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  1. Article ; Online: Loss of ZNF148 enhances insulin secretion in human pancreatic β cells

    Eleonora de Klerk / Yini Xiao / Christopher H. Emfinger / Mark P. Keller / David I. Berrios / Valentina Loconte / Axel A. Ekman / Kate L. White / Rebecca L. Cardone / Richard G. Kibbey / Alan D. Attie / Matthias Hebrok

    JCI Insight, Vol 8, Iss

    2023  Volume 11

    Abstract: Insulin secretion from pancreatic β cells is essential to the maintenance of glucose homeostasis. Defects in this process result in diabetes. Identifying genetic regulators that impair insulin secretion is crucial for the identification of novel ... ...

    Abstract Insulin secretion from pancreatic β cells is essential to the maintenance of glucose homeostasis. Defects in this process result in diabetes. Identifying genetic regulators that impair insulin secretion is crucial for the identification of novel therapeutic targets. Here, we show that reduction of ZNF148 in human islets, and its deletion in stem cell–derived β cells (SC–β cells), enhances insulin secretion. Transcriptomics of ZNF148-deficient SC–β cells identifies increased expression of annexin and S100 genes whose proteins form tetrameric complexes involved in regulation of insulin vesicle trafficking and exocytosis. ZNF148 in SC–β cells prevents translocation of annexin A2 from the nucleus to its functional place at the cell membrane via direct repression of S100A16 expression. These findings point to ZNF148 as a regulator of annexin-S100 complexes in human β cells and suggest that suppression of ZNF148 may provide a novel therapeutic strategy to enhance insulin secretion.
    Keywords Metabolism ; Stem cells ; Medicine ; R
    Subject code 571
    Language English
    Publishing date 2023-06-01T00:00:00Z
    Publisher American Society for Clinical investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Species-specific roles for the MAFA and MAFB transcription factors in regulating islet β cell identity

    Jeeyeon Cha / Xin Tong / Emily M. Walker / Tehila Dahan / Veronica A. Cochrane / Sudipta Ashe / Ronan Russell / Anna B. Osipovich / Alex M. Mawla / Min Guo / Jin-hua Liu / Zachary A. Loyd / Mark O. Huising / Mark A. Magnuson / Matthias Hebrok / Yuval Dor / Roland Stein

    JCI Insight, Vol 8, Iss

    2023  Volume 16

    Abstract: Type 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet β cells, characterized by inappropriate production of other islet cell–enriched hormones. Here, we examined how hormone misexpression was influenced by ... ...

    Abstract Type 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet β cells, characterized by inappropriate production of other islet cell–enriched hormones. Here, we examined how hormone misexpression was influenced by the MAFA and MAFB transcription factors, closely related proteins that maintain islet cell function. Mice specifically lacking MafA in β cells demonstrated broad, population-wide changes in hormone gene expression with an overall gene signature closely resembling islet gastrin+ (Gast+) cells generated under conditions of chronic hyperglycemia and obesity. A human β cell line deficient in MAFB, but not one lacking MAFA, also produced a GAST+ gene expression pattern. In addition, GAST was detected in human T2D β cells with low levels of MAFB. Moreover, evidence is provided that human MAFB can directly repress GAST gene transcription. These results support a potentially novel, species-specific role for MafA and MAFB in maintaining adult mouse and human β cell identity, respectively. Here, we discuss the possibility that induction of Gast/GAST and other non–β cell hormones, by reduction in the levels of these transcription factors, represents a dysfunctional β cell signature.
    Keywords Cell biology ; Endocrinology ; Medicine ; R
    Language English
    Publishing date 2023-08-01T00:00:00Z
    Publisher American Society for Clinical investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Transcriptional changes and the role of ONECUT1 in hPSC pancreatic differentiation

    Sandra Heller / Zhijian Li / Qiong Lin / Ryan Geusz / Markus Breunig / Meike Hohwieler / Xi Zhang / Gopika G. Nair / Thomas Seufferlein / Matthias Hebrok / Maike Sander / Cécile Julier / Alexander Kleger / Ivan G. Costa

    Communications Biology, Vol 4, Iss 1, Pp 1-

    2021  Volume 12

    Abstract: Heller et al analyze transcriptomic and epigenetic datasets from human PSCs differentiating into pancreatic progenitors to elucidate the regulatory mechanisms behind pancreatic development. The authors report that the transcription factor ONECUT1 is ... ...

    Abstract Heller et al analyze transcriptomic and epigenetic datasets from human PSCs differentiating into pancreatic progenitors to elucidate the regulatory mechanisms behind pancreatic development. The authors report that the transcription factor ONECUT1 is expressed specifically in pancreatic development and associates with other key TFs (such as FOXA2, GATA6, PDX1) during endocrine specification.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2021-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Loss of the transcription factor MAFB limits β-cell derivation from human PSCs

    Ronan Russell / Phichitpol P. Carnese / Thomas G. Hennings / Emily M. Walker / Holger A. Russ / Jennifer S. Liu / Simone Giacometti / Roland Stein / Matthias Hebrok

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 15

    Abstract: The MAF bZIP transcription factor B (MAFB) is present in postnatal human beta cells but its role is unclear. Here, the authors show that MAFB regulates endocrine pancreatic cell fate specification. ...

    Abstract The MAF bZIP transcription factor B (MAFB) is present in postnatal human beta cells but its role is unclear. Here, the authors show that MAFB regulates endocrine pancreatic cell fate specification.
    Keywords Science ; Q
    Language English
    Publishing date 2020-06-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Loss of the transcription factor MAFB limits β-cell derivation from human PSCs

    Ronan Russell / Phichitpol P. Carnese / Thomas G. Hennings / Emily M. Walker / Holger A. Russ / Jennifer S. Liu / Simone Giacometti / Roland Stein / Matthias Hebrok

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 15

    Abstract: The MAF bZIP transcription factor B (MAFB) is present in postnatal human beta cells but its role is unclear. Here, the authors show that MAFB regulates endocrine pancreatic cell fate specification. ...

    Abstract The MAF bZIP transcription factor B (MAFB) is present in postnatal human beta cells but its role is unclear. Here, the authors show that MAFB regulates endocrine pancreatic cell fate specification.
    Keywords Science ; Q
    Language English
    Publishing date 2020-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Elimination of von Hippel-Lindau function perturbs pancreas endocrine homeostasis in mice.

    Sapna Puri / Alejandro García-Núñez / Matthias Hebrok / David A Cano

    PLoS ONE, Vol 8, Iss 8, p e

    2013  Volume 72213

    Abstract: Mutations in the human homolog of the Vhlh gene [encoding the von-Hippel Lindau (VHL) protein] lead to tumor development. In mice, depletion of Vhlh in pancreatic ß-cells causes perturbed glucose homeostasis, but the role of this gene in other pancreatic ...

    Abstract Mutations in the human homolog of the Vhlh gene [encoding the von-Hippel Lindau (VHL) protein] lead to tumor development. In mice, depletion of Vhlh in pancreatic ß-cells causes perturbed glucose homeostasis, but the role of this gene in other pancreatic cells is poorly understood. To investigate the function of VHL/HIF pathway in pancreatic cells, we inactivated Vhlh in the pancreatic epithelium as well as in the endocrine and exocrine lineages. Our results show that embryonic depletion of Vhlh within the pancreatic epithelium causes postnatal lethality due to severe hypoglycemia. The hypoglycemia is recapitulated in mice with endocrine-specific removal of Vhlh, while animals with loss of Vhlh predominantly in the exocrine compartment survive to adulthood with no overt defects in glucose metabolism. Mice with hypoglycemia display diminished insulin release in response to elevated glucose. Significantly, the glucagon response is impaired both in vivo (circulating glucagon levels) as well as in an in vitro secretion assay in isolated islets. Hypoxia also impairs glucagon secretion in a glucagon-expressing cell line in culture. Our results reveal a novel role for the hypoxia/HIF pathway in islet hormone secretion and maintenance of the fine balance that allows for the establishment of normoglycemia.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Aberrant innate immune activation following tissue injury impairs pancreatic regeneration.

    Alexandra E Folias / Cristina Penaranda / Anthony L Su / Jeffrey A Bluestone / Matthias Hebrok

    PLoS ONE, Vol 9, Iss 7, p e

    2014  Volume 102125

    Abstract: Normal tissue architecture is disrupted following injury, as resident tissue cells become damaged and immune cells are recruited to the site of injury. While injury and inflammation are critical to tissue remodeling, the inability to resolve this ... ...

    Abstract Normal tissue architecture is disrupted following injury, as resident tissue cells become damaged and immune cells are recruited to the site of injury. While injury and inflammation are critical to tissue remodeling, the inability to resolve this response can lead to the destructive complications of chronic inflammation. In the pancreas, acinar cells of the exocrine compartment respond to injury by transiently adopting characteristics of progenitor cells present during embryonic development. This process of de-differentiation creates a window where a mature and stable cell gains flexibility and is potentially permissive to changes in cellular fate. How de-differentiation can turn an acinar cell into another cell type (such as a pancreatic β-cell), or a cell with cancerous potential (as in cases of deregulated Kras activity) is of interest to both the regenerative medicine and cancer communities. While it is known that inflammation and acinar de-differentiation increase following pancreatic injury, it remains unclear which immune cells are involved in this process. We used a combination of genetically modified mice, immunological blockade and cellular characterization to identify the immune cells that impact pancreatic regeneration in an in vivo model of pancreatitis. We identified the innate inflammatory response of macrophages and neutrophils as regulators of pancreatic regeneration. Under normal conditions, mild innate inflammation prompts a transient de-differentiation of acinar cells that readily dissipates to allow normal regeneration. However, non-resolving inflammation developed when elevated pancreatic levels of neutrophils producing interferon-γ increased iNOS levels and the pro-inflammatory response of macrophages. Pancreatic injury improved following in vivo macrophage depletion, iNOS inhibition as well as suppression of iNOS levels in macrophages via interferon-γ blockade, supporting the impairment in regeneration and the development of chronic inflammation arises from aberrant activation of the ...
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2014-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Human pancreatic beta-like cells converted from fibroblasts

    Saiyong Zhu / Holger A. Russ / Xiaojing Wang / Mingliang Zhang / Tianhua Ma / Tao Xu / Shibing Tang / Matthias Hebrok / Sheng Ding

    Nature Communications, Vol 7, Iss 1, Pp 1-

    2016  Volume 13

    Abstract: Insulin-producing pancreatic beta cells, generatedin vitro, could lead to new anti-diabetic therapies. Here, Zhu et al. convert human fibroblasts into endodermal progenitors that differentiate in vitrointo glucose-responsive beta-like cells that, ... ...

    Abstract Insulin-producing pancreatic beta cells, generatedin vitro, could lead to new anti-diabetic therapies. Here, Zhu et al. convert human fibroblasts into endodermal progenitors that differentiate in vitrointo glucose-responsive beta-like cells that, following transplantation in mice, protect from diabetes.
    Keywords Science ; Q
    Language English
    Publishing date 2016-01-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Single-cell transcriptome analysis defines heterogeneity of the murine pancreatic ductal tree

    Audrey M Hendley / Arjun A Rao / Laura Leonhardt / Sudipta Ashe / Jennifer A Smith / Simone Giacometti / Xianlu L Peng / Honglin Jiang / David I Berrios / Mathias Pawlak / Lucia Y Li / Jonghyun Lee / Eric A Collisson / Mark S Anderson / Gabriela K Fragiadakis / Jen Jen Yeh / Chun Jimmie Ye / Grace E Kim / Valerie M Weaver /
    Matthias Hebrok

    eLife, Vol

    2021  Volume 10

    Abstract: To study disease development, an inventory of an organ's cell types and understanding of physiologic function is paramount. Here, we performed single-cell RNA-sequencing to examine heterogeneity of murine pancreatic duct cells, pancreatobiliary cells, ... ...

    Abstract To study disease development, an inventory of an organ's cell types and understanding of physiologic function is paramount. Here, we performed single-cell RNA-sequencing to examine heterogeneity of murine pancreatic duct cells, pancreatobiliary cells, and intrapancreatic bile duct cells. We describe an epithelial-mesenchymal transitory axis in our three pancreatic duct subpopulations and identify osteopontin as a regulator of this fate decision as well as human duct cell dedifferentiation. Our results further identify functional heterogeneity within pancreatic duct subpopulations by elucidating a role for geminin in accumulation of DNA damage in the setting of chronic pancreatitis. Our findings implicate diverse functional roles for subpopulations of pancreatic duct cells in maintenance of duct cell identity and disease progression and establish a comprehensive road map of murine pancreatic duct cell, pancreatobiliary cell, and intrapancreatic bile duct cell homeostasis.
    Keywords scRNA-seq ; pancreatic duct ligation ; Osteopontin ; Geminin ; duct heterogeneity ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2021-05-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Replication confers β cell immaturity

    Sapna Puri / Nilotpal Roy / Holger A. Russ / Laura Leonhardt / Esra K. French / Ritu Roy / Henrik Bengtsson / Donald K. Scott / Andrew F. Stewart / Matthias Hebrok

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 12

    Abstract: Adult beta cells, which are highly specialised insulin-secreting cells, rarely replicate. Puri et al. demonstrate that beta cell proliferative capacity is inversely correlated with their functionality and differentiation state, by inducing proliferation ... ...

    Abstract Adult beta cells, which are highly specialised insulin-secreting cells, rarely replicate. Puri et al. demonstrate that beta cell proliferative capacity is inversely correlated with their functionality and differentiation state, by inducing proliferation of adult cells with ectopic overexpression of the cell cycle regulator c-Myc.
    Keywords Science ; Q
    Language English
    Publishing date 2018-02-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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