Bioengineering Endocrine Pancreas - An Approach to Manage Type-1 Diabetes

Introduction

Type-1 diabetes (T1D) involves the immune-driven destruction of insulin-producing beta-cells, causing glucose control issues and hyperglycemia. The primary treatment is administering exogenous insulin through multiple daily injections. An alternative approach is replacing the endocrine mass via transplanting pancreas or pancreatic islets from donors. This is considered for T1D patients facing severe hypoglycemia, glycemic instability, and unawareness. Pancreas transplantation is more common, despite being complex, while islet transplantation is a simpler, less invasive procedure with a success rate in reducing hypoglycemia and enhancing patient well-being.

What Are Endocrine Pancreas?

The human pancreas is a complex organ with both exocrine and endocrine components. The exocrine portion, constituting 98 percent of the organ, releases pancreatic juice aiding digestion. The remaining two percent forms the endocrine section, organized into clusters called islets of Langerhans. These islets are nestled within a capsule composed of extracellular matrix and fibroblasts, where endocrine cells are structured in a non-random manner. Islets receive nourishment from an intricate network of fenestrated capillaries, ensuring proximity to the blood supply. This unique arrangement of cells, extracellular matrix, and capillaries defines the endocrine niche. Understanding this niche has facilitated the recognition of essential components for the bioengineering of pancreatic tissues with endocrine capabilities.

Components of the endocrine pancreas:

1. Beta cells are about 60 to 75 percent of insulin and amylin secretion sources.

2. Alpha cells are about 20 to 30 percent secreting glucagon.

3. Pancreatic polypeptide cells release PP hormones.

Collectively, the endocrine cells collaborate to form an intricate paracrine network, crucial for maintaining effective regulation of blood glucose levels. Furthermore, interactions between these endocrine cells and neighboring microenvironments, including vascular and innate immune cells, play a vital role in this endocrine network's accurate establishment and functioning.

What Is Meant by Bioengineering Endocrine Pancreas?

In the realm of beta-cell replacement, there is a potential benefit in replicating the endocrine niche outside the body. This approach could address the current limitations in treating type 1 diabetes (T1D). Thorough research into the natural environment of pancreatic endocrine cells has provided insights into key elements that can aid in creating a vascularized endocrine pancreas through bioengineering.

Establishing Vascularization and Ensuring Oxygen Supply to the Transplant Site:

In bioengineering, the pancreas tissue can be transplanted into individuals with diabetes to help them regulate their blood sugar levels. Vascularization involves creating a network of blood vessels that can deliver nutrients and oxygen to transplanted cells. Oxygenation ensures that an adequate amount of oxygen reaches the cells to support their metabolic activities.

To improve vascularization, pre-vascularization is encouraged to grow blood vessels in the engineered tissue before transplantation. This involves growing the tissue to encourage blood vessels to form naturally.

Biomaterials, materials engineered to interact with living tissues, can also play a role. Some biomaterials are designed to attract blood vessels and encourage their growth into the transplanted tissue.

Optimizing the transplantation environment is another strategy that includes carefully choosing where the transplantation will occur, ensuring it has good blood flow and oxygen availability. Researchers also consider factors like the size and density of the transplanted tissue to ensure efficient oxygen and nutrient exchange.

Manipulating the Cellular Makeup of the Endocrine Pancreas:

This involves manipulating the types and proportions of different cell types within the pancreas, specifically focusing on the endocrine cells responsible for producing hormones like insulin. This process is of interest in regenerative medicine and diabetes research to create functional pancreatic tissue for transplantation. The process includes:

1. Cellular Identity: The endocrine pancreas consists of various cell types, including beta cells, alpha cells, delta cells, and others. Researchers seek to manipulate the cellular identity to increase the number of functional beta cells, which are crucial for insulin production.

2. Cell Reprogramming: One approach is reprogramming, where non-beta cells, such as alpha or delta, are converted to beta cells. This is achieved by introducing specific genes or molecules into these cells to reprogram their genetic expression and transform them into functional beta-like cells.

3. Gene Expression: Scientists identify key transcription factors responsible for beta cell development. By manipulating these factors, they can promote the transformation of other cell types into beta cells.

4. Epigenetic Modification: Epigenetic changes are alterations in gene expression patterns that do not involve changes to the underlying DNA sequence. Researchers work on inducing epigenetic modifications to guide cells toward a beta-cell fate.

5. Stem Cell Differentiation: Another approach involves using stem cells, which can potentially develop into various cell types. Researchers differentiate stem cells into beta-like cells in a controlled environment, mimicking the conditions for beta-cell development.

6. Microenvironment Factors: The cellular microenvironment plays a crucial role in determining cell fate. Scientists work on creating optimal conditions, such as providing specific growth factors, nutrients, and physical cues, to guide cells toward becoming beta cells.

7. Cell Expansion and Quality Control: Once reprogrammed or differentiated cells take on beta cell characteristics, they need to be expanded in number without compromising their functionality. Quality control tests are performed to ensure that the newly generated beta-like cells can produce insulin and respond to glucose levels.

8. Transplantation and Therapy: The redrawn endocrine pancreatic cells, particularly the generated beta-like cells, can be considered for transplantation into individuals with diabetes. These cells ideally restore insulin production and glucose regulation.

The ECM and Microarchitecture:

ECM (extracellular matrix) provides a supportive environment for cells within the pancreas tissue being engineered. Its functions include

1. To serve as a scaffold for the transplanted cells, helping them to adhere and arrange in a way that mimics their natural environment within the pancreas.

2. ECM components contain signaling molecules that influence cellular behavior. Hence, ECM molecules are incorporated to promote the differentiation of stem cells into insulin-producing beta cells, enhancing the overall function of engineered tissue.

3. ECM also aids in establishing a network of blood vessels within the engineered tissue to receive necessary nutrients and oxygen for survival and function.

Microarchitecture refers to the spatial arrangement of cells and ECM components within the engineered tissue. This plays a role in:

1. It influences the cell-to-cell interactions that are essential for coordinated insulin release and glucose regulation.

2. Enhance beta-cell arrangement to release insulin in response to changing glucose levels.

3. Affects the establishment of blood vessels within the engineered tissue, ensuring efficient nutrient and oxygen supply.

4. It also contributes to the overall mechanical integrity of the engineered tissue. It determines the tissue's strength, flexibility, and resilience, which are critical for transplantation and long-term functionality.

Xenogenic Sources:

This refers to material obtained from different species for use in various applications like transplantation or regenerative medicine using tissues, organs, or cells from different animal species, particularly pigs, for therapeutic purposes such as islet xenotransplantation to treat diabetes. Xenogeneic-derived biomaterials and extracellular matrix scaffolds offer a supportive microenvironment for growing and transplanting human pancreatic cells. Additionally, xenogenic sources aid in studying pancreas function, disease mechanisms, and immune responses. However, challenges related to immune compatibility, ethical considerations, and integration must be addressed to effectively harness the potential of xenogenic sources.

Conclusion

Bioengineering techniques are promising for advancing our understanding and manipulation of the endocrine pancreas. Creating functional pancreatic tissue through bioengineering opens avenues for improved diabetes treatment and potential cures. While challenges remain, such as achieving long-term viability and avoiding immune rejection, the progress made in this field underscores its potential to revolutionize healthcare and enhance the quality of life for diabetic individuals.