Creating New Insulin-Producing Cells To Repair Damaged Pancreas

Posted in Successfully Funded

Kristin-Mussar in a labcoat

Creating New Insulin-Producing Cells To Repair Damaged Pancreas

Kristin-Mussar in a labcoat Project Researcher: Kristin Mussar, Ph.D. – University of Washington

Project Description

Diabetes mellitus is a severely debilitating disease that would significantly benefit from new tissue regenerative treatments. We investigated how specialized cells of the innate immunity, named macrophages, could be manipulated to trigger and sustain pro-regenerative functions on injured pancreatic islet cells. This line of work holds significant translational value as it may lead to the use of myeloid cell therapies to support tissue regeneration.

In initial experiments, we characterized the populations of macrophages residing in the pancreas, comparing the ones present in the fetal stage of development to those associated with the significant islet proliferation occurring in the perinatal period. Using animal models in which macrophages can be selectively eliminated in vivo, we discovered that there are populations of these immune cells that are critically required for the expansion of pancreatic islet cell mass in the perinatal period. In the absence of these macrophages, the islet cell mass remains underdeveloped and dysfunctional. In these studies, we learned of the mechanisms involved in the recruitment of these immune cells to the pancreas and of those regulating their number in this tissue. We further discovered that progenitors of these populations of macrophages exist in the bone marrow of adult animals and that recruitment of these cells to the injured pancreas of diabetic hosts leads to islet cell recovery and normalization of the glycemia in a relatively short time.

We have undertaken a detailed characterization of the signaling pathways activated in these macrophage populations to pinpoint the ones relevant to these pro-growth effects on islet cell types. Further experiments are underway to validate these pathways in culture models, and to elicit their pharmacologic activation in diabetic animal models. In future studies, we foresee that activation of these pathways in combination with immune-regulatory therapies may represent an effective therapeutic strategy to elicit islet regeneration in Type 1 diabetic hosts.

Project Updates

Final Update:
I completed this project and published the findings in the Journal of Clinical Investigation. Our project set out to create new insulin-producing cells to repair a damaged pancreas. We found evidence that macrophages, a type of white cell that is usually associated with infections, also play an important role in the development of islets, where insulin is made, just before and immediately after birth. The published report shows how macrophages help the islets grow indicating that selected agents may activate the cascade of proteins enhancing islet growth, an important contribution for future treatments in type 1 diabetes. Click here to read the full report.

Update as of 8/31/16:
In this project, we identified a population of white cells called macrophages residing in the pancreas of newborns that is necessary for islet cells to expand in number as well as to mature into functional insulin-producing cells. We found that a functionally similar population capable of boosting islet proliferation exists in the bone marrow of adult individuals, which suggests that there might be potential for islet repair in adults. Our lab is currently investigating whether this bone marrow population can be used as a cell therapy to enhance the repair process of islet cells in adult mouse models of injury. This project is important because it has identified a different set of white blood cells that may allow the proliferation of insulin-producing cells in the pancreas of diabetic patients, offering hope for a cure.

Update as of 4/20/16:
In our last update, we identified a population of macrophages residing in the pancreas of newborns that was necessary for islet cells to expand in number as well as to mature into functional insulin-producing cells. Recently, we found that a functionally similar population capable of boosting islet proliferation exists in the bone marrow of adult individuals, which suggests that there might be potential for islet repair in adults. We are currently investigating whether this bone marrow population can be used as a cell therapy to enhance the repair process of islet cells in adult mouse models of injury. Additionally, we are still working to characterize the molecular signals underlying the effects that this cell population has on islet cell expansion and maturation. Thank you again for donating and making this research possible!

Update as of 12/15/15:
In the past four months, we were able to isolate and begin to characterize a population of macrophages that appears to drive islet cells to expand in number. Importantly, we found that these cells are required for islets to form and secrete insulin in newborns. Our most recent efforts are focused on finding out the growth signals that these cells produce to drive the expansion of beta cells. These results support our original hypothesis that one day these cells may be used as a therapeutic strategy to elicit islet cell regeneration in Type 1 diabetics.

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