Abstract
Embryonic and pluripotent stem cells hold great promise in generating β-cells for both replacing medicine and novel therapeutic discoveries in diabetes mellitus. However, their differentiation in vitro is still inefficient, and functional studies reveal that most of these β-like cells still fail to fully mirror the adult β-cell physiology. For their proper growth and functioning, β-cells require a very specific environment, the islet niche, which provides a myriad of chemical and physical signals. While the nature and effects of chemical stimuli have been widely characterized, less is known about the mechanical signals. We here review the current status of knowledge of biophysical cues provided by the niche where β-cells normally live and differentiate, and we underline the possible machinery designated for mechanotransduction in β-cells. Although the regulatory mechanisms remain poorly understood, the analysis reveals that β-cells are equipped with all mechanosensors and signaling proteins actively involved in mechanotransduction in other cell types, and they respond to mechanical cues by changing their behavior. By engineering microenvironments mirroring the biophysical niche properties it is possible to elucidate the β-cell mechanotransductive-regulatory mechanisms and to harness them for the promotion of β-cell differentiation capacity in vitro.
Highlights
Secreting insulin, endocrine β-cells of the pancreas are critically involved in the control of blood glucose homeostasis
Cells grown on the nanotopographical substrates instead adopt a round shape, which favors the establishment of cell–cell contacts and the organization in islet-like clusters where β-cells are full of insulin granules
During development and in adult life, β-cells experience biophysical cues deriving from the extracellular matrix (ECM) microenvironment, neighboring cells, and hemodynamic shear stress
Summary
Endocrine β-cells of the pancreas are critically involved in the control of blood glucose homeostasis. We are able to reproduce, in vitro, the time-dependent expression of critical transcription factors that induce β-cell differentiation, and gene profiling of ‘terminally differentiated’ stem-cell-derived β-cells provides evidence that the main proteins involved in glucose-sensing, insulin production, and secretion are expressed [20]. The growth of stem cells in 3D structures characterized by biophysical properties and organization similar to those of the pancreas, and in vivo transplantation of stem-cell-derived immature β-cells in mice, gives rise to insulin-secreting β-cells that can restore euglycemia This provides evidence that the in vivo environment presents cues permissive for inducing and preserving β-cell identity that until now have not yet been sufficiently reproduced in vitro [28,29,30]. If we want to replicate in vitro what normally occurs in vivo, a full characterization and comprehension of the environmental cues of the niche, where β-cells normally develop and mature, is clearly imperative
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