Plasticity of Schwann cells and pericytes in response to islet injury in mice

Abstract

Aims/hypothesis Islet Schwann (glial) cells and pericytes are the microorgan's accessory cells positioned at the external and internal boundaries facing the exocrine pancreas and endothelium, respectively, adjacent to the endocrine cells. Plasticity of glial cells and pericytes is shown in the glial scar formation after injury to the central nervous system. It remains unclear whether similar reactive cellular responses occur in insulitis. We applied three-dimensional (3D) histology to perform qualitative and quantitative analyses of the islet Schwann cell network and pericytes in normal, streptozotocin-injected (positive control of gliosis) and NOD mouse models. Methods Vessel painting paired with immunostaining of mouse pancreatic tissue was used to reveal the islet Schwann cells and pericytes and their association with vasculature. Transparent islet specimens were prepared by optical clearing to facilitate 3D confocal microscopy for panoramic visualisation of the tissue networks.Results In-depth microscopy showed that the islet Schwann cell network extends from the peri-islet domain into the core. One week after streptozotocin injection, we observed intraislet perivascular gliosis and an increase in pericyte density. In early/moderate insulitis in the NOD mice, perilesional gliosis occurred at the front of the lymphocytic infiltration with atypical islet Schwann cell morphologies, including excessive branching and perivascular gliosis. Meanwhile, pericytes aggregated on the walls of the feeding arteriole at the peri-and intralesional domains with a marked increase in surface marker density. Conclusions/interpretationThe reactive cellular responses demonstrate plasticity and suggest a stop-gap mechanism consisting of the Schwann cells and pericytes in association with the islet lesion and vasculature when injury occurs.

PanIN-associated pericyte, glial, and islet remodeling in mice revealed by 3D pancreatic duct lesion histology

“…Perilesional increases in NG2 expression and GFAP-positive fibers confirm the reactivity of pericytes and glial cells in response to early stage duct lesion formation. Because activation of the two cell types was also identified in early insulitis (40), these results suggest the sensitivity of pericytes and glial cells in detecting subtle changes in the pancreatic microenvironment and their potential use as early stage markers for lesion detection. Also, because pericytes and glial cells are known to release angiogenic and neurotrophic factors for neurovascular recruitment (16,21), we suspect that their activation is linked to structural remodeling (i.e., formation of the epithelial bud and stroma; Fig.…”

“…First, in rodent models of pancreatic islet injury induced by lymphocytic invasion or streptozotocin injection, both pancreatic glial cells and pericytes become reactive following islet lesion formation and vascular damage (40,41). Second, in an in vitro assessment of the microenvironment in chronic pancreatitis and pancreatic cancer, human tissue extracts derived from both conditions induce neural tissue outgrowth, including an increase in glial cell density (9).…”

A Challenge for the Autoimmune Diabetogenic Mechanisc in Type 1 Diabetes?

“…Using this technique, they observed the essential role of a subset of Dendritic Cells (DC). Also recently and using a tridimensional imaging of mice islets, Tang et al (51) demonstrated the role of the glio-endothelial barrier (formed by Schwann-glial cells and the endothelial associated pericytes), reacting to any islet lesion, including that associated with peri-insulitis.…”

Three-dimensional islet graft histology: panoramic imaging of neural plasticity in sympathetic reinnervation of transplanted islets under the kidney capsule

“…As a result, the microtome-based tissue analysis offers only a limited view of the graft and the surrounding tissues of the host. For example, in animal models of islet transplantation, although investigators were able to locally identify graft reinnervation (14, 20, 28 -30, 32, 34, 35), global visualization and comparison of the innervation patterns between the pancreatic islets in situ and the engrafted islets in ectopic locations have not been systematically performed to specify their difference in neuroanatomy to understand the neural network reinnervation and remodeling after transplantation.To visualize the islet neurovascular complex in situ, we previously developed a penetrative confocal imaging method, based on preparation of transparent specimens by optical clearing (9, 11, 12, 21-23, 37, 41), to perform 3D islet histology in mice (1,6,10,39). Through in-depth projection of blood vessels and nerves, we revealed the intraislet, perivascular sympathetic innervation, in addition to peri-islet contacts of sympathetic nerves with ␣-cells (6).…”

“…To visualize the islet neurovascular complex in situ, we previously developed a penetrative confocal imaging method, based on preparation of transparent specimens by optical clearing (9, 11, 12, 21-23, 37, 41), to perform 3D islet histology in mice (1,6,10,39). Through in-depth projection of blood vessels and nerves, we revealed the intraislet, perivascular sympathetic innervation, in addition to peri-islet contacts of sympathetic nerves with ␣-cells (6).…”