Abstract
Human pluripotent stem cells, including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), hold promise as novel therapeutic tools for diabetes treatment because of their self-renewal capacity and ability to differentiate into beta (β)-cells. Small and large molecules play important roles in each stage of β-cell differentiation from both hESCs and hiPSCs. The small and large molecules that are described in this review have significantly advanced efforts to cure diabetic disease. Lately, effective protocols have been implemented to induce hESCs and human mesenchymal stem cells (hMSCs) to differentiate into functional β-cells. Several small molecules, proteins, and growth factors promote pancreatic differentiation from hESCs and hMSCs. These small molecules (e.g., cyclopamine, wortmannin, retinoic acid, and sodium butyrate) and large molecules (e.g. activin A, betacellulin, bone morphogentic protein (BMP4), epidermal growth factor (EGF), fibroblast growth factor (FGF), keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), noggin, transforming growth factor (TGF-α), and WNT3A) are thought to contribute from the initial stages of definitive endoderm formation to the final stages of maturation of functional endocrine cells. We discuss the importance of such small and large molecules in uniquely optimized protocols of β-cell differentiation from stem cells. A global understanding of various small and large molecules and their functions will help to establish an efficient protocol for β-cell differentiation.
Highlights
Diabetes mellitus is the most common metabolic disorder with increasing incidence worldwide, predicted to exceed 350 million by 2030 [1]
There are three different stages during pancreatic cell differentiation: specification, expansion, and differentiation. human embryonic stem cells (hESCs) differentiate into insulin-producing cells through stages in the following order: Definitive endoderm (DE) pancreas specification such as primitive gut tube and pancreatic foregut, pancreas progenitor development, and development of mature differentiated β-cells characterized by expression of various transcription factors (Figure 1 and Table 1)
Stem cell therapy is promising for the treatment of diabetes [175,176,177,178,179]
Summary
Diabetes mellitus is the most common metabolic disorder with increasing incidence worldwide, predicted to exceed 350 million by 2030 [1]. The human iPSCs (hiPSCs) can be derived from various non-pluripotent cells, such as adipose cells, amniotic fluid cells, hepatocytes, blood cells, fibroblasts, and bone marrow cells [9,10,11,12,13,14]. These hiPSCs have self-renewal and gene expression characteristics similar to those of ESCs and are less problematic in terms of ethical issues [15]. We will discuss the signaling pathways involved in β-cell differentiation
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