Development of the endocrine pancreas and novel strategies for β-cell mass restoration and diabetes therapy

Abstract

Diabetes mellitus represents a serious public health problem owing to its global prevalence in the last decade. The causes of this metabolic disease include dysfunction and/or insufficient number of β cells. Existing diabetes mellitus treatments do not reverse or control the disease. Therefore, β-cell mass restoration might be a promising treatment. Several restoration approaches have been developed: inducing the proliferation of remaining insulin-producing cells, de novo islet formation from pancreatic progenitor cells (neogenesis), and converting non-β cells within the pancreas to β cells (transdifferentiation) are the most direct, simple, and least invasive ways to increase β-cell mass. However, their clinical significance is yet to be determined. Hypothetically, β cells or islet transplantation methods might be curative strategies for diabetes mellitus; however, the scarcity of donors limits the clinical application of these approaches. Thus, alternative cell sources for β-cell replacement could include embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells. However, most differentiated cells obtained using these techniques are functionally immature and show poor glucose-stimulated insulin secretion compared with native β cells. Currently, their clinical use is still hampered by ethical issues and the risk of tumor development post transplantation. In this review, we briefly summarize the current knowledge of mouse pancreas organogenesis, morphogenesis, and maturation, including the molecular mechanisms involved. We then discuss two possible approaches of β-cell mass restoration for diabetes mellitus therapy: β-cell regeneration and β-cell replacement. We critically analyze each strategy with respect to the accessibility of the cells, potential risk to patients, and possible clinical outcomes.

Figure 1. Schematic of pancreatic progenitors toward differentiated lineages. Upon activation of PDx1, the pancreatic fate is induced from endoderm progenitors. Pancreatic progenitors give rise to acini, ductal, and endocrine progenitors. Endocrine progenitors then differentiate into specific hormone secreting cells: α, β, δ, PP, and ε cells. Key transcription factors involved in each differentiation step and the time they are expressed are indicated.

Figure 2. Functional and morphological postnatal pancreatic maturation. After weaning, normal β-cell development culminates in two crucial maturation events: the left panel shows glucose sensing machinery is enhanced when insulin production per cell changes, leading to increases in insulin-containing dense core secretory granules. This results in the maturation of stimulus-secretion coupling. The right panel illustrates the establishment of appropriate β-cell mass in proportion to an individual’s body weight and pancreatic islet remodeling, leading to morphological maturation. Overexpression of key genes involved in the maturation process is indicated.

Figure 3. Different strategies for β-cell mass restoration. Novel strategies for β-cell mass restoration in diabetes therapy can be divided into the following groups: 1) β-cell regeneration, which includes proliferation (a), neogenesis (b), and transdifferentiation (c), and 2) β-cell replacement, which involves the transplantation of insulin-producing cells differentiated from embryonic stem cells (ESC) (d), induced pluripotent stem cells (iPSCs) (e), and mesenchymal stem cells (MSC) (f).