Objective
Our research aims to improve the development of insulin-producing cells from stem cells, which could lead to better treatments for type 1 diabetes (T1D) and better model cells for future research. Although scientists have made significant progress in creating these cells, known as stem-cell-derived islets (SC-islets), they still do not function exactly like the natural insulin-producing cells in the human pancreas. We hope to understand why these differences exist and find ways to make SC-islets more like the real thing. To achieve this, we have three main objectives:
1. Compare SC-islets from Different Sources to Human Islets: We will collect SC-islets produced using different methods and from various research groups. We will analyze these cells at the molecular and metabolic levels, and test how well they secrete insulin in response to sugar and other nutrients. By comparing these SC-islets to human islets from hundreds of donors, we will identify specific differences and similarities.
2. Use Advanced Data Analysis to Identify Key Differences: We will employ artificial intelligence and machine learning tools to analyze the large amounts of data we collect. These tools can detect patterns and relationships that might not be obvious otherwise. By integrating information about gene expression, protein levels, and cell function, we aim to pinpoint the exact areas where SC-islets differ from natural cells. This analysis will help us understand what aspects of the SC-islets need improvement.
3. Find Ways to Improve SC-islet Development: Using the insights from our comparisons and data analysis, we will conduct experiments to find compounds or factors that can enhance the development of SC-islets. We will screen thousands of potential compounds using both computer simulations and laboratory tests for drugs that may make the SC-islets function more like mature islet cells. Promising candidates will be tested further to confirm their effectiveness.
By accomplishing these objectives, we hope to develop SC-islets that are more mature and functionally similar to mature human pancreatic beta cells. This could lead to better cell-based therapies for type 1 diabetes, improving the regulation of blood sugar levels and reducing the risk of complications. Additionally, these improved SC-islets could be valuable for research purposes, such as testing new drugs or studying the disease process in diabetes.
Our project brings together experts in stem cell biology, diabetes research, and data analysis. We will collaborate closely to ensure that our methods are standardized and our findings are robust. We also plan to share our data and tools through our online platform, allowing other researchers to benefit from our work and contribute to the collective effort to combat type 1 diabetes.
Background Rationale
In type 1 diabetes (T1D) the body’s immune system mistakenly attacks and destroys the insulin-producing islet beta-cells in the pancreas. Insulin is essential for regulating blood sugar, and without it, people with T1D must rely on insulin injections or pumps to control blood sugar. Researchers have long sought ways to replace these lost beta cells to restore natural insulin production. One promising approach is to create new beta cells from stem cells, and recent decades have seen the development of methods to reproduce the early development of the pancreas in order to differentiate stem cells into insulin-producing cells (and other cells of the islet). We refer to these as stem-cell-derived islets (SC-islets), which have the potential to produce insulin in a regulated manner, and to reverse diabetes in laboratory animals, and potentially in patients with T1D. Early clinical trials in humans suggest positive results.
However, the SC-islets produced so far do not fully mimic the function of primary human islet and beta cells, often behaving more like immature or neonatal beta cells, which do not regulate blood sugar as precisely. For instance, current SC-islets may not respond appropriately to changes in blood sugar levels, releasing too much insulin when blood sugar is low and possibly contributing to dangerously low blood sugar levels (hypoglycemia). They may also respond to different nutrients (fats, for example). Additionally, much research is focused on understanding the causes of T1D and potential treatments using SC-islets. But there is little or no systematic comparison of these different SC-islets to each other or to primary islet beta cells. Without a clear understanding of how these cells differ, it’s challenging to improve them or develop standardized therapies and research tools.
Our team has developed a comprehensive database of information from hundreds of human islet donors, including data on gene expression, protein levels, and cell function. This resource, at HumanIslets.com, allows for detailed analysis and comparison of beta cells from different individuals and is available for the worldwide diabetes community to access. To advance the development of SC-islets, we plan to compare them directly to human beta cells and to SC-islets produced by different methods using this platform. By identifying the specific differences, we can focus on ways to improve the SC-islets’ development and function. Advances in data analysis tools, such as artificial intelligence and machine learning, will allow us to analyze and compare complex datasets more effectively. These tools can uncover patterns and relationships in the data that might not be apparent through traditional analysis methods.
In summary, while the creation of SC-islets offers great promise for T1D, there is a critical need to understand how these lab-grown cells differ from natural beta cells and to find ways to improve them. Our project aims to fill this gap by conducting comprehensive comparisons and using advanced data analysis to guide improvements in SC-islet development.
Description of Project
Advancements in stem cell research are bringing us closer to innovative treatments type 1 diabetes (T1D) in part through the development of approaches to make insulin-producing cells from stem cells (called 'SC-islets'). These cells have the potential to replace lost insulin-producing pancreatic beta-cells in people with T1D, and separately can also be studied as a model system for T1D. However, the SC-islets developed so far don’t fully mimic the function of true mature insulin-producing beta-cells. They often behave more like immature cells, which means they might not respond to blood sugar changes as effectively as needed. This limitation poses challenges for their use in treating and studying diabetes.
We hope to bridge this gap by thoroughly comparing SC-islets produced from different sources, using distinct methods, to an 'atlas' of human islets cells that we have recently developed. By understanding differences, and similarities, we hope to identify ways to improve SC-islets so they function more like the real thing. We will use advanced techniques to analyze the SC-islets at a molecular level, examining which genes and proteins they express, which metabolic pathways are active, and how they perform in response to glucose and other nutrients.
To achieve this, we will use information from hundreds of human islet donors, which includes data on gene expression, protein levels, and cell functionality. This resource, at www.HumanIslets.com, will allow us to compare SC-islets directly to human pancreatic beta-cells. Additionally, we will employ artificial intelligence and machine learning tools to analyze this complex data, helping us identify patterns and key differences that might not be obvious otherwise. We will also screen thousands of compounds to see if any can enhance the development and maturity of SC-islets. Using both computer simulations and laboratory experiments, we aim to find substances that encourage SC-islets to function more like mature beta cells. Promising candidates will be tested further to confirm their effectiveness.
Our team consists of experts in stem cell biology, diabetes research, and data analysis. By collaborating closely and sharing our findings through an online platform, we hope to accelerate progress in this field. This open approach allows other researchers to benefit from our work and contribute to improving SC-islets. Ultimately, our goal is to develop new approaches to study SC-islets and to improve their function. This will benifit both potential treatment approaches for people with type 1 diabetes, and also improve the ability of SC-islets to serve as valuable tools for studying diabetes and testing new drugs, further advancing medical research.
Anticipated Outcome
We anticipate that this research will produce important outcomes relevant to advancing stem cell research and SC-islet generation:
1. We expect to improve our understanding of SC-islets: By comparing SC-islets generated from different sources, using up-to-date protocols, with eachother and with primary human beta-cells, we expect to produce a better understanding of the deficiencies in SC-islets. Effectively this will let us know where things stand in the field currently, insight that is presently lacking, and highlight needed improvements in SC-islets differentiations.
2. Improved SC-islet protocols: Through our screening approach, coupled with benchmarking of results, we aim to identify and test compounds that can improve the maturation and functionality of SC-islets. We anticipate developing improved protocols that produce SC-islets with insulin secretion that is more appropriately coupled glucose, better mimicking the behavior of primary human beta cells. This may result in improved protocols for future transplant therapies, and for diabetes modelling.
3. Creation of benchmarking tools: We will integrate results and benchmarking methods into our existing online platform, HumanIslets.com, allowing for easy comparison of SC-islets against a large dataset of human islets. This will be invaluable for researchers worldwide, providing a template for future assessment and comparisons of SC-islet preparations using standardized criteria.
4. Collaboration and data sharing: By sharing our data and analytical tools openly, we hope to foster collaboration among researchers in the field. This collective effort can accelerate progress, leading to faster advancements and innovations in stem cell research and diabetes treatment.
In summary, we expect our research to lead to significant advancements in developing functional SC-islets, provide valuable resources for the scientific community, and ultimately contribute to improved therapies for people living with type 1 diabetes.
Relevance to T1D
Type 1 diabetes (T1D) results from the immune-mediated destruction of insulin-producing beta cells within the pancreatic islets. Without these cells, the body cannot regulate blood sugar levels properly, leading to a dependence on insulin injections or infusions and the risk of serious complications. Our proposed research is relevant to T1D in that it is focused on, firstly, understanding the current state of stem-cell derived islet cells (SC-islets) compared with human primary islets from organ donors; and, secondly, on developing approaches to produce more fully mature SC-islets. This can contribute both to the development of better models in which to study T1D in a dish, and to potential new approaches to replace the lost beta cells in T1D patients as a renewable and reliable source of cells for transplantation therapies.
Understanding and improving SC-islets has several potential benefits for people with T1D:
1. Transplanting functional SC-islets into patients holds promise for the treatment of T1D, potentially reducing or eliminating the need for insulin injections and improving quality of life through improved blood sugar regulation since more precise regulation can reduce the risk of complications associated with T1D.
2. One danger of current SC-islets is that they may release insulin even when blood sugar is low, leading to hypoglycemia. By improving the maturity and functionality of SC-islets, we hope to understand how to produce cells that release insulin in a more glucose-responsive manner.
3. Using patient-derived induced pluripotent stem cells (iPSCs) holds promise for 'personalized therapy' using a person's own, genetically matched, cells, reducing the risk of immune rejection and potentially eliminating the need for immunosuppressive drugs after transplantation. We will provide proof of concept benchmarking for iPSC-derived SC-islets.
4. Improved SC-islets can be used in research to better understand the mechanisms of T1D (for example by studying why beta-cells may be destroyed in certain individuals) and test for drugs that may promote beta-cell survival (for example in screening for new drugs). Improved SC-islet cell benchmarking and maturation will contribute importantly to these efforts.
5. Broad sharing of data, and increasing it's usabiliy by the resaerch community, will speed up research progress and foster collaboration to the benefit of T1D research.
Overall, our research is highly relevant to T1D because it addresses a fundamental need: understanding how closely current SC-islets really resemble primay pancreatic beta-cells from adult humans, developing methods to assess improvements in SC-islet development, and sharing this with the resaerch community through our online resource.