Pancreatic neuro-insular network in young mice revealed by 3D panoramic histology

Tang, Shiue–Cheng; Shen, Chia‐Ning; Lin, Pei Yu; Peng, Shih-Jung; Chien, Hung Jen; Chou, Ya Hsien; Chamberlain, Chester E.; Pasricha, Pankaj J.

doi:10.1007/s00125-017-4408-y

Cited by 51 publications

(54 citation statements)

References 35 publications

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“…In this research, the human pancreatic neurovascular networks are visualised via 3D panoramic histology with tissue clearing [10] to characterise the network architecture in a space continuum. Using the 3D image data, we identify a pancreatic neuro-insular network and islet-ganglionic associations in health and fatty infiltration.…”

Section: Discussionmentioning

confidence: 99%

“…Propidium iodide or SYTO 16 staining was performed to reveal the nuclei. The labelled specimens were immersed in the optical clearing solution (RapiClear 1.52 solution, SunJin Lab, Hsinchu, Taiwan) before imaging via confocal microscopy [10,23]. To quantify the tissue transparency, the percentage of light transmittance was measured with the microplate reader (SpectraMax M2e; Molecular Devices, Sunnyvale, CA, USA) [25].…”

Section: Methodsmentioning

confidence: 99%

“…In contrast, in severe hypoglycaemia (glucose level ≤ 1.94 mmol/l) the activation of pancreatic sympathetic nerves contributes to an overall increase in glucagon secretion in dogs [9]. These functional links, as well as the neuro-insular network identified in mice [10], indicate an association between islets and the autonomic nervous system. The mouse neuro-insular network also implicates a similar neuro-insular association in the human pancreas.…”

Section: Introductionmentioning

confidence: 95%

“…The human pancreas is a solid organ with intra-lobular islets closely surrounded by the exocrine acini, whereas the mouse pancreas is a collection of soft lobules with islets primarily residing in the inter-lobular space [11], in which the ganglia also reside to establish the neuroinsular network [10]. In the human pancreas, there have been no comprehensive studies to identify the location of the intrapancreatic ganglia or to depict the spatial arrangement of an islet-ganglionic association.…”

Section: Introductionmentioning

confidence: 99%

“…To examine the neuro-insular network in health and fatty infiltration, we applied 3D histology with tissue clearing [10,22,23] to acquire tissue maps and high-definition images of the human pancreas. Taking full advantage of the 3D image data, we also compared the human pancreatic microenvironment with its counterpart in mice, highlighting the differences and similarities between the two systems.…”

Section: Introductionmentioning

confidence: 99%

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Human pancreatic neuro-insular network in health and fatty infiltration

et al. 2017

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Aims/hypothesis Identification of a pancreatic neuro-insular network in mice suggests that a similar integration of islets and nerves may be present in the human pancreas. To characterise the neuro-insular network and the intra-pancreatic ganglia in a clinically related setting, we examined human pancreases in health and with fatty infiltration via 3-dimensional (3D) histology and compared the human pancreatic microenvironment with its counterpart in mice. Methods Human pancreatic specimens from individuals with normal BMI, high BMI (≥ 25) and type 2 diabetes were used to investigate the neuro-insular network. Transparent specimens were prepared by tissue clearing for transmitted light and deeptissue fluorescence imaging to simultaneously visualise infiltrated adipocytes, islets and neurovascular networks. Results High-definition images of human islets reveal that both the sympathetic and parasympathetic nerves enter the islet core and reside in the immediate microenvironment of islet cells. Around the islets, the neuro-insular network is visualised with 3D histology to identify the intra-pancreatic ganglia (peri-lobular and intra-parenchymal ganglia) and the islet-ganglionic association. In humans, but not in mice, pancreatic fatty infiltration (BMI dependent) features adipocytes infiltrating into the parenchyma and accumulating in the perilobular space, in which the peri-lobular ganglia also reside. We identified the formation of adipose-ganglionic complexes in the peri-lobular space and enlargement of ganglia around adipocytes. In the specimen from the individual with type 2 diabetes, an increase in the number of nerve projections from the intra-parenchymal ganglia is associated with severe fatty infiltration. Conclusions/interpretation We present new perspectives of human pancreas and islet innervation via 3D histology. Our results strongly suggest that fatty infiltration in the human pancreas creates a neurotrophic microenvironment and promotes remodelling of pancreatic innervation.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human pancreatic neuro-insular network in health and fatty infiltration

et al. 2017

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Roles of the nervous system in pancreatic cancer

Wakiya

Ishido

Yoshizawa

et al. 2021

Annals of Gastroent Surgery

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Pancreatic ductal adenocarcinoma (PDAC), with its extremely poor prognosis, presents a substantial health problem worldwide. Outcomes have improved thanks to progress in surgical technique, chemotherapy, pre‐/postoperative management, and centralization of patient care to high‐volume centers. However, our goals are yet to be met. Recently, exome sequencing using PDAC surgical specimens has demonstrated that the most frequently altered genes were the axon guidance genes, indicating involvement of the nervous system in PDAC carcinogenesis. Moreover, perineural invasion has been widely identified as one poor prognostic factor. The combination of innovative technologies and extensive clinician experience with the nervous system come together here to create a new treatment option. However, evidence has emerged that suggests that the relationship between cancer and nerves in PDAC, the underlying mechanism, is not fully understood. In an attempt to tackle this lethal cancer, this review summarizes the anatomy and physiology of the pancreas and discusses the role of the nervous system in the pathophysiology of PDAC.

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Phosphoproteome reveals molecular mechanisms of aberrant rhythm in neurotransmitter‐mediated islet hormone secretion in diabetic mice

Sun

et al. 2022

Clinical & Translational Med

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Background: Acetylcholine (ACh) and norepinephrine (NE) are representative neurotransmitters of parasympathetic and sympathetic nerves, respectively, that antagonize each other to coregulate internal body functions. This also includes the control of different kinds of hormone secretion from pancreatic islets. However, the molecular mechanisms have not been fully elucidated, and whether innervation in islets is abnormal in diabetes mellitus also remains unclear. Methods and results: Immunofluorescence colocalization and islet perfusion were performed and the results demonstrated that ACh/NE and their receptors were highly expressed in islet and rapidly regulated different hormones secretion. Phosphorylation is considered an important posttranslational modification in islet innervation and it was identified by quantitative proteomic and phosphoproteomic analyses in this study. The phosphorylated islet proteins were found involved in many biological and pathological processes, such as synaptic signalling transduction, calcium channel opening and insulin signalling pathway.Then, the kinases were predicted by motif analysis and further screened and verified by kinase-specific siRNAs in different islet cell lines (αTC1-6, Min6 and TGP52). After functional verification, Ksr2 and Pkacb were considered the key kinases of ACh and NE in insulin secretion, and Cadps, Mlxipl and Pdcd4 were the substrates of these kinases measured by immunofluorescence co-staining.Then, the decreased expression of receptors, kinases and substrates of ACh and NE were found in diabetic mice and the aberrant rhythm in insulin secretion could be improved by combined interventions on key receptors (M3 (pilocarpine) or α2a (guanfacine)) and kinases (Ksr2 or Pkacb).Yunqiang He, Qi Fu and Min Sun contributed equally to this work.

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Pancreatic neuro-insular network in young mice revealed by 3D panoramic histology

Abstract: Our work provides insight into the neuro-insular integration at the organ level and demonstrates a new approach for investigating previously unknown details of the pancreatic tissue network in health and disease.

Cited by 51 publications

References 35 publications

Human pancreatic neuro-insular network in health and fatty infiltration

Human pancreatic neuro-insular network in health and fatty infiltration

Roles of the nervous system in pancreatic cancer

Phosphoproteome reveals molecular mechanisms of aberrant rhythm in neurotransmitter‐mediated islet hormone secretion in diabetic mice

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