells has limited this approach.
Recent efforts have focused on increasing total β-cell mass by understanding the mechanisms involved in their differentiation, proliferation and regeneration. We are actively investigating one such biochemical pathway, known as the Hippo signaling pathway. First discovered in 2007, Hippo signaling is responsible for maintaining proper organ size through its negative effect on Yap. Yap is a transcriptional co-activator responsible for stimulating cell proliferation.
Work has shown that inhibition of the Hippo pathway leads to massive tissue overgrowth, whereas over activation leads to tissue degeneration. Balance in Hippo signaling is therefore required for maintaining a tissue in its homoeostatic state. Hippo signaling is also essential during periods of tissue regeneration, for example in wound healing. In these circumstances Hippo signaling is down regulated allowing for an increased expression of Yap-dependent transcription genes required for cell proliferation and tissue remodeling. Proper signaling through this pathway is required for maintenance of progenitor cell populations. This is important since progenitors are generally the source of new cells during periods of regeneration and day-to-day tissue maintenance.
We have identified active Hippo signaling (known as PO4-Mst1/2) throughout human and mouse pancreas and have observed hyper-active Hippo signaling within pancreatic islets. The target gene of Hippo signaling, Yap, is greatly suppressed within the islets, where growth is limited, however, the highest levels of Yap expression are seen in the pancreatic ducts. These ductal structures have a high mitotic rate and also contain pancreas progenitor properties.
Extensive loss of β-cell mass and functionality is the main factor afflicting those with diabetes. Replenishing this vital cell source, as completed in islet cell transplants for example, has the potential to reverse complications produced by the disease. Currently, the availability of donor islet tissue is limiting, rendering this approach the exception rather than the norm. We hope that our research will produce novel insights on the biochemical signaling that regulates β-cell development and regeneration. Results from this research can be applied to what we already know about basic pancreas and islet biology and serve to enhance the clinical outcomes of islet transplantation.