Making More And Better Insulin Producing Cells With Cell Regeneration

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Project Researcher: Sangeeta Dhawan, Ph.D. – UCLA

Project Description

Type 1 Diabetes results from destruction of functional insulin producing cells, and can be reversed by replacement of these cells by transplantation. However, due to shortage of donor tissue material, this approach has limited application for treatment.  Expansion of the insulin producing cells, therefore, presents itself as an attractive therapeutic alternative. This may be potentially achieved by expanding the insulin producing cells from donors in the lab prior to transplantation, or expanding these cells inside the body. A lot of research has been devoted to development of sources of insulin producing cells. While promising in terms of providing sufficient number of cells, most current approaches often result in cells that do not function properly. Thus, the ideal approach of cell replacement therapy would be to combine expansion of cell number, with improved function. Our project aims to develop a novel approach by which we can first expand the number of insulin producing cells, and then make them functional.

The key innovative aspect of this project is that we are applying knowledge gained from our studies on how insulin producing cells are formed and expand in the body prior in fetal life and how they subsequently learn to secrete insulin to respond to changes in blood sugar. Insulin producing cells expand in numbers during fetal life by rapid duplication, though at this point they do not function properly. Soon after birth, they slow down duplication and acquire proper function. Most of the donor tissue available is from adults. However, the insulin producing cells in adults rarely duplicate. So how do we expand these cells and also make sure that they function? We have identified a molecular switch that regulates the transition from fast duplication, non-functional insulin cells of the fetus to slow duplicating, fully functional cells after birth. We propose to manipulate this switch to first expand adult insulin producing cells and then make them functional.

Type 1 diabetes is an autoimmune disease afflicting 5%–10% (approximately 1 million people) of the diagnosed diabetic population in the United States (Centers for Disease Control and Prevention, 2003). As T1D patients require life- long insulin therapy and have a high risk of medical complications, preventative or curative therapies are urgently needed. This work will lead to future development of novel drugs that can be delivered as oral medication for diabetes. I have extensive experience in diabetes research and I work in an environment that fosters translation of research from bench to bedside. Our center is home to cutting edge research on diabetes biology which is supported by organization such as National Institutes of Health and Juvenile Diabetes Research Foundation.

The main goal of this project is to develop a method to derive abundant numbers of functional insulin producing cells for Type 1 diabetes therapy. This project will not only be a big step towards expanding adult functional insulin producing cells transplantation therapy, but will also provide a way to expand patient’s own cells inside the body.

 

Project Updates

Update on 6-30-17

The project was based on the idea of expanding insulin-producing cells (beta cells) to replenish the cell loss from diabetes. We found a protein able to expand the rapidly proliferating cells found in fetal tissues and proceeded to place the protein within adult beta cells to see if we could make the cells proliferate. Our experiments were successful in the cells treated in culture plates. This finding will be useful for further experiments with expanded cells to replenish the diminished mass of beta cells found in the diabetic pancreas.

Update on 4-12-17

This DRC sponsored project is aimed to develop a model of expanding functional beta cell mass for replenishment therapy. We have identified a key molecular regulator of islet cell proliferation, which marks rapidly expanding, functionally immature beta cells in the fetal life and is absent in functionally mature, non-proliferating beta cells after birth. We therefore proposed to transiently re-express this regulator in beta-cells to drive a rapid burst of proliferation, followed by withdrawal of this factor to stop proliferation and restore beta cell function. Our preliminary data in indicate that inducing this factor in cultured mouse beta cell lines and islets leads to increased proliferation. The generous support provided by DRC has also allowed us to identify additional candidates that can be harnessed to promote islet replication and function. Our ongoing studies are focused on understanding how this factor regulates islet growth and function, and on further developing our beta cell expansion model. This will be a big step towards expanding adult functional insulin-producing cell mass for replacement therapies, and will also provide a way to develop methods for expansion of these cells inside the body. This project will ultimately lead to development of protocols for deriving functional beta cells in abundant quantities for Type 1 diabetes therapy.

Update on 11-2-16

Update on 9-1-16

The lab that Sangeeta Dhawan works in has identified a molecular switch that regulates the transition from fast duplication, non-functional insulin cells of the fetus to slow duplicating, fully functioning cells after birth. This molecule is abundant in the fetal insulin producing cells and makes them duplicate fast. After birth, this switch is turned off, including a program for the cells to become functional. Dhawan proposes to turn this switch on in the slow duplicating insulin-producing cells of the adult to push them to duplicate rapidly. Subsequently, she will turn this switch off for the cells to slow down duplication and acquire function. This approach will be tested in the cells in a dish, and a model will be developed to test this idea in vivo. This will be a big step towards expanding adult functional insulin-producing cell mass for replacement therapies, and will also provide a way to develop methods for expansion of these cells inside the body.