Umeå University's logo

umu.sePublications
Change search
Refine search result
1 - 13 of 13
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Alanentalo, Tomas
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Hahn, Max
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Willekens, Stefanie M. A.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Mesoscopic Optical Imaging of the Pancreas: Revisiting Pancreatic Anatomy and Pathophysiology2021In: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 12, article id 633063Article, review/survey (Refereed)
    Abstract [en]

    The exocrine-endocrine multipart organization of the pancreas makes it an exceedingly challenging organ to analyze, quantitatively and spatially. Both in rodents and humans, estimates of the pancreatic cellular composition, including beta-cell mass, has been largely relying on the extrapolation of 2D stereological data originating from limited sample volumes. Alternatively, they have been obtained by low resolution non-invasive imaging techniques providing little detail regarding the anatomical organization of the pancreas and its cellular and/or molecular make up. In this mini-review, the state of the art and the future potential of currently existing and emerging high-resolution optical imaging techniques working in the mm-cm range with μm resolution, here referred to as mesoscopic imaging approaches, will be discussed regarding their contribution toward a better understanding of pancreatic anatomy both in normal conditions and in the diabetic setting. In particular, optical projection tomography (OPT) and light sheet fluorescence microscopy (LSFM) imaging of the pancreas and their associated tissue processing and computational analysis protocols will be discussed in the light of their current capabilities and future potential to obtain more detailed 3D-spatial, quantitative, and molecular information of the pancreas.

    Download full text (pdf)
    fulltext
  • 2.
    Chotiwan, Nunya
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan, Thailand.
    Rosendal, Ebba
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Willekens, Stefanie M. A.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Schexnaydre, Erin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Nilsson, Emma
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lindquist, Richard
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Hahn, Max
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Mihai, Ionut Sebastian
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Morini, Federico
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Zhang, Jianguo
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Ebel, Gregory D.
    Department of Microbiology, Immunology and Pathology, Colorado State University, CO, Fort Collins, United States.
    Carlson, Lars-Anders
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Henriksson, Johan
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Marcellino, Daniel
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Type I interferon shapes brain distribution and tropism of tick-borne flavivirus2023In: Nature Communications, E-ISSN 2041-1723, Vol. 14, no 1, article id 2007Article in journal (Refereed)
    Abstract [en]

    Viral tropism within the brain and the role(s) of vertebrate immune response to neurotropic flaviviruses infection is largely understudied. We combine multimodal imaging (cm-nm scale) with single nuclei RNA-sequencing to study Langat virus in wildtype and interferon alpha/beta receptor knockout (Ifnar-/-) mice to visualize viral pathogenesis and define molecular mechanisms. Whole brain viral infection is imaged by Optical Projection Tomography coregistered to ex vivo MRI. Infection is limited to grey matter of sensory systems in wildtype mice, but extends into white matter, meninges and choroid plexus in Ifnar-/- mice. Cells in wildtype display strong type I and II IFN responses, likely due to Ifnb expressing astrocytes, infiltration of macrophages and Ifng-expressing CD8+ NK cells, whereas in Ifnar-/-, the absence of this response contributes to a shift in cellular tropism towards non-activated resident microglia. Multimodal imaging-transcriptomics exemplifies a powerful way to characterize mechanisms of viral pathogenesis and tropism.

    Download full text (pdf)
    fulltext
  • 3.
    Davies, Wayne I. L.
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Sghari, Soufien
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Upton, Brian A.
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Hahn, Max
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Lang, Richard A.
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Distinct opsin 3 (Opn3) expression in the developing nervous system during mammalian embryogenesis2021In: eNeuro, E-ISSN 2373-2822, Vol. 8, no 5, article id ENEURO.0141-21.2021Article in journal (Refereed)
    Abstract [en]

    Opsin 3 (Opn3) is highly expressed in the adult brain, however, information for spatial and temporal expression patterns during embryogenesis is significantly lacking. Here, an Opn3-eGFP reporter mouse line was used to monitor cell body expression and axonal projections during embryonic and early postnatal to adult stages. By applying 2D and 3D fluorescence imaging techniques, we have identified the onset of Opn3 expression, which predominantly occurred during embryonic stages, in various structures during brain/head development. In ad-dition, this study defines over twenty Opn3-eGFP-positive neural structures never reported before. Opn3-eGFP was first observed at E9.5 in neural regions, including the ganglia that will ultimately form the trigeminal, facial and vestibulocochlear cranial nerves (CNs). As development proceeds, expanded Opn3-eGFP expression coincided with the formation and maturation of critical components of the central and peripheral nervous systems (CNS, PNS), including various motor-sensory tracts, such as the dorsal column-medial lemniscus (DCML) sensory tract, and olfactory, acoustic, and optic tracts. The widespread, yet distinct, detection of Opn3-eGFP already at early embryonic stages suggests that Opn3 might play important functional roles in the developing brain and spinal cord to regulate multiple motor and sensory circuitry systems, including proprio-ception, nociception, ocular movement, and olfaction, as well as memory, mood, and emotion. This study presents a crucial blueprint from which to investigate autonomic and cognitive opsin-dependent neural development and resultant behaviors under physiological and pathophysiological conditions.

    Download full text (pdf)
    fulltext
  • 4.
    Hahn, Max
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Characterizing the pancreatic "isletome": 3D optical imaging to study diabetes2022Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The pancreas is a specialised multipurpose organ, that can be separated into two major compartments: endocrine and exocrine. The exocrine part makes up the majority of the organ volume and functions to secrete digestive enzymes into the small intestine. Notably, endocrine islets of Langerhans are embedded and scattered in vast numbers throughout the exocrine space. These miniature functional units are composed of different cell types that secrete hormones into the blood stream. The most abundant islet-cell is the insulin-producing β-cell. Highly coordinated, the endocrine cells are the primary regulators of energy homeostasis in the body. Together, the collective islet volume constitutes the pancreatic “isletome”, a synchronised, complex and size-equilibrated system that is able to respond to various metabolic conditions. Indeed, environmental and/or genetic conditions often lead to impaired islet function and/or β-cell destruction leading to elevated blood glucose levels over time and eventually diabetes. 

    Diabetes mellitus is a disease that currently affects more than 400 million individuals worldwide. As such, understanding pancreatic disease-related mechanisms is pivotal to the development of new and more effective therapeutic, or even curative, regimens. The deep location of the pancreas in the abdomen and the relatively low resolution of current clinical imaging approaches, however, render the pancreatic islets difficult to study when visually assessing endocrine function. Although non-invasive imaging techniques have yet to reach their full potential, post-mortem studies of the pancreas and rodent disease models offer unique insights into the process of diabetes disease dynamics.

    Diabetes induced by streptozotocin (STZ) is a widely used model system in pre-clinical research, where it is generally believed that the b-cells are depleted upon the administration of the drug. Yet, quantification of β-cell volume dynamics and underlying disease mechanisms have not been extensively described. Using optical projection tomography (OPT), light sheet fluorescence microscopy (LSFM) and advanced protocols for ex vivo whole organ three-dimensional (3D) imaging, this study demonstrated that STZ-induced β-cell depletion is modest, primarily affecting large islets, and is not the primary cause for the development of diabetes in STZ-diabetic mice. Combined with islet gene expression studies, the remaining β-cell volume in STZ-diabetic mice displayed a downregulation of glucose transporter type 2 (GLUT2), a transmembrane carrier vital for sensing blood glucose levels. Islet transplantation into the anterior chamber of the eye (ACE) reversed the STZ-induced hyperglycaemia and partially restored islet function, including GLUT2, but did not restore β-cell volume loss. Extensive 3D image datasets were generated as a resource to the research community. The combined results of this study indicated that STZ-induced hyperglycaemia is not caused by β-cell loss, but rather by dysfunctional β-cells and that recovery of islet function is restrained by continuous hyperglycaemia.

    3D imaging using OPT has proven to be a reliable technique in quantifying cellular/anatomical features of the mouse pancreas. However, the technique has rarely been applied to patient-derived tissues. Here, a label-free and non-destructive method was developed to assess clinical biopsies within hours of collection. Specifically, this study showed that autofluorescence-based imaging can be used to delineate tumours of the pancreas (pancreatic ductal adenocarcinoma, PDAC) in 3D, which may aid in identifying tumour margins in conjunction with resective surgery. Importantly, the protocol included a reversal pipeline so that other histological workflows could be applied to the same specimen. Furthermore, this study demonstrated that natural fluorescent substances in the endocrine cells provide sufficient contrast when quantifying both the volume and number of islets of Langerhans in the healthy pancreas. Altogether, the developed technique may provide a novel tool for the rapid 3D analysis of pancreatic biopsies that may complement and improve traditional pathological assessments.

    With the emergence of islet transplantation networks worldwide, access to fixed pancreatic tissues from diseased donors has dramatically improved. Hereby, the near instant autolysis of the pancreas post-mortem can generally be avoided, which provides the opportunity to quantitatively study the entire gland ex vivo within a conserved spatial context. Yet, mesoscopic 3D imaging of the pancreas (by OPT and/or LSFM) has been limited predominantly due to the obstacle of labelling larger tissue volumes. As such, a simple approach to antibody labelling and cellular imaging was developed in cubic centimetre-sized tissue cuboids that were mapped to the whole organ. By stitching the resultant datasets back into 3D space, this approach demonstrated how essentially any human organ may be analysed in full with high resolution. This technique was applied to pancreata from non-diabetic and type 2 diabetic (T2D) donors, analysing over 200 thousand islets, revealing features of the human pancreas that were not analysed in 3D previously, including high islet dense regions and intra-islet haemorrhaging. Crucially, this new technique may contribute to unveil a wealth of new insights into the complex pathophysiology of the “diabetic pancreas”.

    By applying the above method to the entire volume of the human pancreas, the absolute distribution and volume of insulin-positive cells in a pancreas from a donor with longstanding type 1 diabetes (T1D) was demonstrated for the first time. By dividing the 19 cm long organ into smaller pieces, followed by insulin labelling, OPT imaging and reconstruction in 3D space, approximately 173,000 insulin-positive objects were identified. By utilising tissue autofluorescence, the entire organ was reconstructed in 3D, together with blood vessels and ducts. These data indicated several important regional differences in β-cell mass, such as the uncinate process showing the highest density, which potentially reflects key aspects of disease dynamics. Furthermore, regions with a “punctated distribution” of single β-cells in close proximity to each other were identified. Although the significance of these observations needs to be elucidated, we speculate that these regions could be associated with pancreatic regeneration, which might permit the development of new interventions for clinical regenerative processes in the future. Altogether, this study represents the first whole organ account of β-cell distribution at the current level of resolution in an entire organ. As such, it may serve as an important advancement towards detailed whole organ analyses of endocrine cell identity/function, via a wide range of markers, in the study of normal anatomy and pathophysiology of the human pancreas.

    Download full text (pdf)
    fulltext
    Download (pdf)
    spikblad
    Download (jpg)
    presentationsbild
  • 5.
    Hahn, Max
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    3D optical molecular imaging of the rodent pancreas by OPT and LSFM2023In: Type-1 diabetes: methods and protocols / [ed] Anna Moore; Ping Wang, New York: Humana Press, 2023, , p. 19p. 1-19Chapter in book (Refereed)
    Abstract [en]

    The rodent pancreas is the prevalent model system for preclinical diabetes research. However, due to the compound endocrine–exocrine organization of the gland, with the endocrine islets of Langerhans scattered by the thousands throughout the much greater exocrine parenchyma, stereological assessments of endocrine cell mass, commonly insulin-producing ß-cells, are exceedingly challenging. In recent years, optical mesoscopic imaging techniques such as optical projection tomography (OPT) and light sheet fluorescence microscopy (LSFM) have seen dramatic developments, enabling 3D visualization of fluorescently labeled cells in mm- to cm-sized tissues with μm resolution. Here we present a protocol for 3D visualization and “absolute” quantitative assessments of, for example, islet mass throughout the volume of rodent pancreata with maintained spatial context.

  • 6.
    Hahn, Max
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Davies, W.I.L.
    Nord, C.
    Alanentalo, T.
    Korsgren, O.
    Ahlgren, U.
    Characterising the complete β-cell mass distribution in longstanding type 1 diabetes - evidence for isolated β-cell clustersManuscript (preprint) (Other academic)
  • 7.
    Hahn, Max
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Morini, Federico
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Alanentalo, Tomas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Korsgren, Olle
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    3D imaging of human organs with micrometer resolution - applied to the endocrine pancreas2021In: Communications Biology, E-ISSN 2399-3642, Vol. 4, no 1, article id 1063Article in journal (Refereed)
    Abstract [en]

    The possibility to quantitatively study specific molecular/cellular features of complete human organs with preserved spatial 3D context would have widespread implications for pre-clinical and clinical medicine. Whereas optical 3D imaging approaches have experienced a formidable revolution, they have remained limited due to current incapacities in obtaining specific labelling within large tissue volumes. We present a simple approach enabling reconstruction of antibody labeled cells within entire human organs with preserved organ context. We demonstrate the utility of the approach by providing volumetric data and 3D distribution of hundreds of thousands of islets of Langerhans within the human pancreas. By assessments of pancreata from non-diabetic and type 2 diabetic individuals, we display previously unrecognized features of the human islet mass distribution and pathology. As such, this method may contribute not only in unraveling new information of the pancreatic anatomy/pathophysiology, but it may be translated to essentially any antibody marker or organ system.

    Download full text (pdf)
    fulltext
  • 8.
    Hahn, Max
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Franklin, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Alanentalo, Tomas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Isaksson Mettävainio, Martin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Morini, Federico
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Korsgren, Olle
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Department of Surgical and Perioperative Sciences/Surgery, Umeå University Hospital, Umeå, Swede.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Mesoscopic 3D imaging of pancreatic cancer and Langerhans islets based on tissue autofluorescence2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 18246Article in journal (Refereed)
    Abstract [en]

    The possibility to assess pancreatic anatomy with microscopic resolution in three dimensions (3D) would significantly add to pathological analyses of disease processes. Pancreatic ductal adenocarcinoma (PDAC) has a bleak prognosis with over 90% of the patients dying within 5 years after diagnosis. Cure can be achieved by surgical resection, but the efficiency remains drearily low. Here we demonstrate a method that without prior immunohistochemical labelling provides insight into the 3D microenvironment and spread of PDAC and premalignant cysts in intact surgical biopsies. The method is based solely on the autofluorescent properties of the investigated tissues using optical projection tomography and/or light-sheet fluorescence microscopy. It does not interfere with subsequent histopathological analysis and may facilitate identification of tumor-free resection margins within hours. We further demonstrate how the developed approach can be used to assess individual volumes and numbers of the islets of Langerhans in unprecedently large biopsies of human pancreatic tissue, thus providing a new means by which remaining islet mass may be assessed in settings of diabetes. Generally, the method may provide a fast approach to provide new anatomical insight into pancreatic pathophysiology.

    Download full text (pdf)
    fulltext
  • 9.
    Hahn, Max
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    van Krieken, Pim P.
    Berggren, Per-Olof
    Ilegems, Erwin
    Cheddad, Abbas
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Quantitative 3D OPT and LSFM datasets of pancreata from mice with streptozotocin-induced diabetes2022In: Scientific Data, E-ISSN 2052-4463, Vol. 9, article id 558Article in journal (Refereed)
    Abstract [en]

    Mouse models for streptozotocin (STZ) induced diabetes probably represent the most widely used systems for preclinical diabetes research, owing to the compound’s toxic effect on pancreatic β-cells. However, a comprehensive view of pancreatic β-cell mass distribution subject to STZ administration is lacking. Previous assessments have largely relied on the extrapolation of stereological sections, which provide limited 3D-spatial and quantitative information. This data descriptor presents multiple ex vivo tomographic optical image datasets of the full β-cell mass distribution in mice subject to single high and multiple low doses of STZ administration, and in glycaemia recovered mice. The data further include information about structural features, such as individual islet β-cell volumes, spatial coordinates, and shape as well as signal intensities for both insulin and GLUT2. Together, they provide the most comprehensive anatomical record of the effects of STZ administration on the islet of Langerhans in mice. As such, this data descriptor may serve as reference material to facilitate the planning, use and (re)interpretation of this widely used disease model.

    Download full text (pdf)
    fulltext
  • 10.
    Hahn, Max
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    van Krieken, Pim P.
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Alanentalo, Tomas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Morini, Federico
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Xiong, Yan
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Mayer, Jurgen
    Kostromina, Elena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ruas, Jorge L.
    Sharpe, James
    Pereira, Teresa
    Berggren, Per-Olof
    Ilegems, Erwin
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Topologically selective islet vulnerability and self-sustained downregulation of markers for β-cell maturity in streptozotocin-induced diabetes2020In: Communications Biology, E-ISSN 2399-3642, Vol. 3, no 1, article id 541Article in journal (Refereed)
    Abstract [en]

    Mouse models of Streptozotocin (STZ) induced diabetes represent the most widely used preclinical diabetes research systems. We applied state of the art optical imaging schemes, spanning from single islet resolution to the whole organ, providing a first longitudinal, 3D-spatial and quantitative account of β-cell mass (BCM) dynamics and islet longevity in STZ-treated mice. We demonstrate that STZ-induced β-cell destruction predominantly affects large islets in the pancreatic core. Further, we show that hyperglycemic STZ-treated mice still harbor a large pool of remaining β-cells but display pancreas-wide downregulation of glucose transporter type 2 (GLUT2). Islet gene expression studies confirmed this downregulation and revealed impaired β-cell maturity. Reversing hyperglycemia by islet transplantation partially restored the expression of markers for islet function, but not BCM. Jointly our results indicate that STZ-induced hyperglycemia results from β-cell dysfunction rather than β-cell ablation and that hyperglycemia in itself sustains a negative feedback loop restraining islet function recovery.

    Download full text (pdf)
    fulltext
  • 11.
    Lehrstrand, Joakim
    et al.
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    Davies, Wayne I. L.
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    Hahn, Max
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    Korsgren, Olle
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Alanentalo, Tomas
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    Illuminating the complete ß-cell mass of the human pancreas - signifying a new view on the islets of Langerhans2024In: Nature Communications, E-ISSN 2041-1723, Vol. 15, no 1, article id 3318Article in journal (Refereed)
    Abstract [en]

    Pancreatic islets of Langerhans play a pivotal role in regulating blood glucose homeostasis, but critical information regarding their mass, distribution and composition is lacking within a whole organ context. Here, we apply a 3D imaging pipeline to generate a complete account of the insulin-producing islets throughout the human pancreas at a microscopic resolution and within a maintained spatial 3D context. These data show that human islets are far more heterogenous than previously accounted for with regards to their size distribution and cellular make up. By deep tissue 3D imaging, this in-depth study demonstrates that 50% of the human insulin-expressing islets are virtually devoid of glucagon-producing α-cells, an observation with significant implications for both experimental and clinical research.

    Download full text (pdf)
    fulltext
  • 12.
    Serra-Navarro, Berta
    et al.
    Diabetes and Obesity Research Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149-153, Barcelona, Spain; University of Barcelona, Barcelona, Spain.
    Fernandez-Ruiz, Rebeca
    Diabetes and Obesity Research Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149-153, Barcelona, Spain; University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
    García-Alamán, Ainhoa
    Diabetes and Obesity Research Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149-153, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
    Pradas-Juni, Marta
    Diabetes and Obesity Research Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149-153, Barcelona, Spain; University of Barcelona, Barcelona, Spain.
    Fernandez-Rebollo, Eduardo
    Diabetes and Obesity Research Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149-153, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
    Esteban, Yaiza
    Diabetes and Obesity Research Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149-153, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
    Mir-Coll, Joan
    Diabetes and Obesity Research Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149-153, Barcelona, Spain; University of Barcelona, Barcelona, Spain.
    Mathieu, Julia
    CHU Montpellier, Laboratory of Cell Therapy for Diabetes (LTCD), Hospital St-Eloi, Montpellier, France.
    Dalle, Stephane
    CHU Montpellier, Laboratory of Cell Therapy for Diabetes (LTCD), Hospital St-Eloi, Montpellier, France.
    Hahn, Max
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Weinstein, Lee S.
    Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, NIH, MD, Bethesda, United States.
    Vidal, Josep
    Diabetes and Obesity Research Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149-153, Barcelona, Spain; University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain; Department of Endocrinology and Nutrition, Hospital Clinic of Barcelona, Barcelona, Spain.
    Gomis, Ramon
    Diabetes and Obesity Research Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149-153, Barcelona, Spain; University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain; Universitat Oberta de Catalunya (UOC), Barcelona, Spain.
    Gasa, Rosa
    Diabetes and Obesity Research Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149-153, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
    Gsα-dependent signaling is required for postnatal establishment of a functional β-cell mass2021In: Molecular Metabolism, ISSN 2212-8778, Vol. 53, article id 101264Article in journal (Refereed)
    Abstract [en]

    Objective: Early postnatal life is a critical period for the establishment of the functional β-cell mass that will sustain whole-body glucose homeostasis during the lifetime. β cells are formed from progenitors during embryonic development but undergo significant expansion in quantity and attain functional maturity after birth. The signals and pathways involved in these processes are not fully elucidated. Cyclic adenosine monophosphate (cAMP) is an intracellular signaling molecule that is known to regulate insulin secretion, gene expression, proliferation, and survival of adult β cells. The heterotrimeric G protein Gs stimulates the cAMP-dependent pathway by activating adenylyl cyclase. In this study, we sought to explore the role of Gs-dependent signaling in postnatal β-cell development.

    Methods: To study Gs-dependent signaling, we generated conditional knockout mice in which the α subunit of the Gs protein (Gsα) was ablated from β-cells using the Cre deleter line Ins1Cre. Mice were characterized in terms of glucose homeostasis, including in vivo glucose tolerance, glucose-induced insulin secretion, and insulin sensitivity. β-cell mass was studied using histomorphometric analysis and optical projection tomography. β-cell proliferation was studied by ki67 and phospho-histone H3 immunostatining, and apoptosis was assessed by TUNEL assay. Gene expression was determined in isolated islets and sorted β cells by qPCR. Intracellular cAMP was studied in isolated islets using HTRF-based technology. The activation status of the cAMP and insulin-signaling pathways was determined by immunoblot analysis of the relevant components of these pathways in isolated islets. In vitro proliferation of dissociated islet cells was assessed by BrdU incorporation.

    Results: Elimination of Gsα in β cells led to reduced β-cell mass, deficient insulin secretion, and severe glucose intolerance. These defects were evident by weaning and were associated with decreased proliferation and inadequate expression of key β-cell identity and maturation genes in postnatal β-cells. Additionally, loss of Gsα caused a broad multilevel disruption of the insulin transduction pathway that resulted in the specific abrogation of the islet proliferative response to insulin.

    Conclusion: We conclude that Gsα is required for β-cell growth and maturation in the early postnatal stage and propose that this is partly mediated via its crosstalk with insulin signaling. Our findings disclose a tight connection between these two pathways in postnatal β cells, which may have implications for using cAMP-raising agents to promote β-cell regeneration and maturation in diabetes.

    Download full text (pdf)
    fulltext
  • 13.
    Willekens, Stefanie M. A.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Department of Medical and Translational Biology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Morini, Federico
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    Mediavilla, Tomás
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    Nilsson, Emma
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Orädd, Greger
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    Hahn, Max
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    Chotiwan, Nunya
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Visa, Montse
    The Rolf Luft Research Centre for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden.
    Berggren, Per-Olof
    The Rolf Luft Research Centre for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden.
    Ilegems, Erwin
    The Rolf Luft Research Centre for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden.
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    Marcellino, Daniel
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    An MR-based brain template and atlas for optical projection tomography and light sheet fluorescence microscopy in neuroscience2024In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 18, article id 1328815Article in journal (Refereed)
    Abstract [en]

    Introduction: Optical Projection Tomography (OPT) and light sheet fluorescence microscopy (LSFM) are high resolution optical imaging techniques, ideally suited for ex vivo 3D whole mouse brain imaging. Although they exhibit high specificity for their targets, the anatomical detail provided by tissue autofluorescence remains limited.

    Methods: T1-weighted images were acquired from 19 BABB or DBE cleared brains to create an MR template using serial longitudinal registration. Afterwards, fluorescent OPT and LSFM images were coregistered/normalized to the MR template to create fusion images.

    Results: Volumetric calculations revealed a significant difference between BABB and DBE cleared brains, leading to develop two optimized templates, with associated tissue priors and brain atlas, for BABB (OCUM) and DBE (iOCUM). By creating fusion images, we identified virus infected brain regions, mapped dopamine transporter and translocator protein expression, and traced innervation from the eye along the optic tract to the thalamus and superior colliculus using cholera toxin B. Fusion images allowed for precise anatomical identification of fluorescent signal in the detailed anatomical context provided by MR.

    Discussion: The possibility to anatomically map fluorescent signals on magnetic resonance (MR) images, widely used in clinical and preclinical neuroscience, would greatly benefit applications of optical imaging of mouse brain. These specific MR templates for cleared brains enable a broad range of neuroscientific applications integrating 3D optical brain imaging.

    Download full text (pdf)
    fulltext
1 - 13 of 13
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf