Shaping Pancreatic β-Cell Differentiation and Functioning: The Influence of Mechanotransduction

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.

Proteomic Analysis Reveals a Mitochondrial Remodeling of βTC3 Cells in Response to Nanotopography

“…In turn, this modification probably drags the decrease in TCA cycle and aerobic respiration observed in cells grown on nanosubstrates. Immunoblotting and morphological studies revealed same modifications in two distinct beta cell lines (βTC3 and INS1E), thus suggesting that it may be a general mechanism of beta cell adaptation to changes in substrate topography (Galli et al, 2020).…”

“…This phenomenon, i.e., the conversion of microenvironmental biophysical information into corresponding cellular responses, is defined as mechanotransduction: the extracellular matrix (ECM) configuration affects the assembly of integrin adhesion complexes (IAC) and their signaling. This impacts the nuclear architecture and mechanosensitive transcription factors, eventually leading to modifications of the cell program (Chen et al, 2014;Schulte et al, 2016;Galli et al, 2018Galli et al, , 2020Maffioli et al, 2018;Chighizola et al, 2019).…”

“…Recently, using cluster-assembled zirconia substrates with tailored roughness produced by SCBD, we provide evidence that β-cells can perceive the nanotopography of the substrate and can convert this information into a mechanotransductive process, which preserves β-cell differentiation and function in long-term in vitro culture of human islets (Galli et al, 2018(Galli et al, , 2020.…”

“…Indeed, we demonstrated that human β cells, using integrines as mechanosensors, can channel mechanical forces, through actin fibers, directly to the nucleus where they cause nuclear envelope modifications and activation of a specific transcriptional program which supports β-cell survival and preserves β-cell differentiation and insulin secretion. This phenomenon depends on the nanoscale surface topography since only cells grown on cluster-assembled films maintain the functional phenotype (Galli et al, 2018(Galli et al, , 2020. Whether other organelles are involved in the phenomenon is unknown.…”

Insulin/Glucose-Responsive Cells Derived from Induced Pluripotent Stem Cells: Disease Modeling and Treatment of Diabetes

“…Pancreatic islet architecture with intra-islet cell-cell communication between β-cells and other endocrine cell types are essential for β-cell functionality and glucose responsiveness. During islet development, for proper β-cell lineage specification, differentiation and maturation, intact cell-cell (via intercellular adherents junctions: cadherins, connexins, and nectins) and cell-matrix (via mechanical cues through extracellular matrix (ECM) stiffness, topography, fluid shear forces, and geometry) interactions are crucial for coordinating and supporting cells [ 107 , 108 , 109 , 110 , 111 , 112 ]. The pancreas is considered a soft organ based on its ECM composition.…”