News & Research

    Cleveland Clinic, Cleveland, Ohio

Notch signaling during pancreatic progenitor patterning and induction of the insulin cell fate

General Research Subject: Type 1 Diabetes

Focus: Islet Biology\Beta Cell Growth and Differentiation, Islet Biology\Beta Cell Transcription Regulation, Stem Cell Research\Human\Adult

Type of Grant: Basic Science

Project Start Date: January 1, 2011

Project End Date: December 31, 2013

Research Description

A cure for type I diabetes is urgently needed. While much effort is ongoing towards creating insulin-replacement cells this goal has not been achieved. All current efforts rely on the understanding of how the pancreas develops in the embryo, and at the moment, we lack critical details. We particularly lack a functional understanding pancreatic centralized patterning -- that is, how is it that the immediate progenitor for the insulin producing cells is formed?
Our over-arching hypothesis is that control of centralized patterning in the pancreas can be used to specifically promote the insulin-producing cell type at high efficiency. Our preliminary data specifically informs about the mechanisms operating in the pancreas that normally governs this process. Of importance, the transcription factor Ngn3 can control centralized patterning.

This occurs through signaling events between neighboring cells. The receptor protein Notch is critical for this. Additionally, evidence suggests that the pancreatic glucagon and insulin cell fate choices are also governed by the level of Notch signaling when their fates are decided. This surprising finding is the first demonstration of a plausible mechanistic solution to why glucagon and insulin-producing cells appear as different cell types from a common stem cell. This knowledge provided us with a successful base to achieve artificial expansion of normal pancreatic stem cells, followed by their subsequent endocrine differentiation. We will explore this knowledge further in this proposal to create pancreatic beta cells at high efficiency, in both the embryo, as well as in the adult regenerating pancreas.

Research Profile

What area of diabetes research does your project cover?  What role will this particular project play in preventing, treating and/or curing diabetes?

Our project covers studies of how a pancreatic beta cell forms, with a particular focus on the role of a particular signaling molecule, Notch, in the specification of insulin-producing cells. Although it has been known for a decade that Notch signaling may inhibit endocrine cell formation, it has not been possible to explore this knowledge to create insulin producing cells. A reason for this is that we have failed to understand how notch controls many levels of pancreatic development, and only recently have we known that Notch not only plays a negative role as first seen, but actually is crucial for development of endocrine cells. We will here utilize this knowledge as a means to develop pancreatic insulin producing cells, initially in the mouse. We will do this both in development, as well as in the adult organ. These studies are necessary for learning to how generate functional beta cells from clinically relevant stem cell sources, such as for instance embryonic, or induced pluripotent stem cells, as well as from adult pancreatic progenitor cells. Our ultimate goal is to cure diabetes using cellular replacement.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

There are many lines of data that currently supports the notion that pancreatic endocrine cells indeed can be coerced to form from non-insulin producing cells having progenitor-like characteristics. There are not one, but many avenues to seek to explore on our quest for deriving new cells. All these paths require fundamental knowledge of the developing pancreas, and rest on an intimate understanding of the critical genes involved. Cellular engineering is advancing rapidly, and our ability to specify individual cells, such as the insulin-producing cells of the pancreas, is improving constantly.

Why is it important for you, personally, to become involved in diabetes research?  What role will this award play in your research efforts?

Diabetes is one of the largest contributors to human disease, being the number one cause for blindness, kidney disease, and amputations. Diabetes is a major contributor to heart disease, and due to the increased levels of obesity nationwide, it is expected to increase in prevalence in the near future. Although diabetes consist mainly of both type I and type II, the common thread is the failure of the pancreatic islet cell to maintain normal blood glucose. We know that providing new insulin producing cells can rectify this situation, and for that reason, focus must be on generating cells that can be considered for transplantation. In the short term, such cells would be made available to type I diabetic individuals, but in the longer term, replacement cells can just as well be imagined as a treatment for type II diabetes. I have been involved in Diabetes research since I started in science. I have strived to understand pancreatic development to the level of being able to harness the information from the embryo, so as to make new beta cells for clinical use. The efforts in our award provided by the ADA is to specifically test how one can harness the ability of the Notch signaling system as a means to increase the formation of specifically insulin cells, with increased frequencies over glucagon-cells. This has not been done before, and the research will critically support this work.

In what direction do you see the future of diabetes research going?

Diabetes research gains ground every on almost all fronts, whether that be the immunological reasons for type I diabetes, the research into inability of the beta cells to meet demands in Type I diabetes, or in the research into how prolonged hyperglycemia leads to a vast array of complications. We need to be better at diagnosing and treating at many levels, and we are improving. However, we are unable to cure. Envisioning a cure is as simple as envisioning a cell. We know from current islet transplant procedures that islet cell replacement works in reality. I see a lot of evidence that convinces me that our current efforts in creating insulin cells for replacement is beginning to pay off. This evidence is on the commercial as well as the academic fronts, and the sails are set. In analogy to a horse race, the gun has sounded, and the horses are well around the first corner, if not longer. However, there are many horses in this play, and a possible winner cannot be determined until the goal line is reached - such as the goal defined by a clinically-approved cell therapy. As the race continues, only the foolhardy would count any horse out. And we all stand to win, if just one passes the goal line.