Small Molecule-Induced Pancreatic β-Like Cell Development: Mechanistic Approaches and Available Strategies

Abstract

Diabetes is a metabolic disease which affects not only glucose metabolism but also lipid and protein metabolism. It encompasses two major types: type 1 and 2 diabetes. Despite the different etiologies of type 1 and 2 diabetes mellitus (T1DM and T2DM, respectively), the defining features of the two forms are insulin deficiency and resistance, respectively. Stem cell therapy is an efficient method for the treatment of diabetes, which can be achieved by differentiating pancreatic β-like cells. The consistent generation of glucose-responsive insulin releasing cells remains challenging. In this review article, we present basic concepts of pancreatic organogenesis, which intermittently provides a basis for engineering differentiation procedures, mainly based on the use of small molecules. Small molecules are more auspicious than any other growth factors, as they have unique, valuable properties like cell-permeability, as well as a nonimmunogenic nature; furthermore, they offer immense benefits in terms of generating efficient functional beta-like cells. We also summarize advances in the generation of stem cell-derived pancreatic cell lineages, especially endocrine β-like cells or islet organoids. The successful induction of stem cells depends on the quantity and quality of available stem cells and the efficient use of small molecules.

In silico discovery of small molecules for efficient stem cell differentiation into definitive endoderm

“…Using three orthogonal drug repurposing approaches, we identified a total of 999 unique candidates inducers for DE differentiation (Table S5). Exploration of the top hits indicates that these compounds are enriched for potential inducers: we observed the presence of PI3K, HDAC and mTOR inhibitors, some of which are used in existing protocols (Thakur et al 2020), as well as HSP90 inhibitors, which are not currently used.…”

Manufacturing clinical‐grade human induced pluripotent stem cell‐derived beta cells for diabetes treatment

“…However, the change has to be thoughtfully considered, selected, tested by manufacturers and vetted and approved by regulatory bodies before incorporating into the finalized hiPSC‐derived β‐cell differentiation procedure. 131 …”

Therapeutic Status and Available Strategies in Pancreatic Ductal Adenocarcinoma

“…Different signaling pathways: PI3K/AKT [ 67 , 68 ], JNK [ 69 ], MEK/ERK [ 70 ], nuclear factor kappaB (NF-κB) [ 71 ], TGF-β [ 72 ], WNT [ 73 , 74 ], and Hedgehog [ 75 , 76 ] are known to crosstalk with Notch signaling pathway or with each other in the progression of pancreatic CSCs [ 77 , 78 , 79 ], because of their crucial role in production and differentiation of pancreatic cells [ 80 , 81 ]. It is therefore believed that the interaction between these signaling pathways and Notch signaling pathway can play an important role in the development of pancreatic tumors [ 78 ].…”