Stem Cell Therapy for Diabetes: Reprogramming Stem Cells for Pancreatic Islet Transplantation

By: Leo Tching

There are more than 38 million Americans with Diabetes; it causes more than a hundred thousand deaths every year in the United States. Despite years of research progress, drug creation, and money invested, over half of Americans are still either Pre-Diabetic or Diabetic (1). In the pursuit of an innovative therapeutic cure, stem cell therapy has emerged as a promising frontier, particularly by reprogramming stem cells for pancreatic islet transplantation. This literature review explores the significance, procedure, and issues in utilizing stem cells for curing diabetes. Analyzing the current state of this technology is crucial to understanding the deep intricacies of this malevolent disease and its pervasive symptoms. This review will not only examine the systematic approach to stem cell therapy but it will also shed light to the challenges and complex ethics that steer this entire process. 

Before examining specific stem cell technology, it is crucial to understand diabetes. Diabetes Mellitus is a chronic metabolic disorder that occurs with high blood glucose levels. The core organ involved is the pancreas; it contains islets with beta cells and alpha cells. The beta cells secrete insulin, an essential hormone that regulates the glucose levels. Hence, when there is an insufficient amount of healthy insulin secreted, glucose levels become dysregulated. Short term effects of diabetes include thirst, hunger, and urination. In the long term diabetes can cause damage to blood vessels leading to cardiovascular and renal disease. Diabetes is categorized by two main types: Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D). T1D is a hereditary autoimmune disorder where T-lymphocytes destroy the crucial beta cells. On the other hand T2D is often associated with insulin resistance. In this case, adipose and liver tissue become insulin resistant over time as a result of an overload of glucose. People with T2D often have beta cells that produce even more insulin in an attempt to compensate for insulin resistance. The result of this is beta cells become damaged and dysfunctional creating unhealthy insulin. Thus, it is clear that both T1D and T2D benefit from an increase in healthy beta cell mass, and a successful beta cell transplantation would be the revolutionary permanent cure. 

However, even if beta cell transplantation is an achievable cure for diabetes, what makes it better than current methods of treating diabetes? The most common treatment for T1D is using artificial insulin pumps. The issue that arises with this is that it only offers symptomatic relief and is often tedious for people to use. The same goes for using drugs that increase insulin sensitivity in T2D. These approaches fail to tackle the root issue of diabetes—insufficient beta cell mass. Thus, this begs the question: How does a pancreatic beta cell transplantation work? To perform a successful and ethical pancreatic beta cell transplantation, there is a three step process: di-differentiation of somatic cells into pluripotent cells, differentiation of pluripotent cells into pancreatic beta cells, and ultimately the transplantation itself. This process along with a post transplantation plan to regulate autoimmunity has amazing potential to permanently change one's life. 

Despite its complexity, the research has progressed to the point of clinical success, demonstrating its clear potential for more widespread use. In a New York Times article one man was able to cure his diabetes. “It’s a whole new life,” Mr. Shelton said. “It’s like a miracle” (2). However, Mr. Shelton's treatment disregarded an important factor: bioethics. Stem cells are cells that are in a pluripotent state. When cells are in their pluripotent state they have the ability to differentiate into a more specialized cell. In the case of diabetes, that would be pancreatic beta cells. But how do we get these pluripotent cells? In Mr. Shelton's treatment, “they came from unused fertilized eggs from a fertility clinic” (2). Using fertilized eggs requires an oocyte donation. Oocyte donations, in itself, are extremely controversial. The very idea of treating human material as a commodity can be seen as inhumane and degrading. For certain groups that believe life begins at the embryonic stage, the destruction of these cells for research is extremely cruel and facetious (3). Therefore, with such controversy, most researchers have opted to use the other method of getting pluripotent stem cells: reprogramming somatic cells to create induced pluripotent stem cells (IPSC’s). 

Although Induced pluripotent stem cells are more ethical, the procedure requires numerous complex steps. The overall process uses skin or blood somatic cells that are already differentiated and then reprograms them into the pluripotent state. This process is called didifferentiation, and the method was discovered by Shinya Yamanaka in 2006 where he conducted in-vitro cell culture experiments to find out that through introducing four transcription factors (Oct3/4, Sox2, c-Myc, and Klf4) he could create induced pluripotent cells (4). This was a revolutionary step in stem cell research as it broke the barriers of ethical concern and paved the way for immense progress in regenerative medicine. 

Using IPSCs for the regenerative medicine of diabetes specifically, requires the IPSCs to be reprogrammed into the beta cells, the pancreatic islet cell that secretes insulin. The process of reprogramming a cell that is in a pluripotent state to a unipotent state is regular differentiation. However, this differentiation is a multi staged process. The first stage requires the IPSCs to be differentiated into definitive endoderm cells (DE). Endoderm cells are the cells in the embryonic stage that have the potential to turn into liver, gallbladder, pancreas, and more cells. IPSCs can be reprogrammed into these definitive endoderm cells through activating transcription factors such as Foxa2, Foxa3, and Sox17 (5). Afterward, through inhibition of nodal signaling and activating further genes such as Pdx1 and FGF7, crucial transcription factors toward regulating pancreatic development, the definitive endoderm cell can be differentiated into pancreatic progenitors (6). Ultimately, by inhibiting notch signaling and activating transcription factors such as Pdx1 and a multitude of others like Ngn3, Pax4, MafA, NeuroD1, and Nkx6, the pancreatic progenitor reaches its final state of an adult pancreatic beta cell (7).

Although the numerous steps of this procedures can add up to over 4 weeks of time, the possibility of being a permanent cure for diabetic people is worth it for most people (8). For both Type and Type 2 diabetics, constant management of treatments that are just symptomatic relievers have caused immense anxiety and stress. This transplantation imitates the natural body system of beta cells, and hence, requires little management after completion.  

Bibliography 

1. Centers for Disease Control and Prevention. (2023, November 29). National Diabetes Statistics Report. Centers for Disease Control and Prevention. https://www.cdc.gov/diabetes/data/statistics-report/index.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fdiabetes%2Fdata%2Fstatistics%2Fstatistics-report.html  

2. Kolata, G. (2021, November 27). A cure for type 1 diabetes? for one man, it seems to have worked. The New York Times. https://www.nytimes.com/2021/11/27/health/diabetes-cure-stem-cells.html  

3. Lo, B., & Parham, L. (2009). Ethical issues in stem cell research. Endocrine reviews, 30(3), 204–213. https://doi.org/10.1210/er.2008-0031  

4. Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663–676. https://doi.org/10.1016/j.cell.2006.07.024 

5. Oh, Y., & Jang, J. (2019). Directed Differentiation of Pluripotent Stem Cells by Transcription Factors. Molecules and cells, 42(3), 200–209. https://doi.org/10.14348/molcells.2019.2439 

6. Dettmer, R., Cirksena, K., Münchhoff, J., Kresse, J., Diekmann, U., Niwolik, I., Buettner, F. F. R., & Naujok, O. (2020). FGF2 Inhibits Early Pancreatic Lineage Specification during Differentiation of Human Embryonic Stem Cells. Cells, 9(9), 1927. https://doi.org/10.3390/cells9091927 

7. Zhu, Y., Liu, Q., Zhou, Z., & Ikeda, Y. (2017). PDX1, Neurogenin-3, and MAFA: critical transcription regulators for beta cell development and regeneration. Stem cell research & therapy, 8(1), 240. https://doi.org/10.1186/s13287-017-0694-z 

8. Kim, M. J., Lee, E. young, You, Y., Yang, H. K., Yoon, K.-H., & Kim, J.-W. (2020, August 18). Generation of ipsc-derived insulin-producing cells from patients with type 1 and type 2 diabetes compared with Healthy Control. Stem Cell Research. https://www.sciencedirect.com/science/article/pii/S1873506120302592