Human Beta Cells Generated from Pluripotent Stem Cells or Cellular Reprogramming for Curing Diabetes
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Diabetes is a group of metabolic diseases characterized by aberrantly high blood glucose levels caused by defects in insulin secretion or its action, or both, which affects approximately 30.3 million people (9.4% of the population) in the USA. This review will focus on using human β cells to treat and cure diabetes because β cells are absent, due to an autoimmune destruction, in type 1 diabetes or dysfunctional in type 2 diabetes. In order to generate enough functional β cells for diabetes treatment (0.1 to 1 billion cells to treat one patient), a basic science approach by mimicking what happens in normal pancreatic development must be closely aligned with engineering. Two general approaches are discussed here. The first one uses human pluripotent stem cells (hPSCs) to perform directed differentiation of hPSCs to β cells. This is advantageous because hPSCs grow indefinitely, providing a virtually unlimited source of material. Therefore, if we develop an efficient β cell differentiation protocol, we can essentially generate an unlimited amount of β cells for disease modeling and diabetes treatment. The second approach is cellular reprogramming, with which we may begin with any cell type and convert it directly into a β cell. The success of this cellular reprogramming approach, however, depends on the discovery of a robust and efficient transcription factor cocktail that can ignite this process, similar to what has been achieved in generating induced pluripotent stem cells. This discovery should be possible through identifying the important transcription factors and pioneer factors via recent advances in single-cell RNA sequencing. In short, a new renaissance in pancreas developmental biology, stem cell engineering, and cellular reprogramming for curing diabetes appears to be on the horizon.
The prevalence of type 1 diabetes is slowly increasing worldwide. It is an autoimmune disease that destroys pancreatic β cells, which are responsible for producing insulin to regulate blood glucose levels in the body. To overcome this deficiency in insulin-producing cells, scientists and researchers have been trying to generate functional β cells from either human pluripotent stem cells, using directed differentiation, or from other somatic cell types, using cellular reprogramming. Here, we discuss the various techniques that have been developed and implemented, both in vitro and in vivo, in the last 20 years. Current methods have some drawbacks, including low efficiency of generating functional β cells after differentiation or reprogramming. Therefore, future works in this field must include increasing the efficiency of functional β cell production, implementing the use of low-cost materials, and testing these methods in diabetic primates and humans.
KeywordsHuman pluripotent stem cells Beta cells Directed differentiation Cellular reprogramming Type 1 diabetes
- 5.Lian X, Hsiao C, Wilson G, Zhu K, Hazeltine LB, Azarin SM, et al. Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling. Proc Natl Acad Sci. 2012;109:E1848–57.Google Scholar
- 13.Hou JC, Min L, Pessin JE. Insulin granule biogenesis, trafficking and exocytosis. Vitam Horm. 2009:478–506. https://doi.org/10.1016/S0083-6729(08)00616-X.Insulin.
- 14.Yoon J-W, Jun H-S. Autoimmune destruction of pancreatic β cells. Am J Ther. 2005;591:580–91.Google Scholar
- 20.Dhanantwari P, Lee E, Krishnan A, Samtani R, Yamada S, Anderson S, et al. Human cardiac development in the first trimester a high-resolution magnetic resonance imaging and episcopic fluorescence image capture atlas. Circulation. 2009;120:343–51. https://doi.org/10.1161/CIRCULATIONAHA.108.796698.CrossRefGoogle Scholar
- 28.Cogger KF, Sinha A, Sarangi F, McGaugh EC, Saunders D, Dorrell C, et al. Glycoprotein 2 is a specific cell surface marker of human pancreatic progenitors. Nat Commun. 2017;8:331. https://doi.org/10.1038/s41467-017-00561-0.
- 36.Herrera PL. Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. Development. 2000;2322:2317–22.Google Scholar
- 50.Bramswig NC, Everett LJ, Schug J, Dorrell C, Liu C, Luo Y, et al. Epigenomic plasticity enables human pancreatic alpha to beta cell reprogramming. J Clin Invest. 2013;123:1275–84.Google Scholar