Objective
The objective of this proposal is to create a sustainable network of blood vessels, nerves, lymphatic vessels, and extracellular matrix within an insulin-producing cell transplantation device, that is placed under the skin. A single strategy that creates such a neurovascular network has been proven to be challenging, but using the secreted factors from stimulated fat-derived stem cells might be a solution. Using the secreted factors of stimulated stem cells might not only improve the network formation within the device but might also play a role in local immune protection. Both will support the long-term functional survival of insulin-producing cells.
Background Rationale
Active functioning insulin-producing cells need high amounts of oxygen and nutrients to survive and need to sense blood glucose changes to release insulin. Normally these processes are regulated via a network of blood vessels, extracellular matrix molecules, and nerves. But during the isolation of these cells before transplantation, this network is disrupted and damaged. Therefore, if we can restore this network by using the secreted factors of specially treated fat-derived stem cells this will increase the long-term success rates of insulin-producing cell transplantation.
Description of Project
Replacement of the deficient insulin-producing cells by healthy insulin-producing cells is a promising treatment for Type 1 Diabetes (T1D). However, there is no transplantation site in the human body that adequately supports the long-term function and survival of these insulin-producing cells. Biomaterials can be used to develop a device, that can be easily implanted under the skin, and in which an optimal environment can be created for the insulin-producing cells. There are three requirements for an optimal environment: 1) oxygen and nutrient supply, 2) communication with other cells, and 3) protection against the immune system. A single strategy to optimize these three requirements is not yet available, but current insights point towards including fat-derived stem cells. They are known to secrete a variety of factors (secretome) that can attribute to creating an optimal environment for insulin-producing cells by influencing processes like blood vessel formation, extracellular matrix (ECM) configuration, and attenuating immune responses. Here we propose to use the secreted factors of these stimulated stem cells to facilitate the functional survival of insulin-producing cells in a biomaterial device under the skin. In a series of rodent experiments, we will investigate how we can modulate the content of the secreted factors to induce a sustainable network of blood vessels, nerves, lymphatic vessels, and ECM within the device. Furthermore, we will determine if the secreted factors from the stimulated stem cells can locally affect the immune responses and might also protect against rejection. Improved functional survival of insulin-producing cells will make this treatment available for a larger group of T1D patients.
Anticipated Outcome
After these studies, we anticipate having created an efficacious device for the transplantation of insulin-producing cells in rodents. We will be ready for investigating larger, human-applicable devices under the skin of pigs, as the pig skin structure resembles that of humans.
Relevance to T1D
Currently, up to 80% of insulin-producing cells do not survive after transplantation. By using a biomaterial device in combination with the secreted factors from stimulated fat-derived stem cells we can create an optimal home for these cells. The optimal microenvironment can support the long-term function and survival of insulin-producing cells. As more insulin-producing cells will survive, we will need fewer cells to treat patients, making this treatment option available for a larger group of patients