The ductal origin of structural and functional heterogeneity between pancreatic islets

Merkwitz, Claudia; Blaschuk, Orest W.; Schulz, Angela; Lochhead, Paul; Meister, Jaroslawna; Ehrlich, Angela; Ricken, Albert

doi:10.1016/j.proghi.2013.09.001

Cited by 23 publications

(15 citation statements)

References 179 publications

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“…Importantly, these findings are in agreement with previously published histological reports focused only on major biomarkers due to the use of affinity probes. 4–7 Here, our non-targeted and multiplex analytical technology generated a dataset to test for differential processing of islet prohormones between anatomical regions of the rat pancreas.…”

Section: Resultsmentioning

confidence: 99%

“…Due to the importance of islets of Langerhans in normal and pathological glucose utilization, the cellular heterogeneity and variability of this microorgan are well studied using approaches such as immunohistochemical profiling, 4–7 single cell transcriptomics analysis, 1,8,9 and metabolomic and proteomic profiling. 10,11 Mass spectrometry (MS) has become an important tool for the investigation of peptide content in organelles, cells, and tissues, such as the endocrine pancreas.…”

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confidence: 99%

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Single Cell Peptide Heterogeneity of Rat Islets of Langerhans

et al. 2016

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Measuring the chemical composition of individual cells in mammalian organs can provide critical insights towards understanding the mechanisms leading to their normal and pathological function. In this work, single cell heterogeneity of islets of Langerhans is characterized with high throughput by microscopy-guided single cell matrix-assisted laser desorption/ionization mass spectrometry. Two levels of chemical heterogeneity were observed from the analysis of more than 3000 individual cells. Within a single islet, cellular heterogeneity was evident from the exclusive expression of the canonical biomarkers glucagon, insulin, pancreatic polypeptide (PP), and somatostatin within α-, β-, γ-, and δ-cells, respectively. We localized the neuropeptide WE-14, a known cell-to-cell signaling molecule, to individual δ-cells. Moreover, several unreported endogenous peptides generated by dibasic site cleavages of PP were detected within individual γ-cells. Of these, PP(27–36) was previously reported to activate the human Y4 receptor, suggesting it has a signaling role in vivo. Heterogeneity in cell composition was also observed between islets as evidenced by a 50-fold larger α–cell population in islets of the dorsal pancreas compared to the ventral-derived pancreatic islets. Finally, PP(27–36) was more abundant in γ-cells from the ventral region of the pancreas, indicating differences in the extent of PP-prohormone processing in the two regions of the pancreas.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Single Cell Peptide Heterogeneity of Rat Islets of Langerhans

et al. 2016

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“…These data support evidence from others indicating b-cell heterogeneity in relation to proximity to other cell types, vasculature, and innervation patterns. 35 Neonatal b-cells have been shown to require a glucose threshold for maturation, and b-cells from extra-islet clusters in young mice are functionally altered than those within islets, including differential expression of the peptide hormone Ucn3. 19 It is well established that mouse b-cells in the immediate postnatal period are immature, with poor GSIS and lower expression of Glut2 compared to adult b-cells.…”

Section: Discussionmentioning

confidence: 99%

Insulin-positive, Glut2-low cells present within mouse pancreas exhibit lineage plasticity and are enriched within extra-islet endocrine cell clusters

Beamish

Strutt

Arany

et al. 2016

Islets

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Regeneration of insulin-producing β-cells from resident pancreas progenitors requires an understanding of both progenitor identity and lineage plasticity. One model suggested that a rare β-cell sub-population within islets demonstrated multi-lineage plasticity. We hypothesized that β-cells from young mice (postnatal day 7, P7) exhibit such plasticity and used a model of islet dedifferentiation toward a ductal epithelial-cell phenotype to test this theory. RIPCre;Z/AP(+/+) mice were used to lineage trace the fate of β-cells during dedifferentiation culture by a human placental alkaline phosphatase (HPAP) reporter. There was a significant loss of HPAP-expressing β-cells in culture, but remaining HPAP(+) cells lost insulin expression while gaining expression of the epithelial duct cell marker cytokeratin-19 (Ck19). Flow cytometry and recovery of β-cell subpopulations from whole pancreas vs. islets suggest that the HPAP(+)Ck19(+) cells had derived from insulin-positive, glucose-transporter-2-low (Ins(+)Glut2(LO)) cells, representing 3.5% of all insulin-expressing cells. The majority of these cells were found outside of islets within clusters of <5 β-cells. These insulin(+)Glut2(LO) cells demonstrated a greater proliferation rate in vivo and in vitro as compared to insulin(+)Glut2(+) cells at P7, were retained into adulthood, and a subset differentiated into endocrine, ductal, and neural lineages, illustrating substantial plasticity. Results were confirmed using RIPCre;ROSA- eYFP mice. Quantitative PCR data indicated these cells possess an immature β-cell phenotype. These Ins(+)Glut2(LO) cells may represent a resident population of cells capable of forming new, functional β-cells, and which may be potentially exploited for regenerative therapies in the future.

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“…Отличительной чертой таких островков являются прежде всего их топо-гра фические характеристики, тогда как клеточный состав и локализация инсулоцитов практически не отличаются от таковых в островках Лангерганса. Интерлобулярные островки описаны у некоторых видов животных [5], однако их функциональная значимость и происхождение остаются неясными. Как известно, эпителий мелких выводных прото-ков рассматривается как основной источник ре-гиональных прогениторных клеток.…”

Section: результаты и их обсуждениеunclassified

Identification of Islet Capacity in Donor’s Pancreas Using Immunomorphological Analysis

Скалецкий

Кирсанова

Бубенцова

et al. 2016

RJTAO

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ФГБУ «Федеральный научный центр трансплантологии и искусственных органов имени академика В.И. Шумакова» Минздрава России, Москва, Российская Федерация Целью работы было детальное морфологическое исследование донорской поджелудочной железы (ДПЖ) для изучения возможностей максимального получения островковой ткани, подходящей для транспланта-ции пациенту с сахарным диабетом 1-го типа. Материалы и методы. Восемь ПЖ были получены в ре-зультате мультиорганного донорского забора. Морфологические исследования проводились с помощью гистологических и специальных иммуногистохимических методов. Результаты. Большинство остров-ков было выявлено в хвостовой части ДПЖ. Помимо расположенных интралобулярно типичных остров-ков Лангерганса с преобладанием мозаично расположенных бета-клеток, в междольковых прослойках соединительной ткани выявлены скопления островковых клеток, формирующих так называемые интер-лобулярные (перилобулярные) островки. Кроме того, в клетках эпителия протоков ДПЖ был выявлен нестин, который является маркером прогениторных клеток. Заключение. Для получения максимального потенциала островковой ткани из ДПЖ необходимо использовать интралобулярно расположенные ост-ровки, а также клетки-предшественники поджелудочной железы, которые имеют способность к транс-дифференцировке в островковые клетки.Ключевые слова: донорская поджелудочная железа, морфологические исследования, интерлобулярные островки, прогениторные клетки. The aim of the work was detailed morphological investigations of donor pancreas (DP) for the study of possibilities of maximal selection of islet tissue suitable for transplantation to a patient of diabetes mellitus type 1. Materials and methods. Eight DPs were received as a result of multiorgan donation. Morphological investigations were performed by means of histological and special immunohistochemical methods. Results. The Majority of islets were revealed in the tail part of the DP. Besides typical Langerhans islets with predominance of mosaically located beta cells, the accumulations of islet cells forming so-called interlobular (perilobular) islets were revealed in the layers of interlobular connecting tissue. In addition, in the cells of ductal epithelium nestin which is a marker of progenitor cells was revealed. Conclusion. To obtain the maximal potential of islet tissue from DP it is necessary to use interlobular located islets as well as to use progenitor cells of pancreas, which have the ability to transdifferentiate into islet cells. IDENTIFICATION OF ISLET CAPACITY IN DONOR'S PANCREAS USING IMMUNOMORPHOLOGICAL ANALYSISN

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The ductal origin of structural and functional heterogeneity between pancreatic islets

Cited by 23 publications

References 179 publications

Single Cell Peptide Heterogeneity of Rat Islets of Langerhans

Single Cell Peptide Heterogeneity of Rat Islets of Langerhans

Insulin-positive, Glut2-low cells present within mouse pancreas exhibit lineage plasticity and are enriched within extra-islet endocrine cell clusters

Identification of Islet Capacity in Donor’s Pancreas Using Immunomorphological Analysis

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