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  • 1.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Exploring the pancreas with optical projection tomography2012In: Imaging in Medicine, ISSN 1755-5191, Vol. 4, no 1, p. 5-7Article in journal (Refereed)
  • 2.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Imaging shows insulin-producing cells in diabetes2013In: TrAC. Trends in analytical chemistry, ISSN 0165-9936, E-ISSN 1879-3142, Vol. 44, p. III-IIIArticle in journal (Other (popular science, discussion, etc.))
  • 3.
    Ahlgren, Ulf
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gotthardt, Martin
    Department of Nuclear Medicine, Nijmegen, Netherlands.
    Approaches for imaging islets2010In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 654, p. 39-57Article in journal (Refereed)
    Abstract [en]

    The establishment of improved technologies for imaging of the pancreas is a key element in addressing several aspects of diabetes pathogenesis. In this respect, the development of a protocol that allows for non-invasive scoring of human islets, or islet beta-cells, is of particular importance. The development of such a technology would have profound impact on both clinical and experimental medicine, ranging from early diagnosis of diabetes to the evaluation of therapeutic regimes. Another important task is the development of modalities for high-resolution imaging of experimental animal models for diabetes. Rodent models for diabetes research have for decades been instrumental to the diabetes research community. The ability to image, and to accurately quantify, key players of diabetogenic processes with molecular specificity will be of great importance for elucidating mechanistic aspects of the disease. This chapter aims to overview current progress within these research areas.

  • 4.
    Ahlgren, Ulf
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Hörnblad, Andreas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Optical imaging of islets: new possibilities by the development of infrared fluorescent proteins2009In: Islets, ISSN 1938-2022, Vol. 1, no 2, p. 163-164Article in journal (Refereed)
    Abstract [en]

    The capacity to record the spatial and quantitative distribution of cellular subtypes involved in diabetogenic processes is a key element in experimental diabetes research. A non-invasive technique to accurately monitor parameters such as pancreatic β-cell mass (BCM) and its distribution would provide a stepping stone in understanding different aspects of diabetes pathogenesis. It would also assist in the development of therapeutic regimes by providing a tool for the evaluation of anti-diabetic drugs or other curative or diagnostic measures. At present, a range of imaging modalities are being explored for this purpose. Whereas nuclear imaging techniques, characterised by their high tissue penetration depth but relatively low spatial resolution, appear most promising for the study of humans and large animals, optical imaging enables a route to cost-effective, high sensitivity, high resolution imaging in rodent models for disease. In this commentary, the potential impact of infrared fluorescent proteins (IFPs), as recently reported by Shu et al in Science, for imaging of the pancreas in small animals will be discussed.

  • 5.
    Ahlgren, Ulf
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Kostromina, Elena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Imaging the pancreatic beta cell: chapter 132011In: Type 1 diabetes: pathogenesis, genetics and immunotherapy / [ed] David Wagner, InTech, 2011Chapter in book (Refereed)
    Abstract [en]

    This book is a compilation of reviews about the pathogenesis of Type 1 Diabetes. T1D is a classic autoimmune disease. Genetic factors are clearly determinant but cannot explain the rapid, even overwhelming expanse of this disease. Understanding etiology and pathogenesis of this disease is essential. A number of experts in the field have covered a range of topics for consideration that are applicable to researcher and clinician alike. This book provides apt descriptions of cutting edge technologies and applications in the ever going search for treatments and cure for diabetes. Areas including T cell development, innate immune responses, imaging of pancreata, potential viral initiators, etc. are considered.

  • 6.
    Alanentalo, Tomas
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Asayesh, Amir
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Morrison, Harris
    Lorén, Christina E
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Sharpe, James
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Tomographic molecular imaging and 3D quantification within adult mouse organs.2007In: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 4, no 1, p. 31-33Article in journal (Refereed)
  • 7.
    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.

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  • 8.
    Alanentalo, Tomas
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Hörnblad, Andreas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Mayans, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Nilsson, Anna Karin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sharpe, James
    Larefalk, Åsa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Quantification and 3-D imaging of the insulitis-induced destruction of β-cells in murine type 1 diabetes2010In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, no 7, p. 1756-1764Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of this study was to refine the information regarding the quantitative and spatial dynamics of infiltrating lymphocytes and remaining beta-cell volume during the progression of type 1 diabetes in the NOD mouse model of the disease.

    Research design and methods: Using an ex vivo technique, optical projection tomography (OPT), we quantified and assessed the 3D spatial development and progression of insulitis and beta-cell destruction in pancreas from diabetes prone NOD and non-diabetes prone congenic NOD.H-2b mice between 3 and 16 weeks of age.

    Results: Together with results showing the spatial dynamics of the insulitis process we provide data of beta-cell volume distributions down to the level of the individual islets and throughout the pancreas during the development and progression of type 1 diabetes. Our data provide evidence for a compensatory growth potential of the larger insulin(+) islets during the later stages of the disease around the time point for development of clinical diabetes. This is in contrast to smaller islets, which appear less resistant to the autoimmune attack. We also provide new information on the spatial dynamics of the insulitis process itself, including its apparently random distribution at onset, the local variations during its further development, and the formation of structures resembling tertiary lymphoid organs at later phases of insulitis progression.

    Conclusions: Our data provides a powerful tool for phenotypic analysis of genetic and environmental effects on type 1 diabetes etiology as well as for evaluating the potential effect of therapeutic regimes.

  • 9.
    Alanentalo, Tomas
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Lorén, Christina E
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Larefalk, Asa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Sharpe, James
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    High-resolution three-dimensional imaging of islet-infiltrate interactions based on optical projection tomography assessments of the intact adult mouse pancreas2008In: Journal of Biomedical Optics, ISSN 1083-3668, E-ISSN 1560-2281, Vol. 13, no 5, p. 054070-Article in journal (Refereed)
    Abstract [en]

    A predicament when assessing the mechanisms underlying the pathogenesis of type-1 diabetes (T1D) has been to maintain simultaneous global and regional information on the loss of insulin-cell mass and the progression of insulitis. We present a procedure for high-resolution 3-D analyses of regions of interest (ROIs), defined on the basis of global assessments of the 3-D distribution, size, and shape of molecularly labeled structures within the full volume of the intact mouse pancreas. We apply a refined protocol for optical projection tomography (OPT)-aided whole pancreas imaging in combination with confocal laser scanning microscopy of site-directed pancreatic microbiopsies. As such, the methodology provides a useful tool for detailed cellular and molecular assessments of the autoimmune insulitis in T1D. It is anticipated that the same approach could be applied to other areas of research where 3-D molecular distributions of both global and regional character is required.

  • 10.
    Asayesh, Amir
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Alanentalo, Tomas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Khoo, Nelson K S
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Developmental expression of metalloproteases ADAM 9, 10, and 17 becomes restricted to divergent pancreatic compartments.2005In: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 232, no 4, p. 1105-1114Article in journal (Refereed)
  • 11.
    Asayesh, Amir
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Sharpe, James
    Watson, Robert P
    Hecksher-Sørensen, Jacob
    Hastie, Nicholas D
    Hill, Robert E
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Spleen versus pancreas: strict control of organ interrelationship revealed by analyses of Bapx1-/- mice.2006In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 20, no 16, p. 2208-2213Article in journal (Refereed)
  • 12. Baeyens, Luc
    et al.
    Lemper, Marie
    Leuckx, Gunter
    De Groef, Sofie
    Bonfanti, Paola
    Stange, Geert
    Shemer, Ruth
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Scheel, David W
    Pan, Fong C
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gu, Guoqiang
    Stoffers, Doris A
    Dor, Yuval
    Ferrer, Jorge
    Gradwohl, Gerard
    Wright, Christopher VE
    Van de Casteele, Mark
    German, Michael S
    Bouwens, Luc
    Heimberg, Harry
    Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice2014In: Nature Biotechnology, ISSN 1087-0156, E-ISSN 1546-1696, Vol. 32, no 1, p. 76-83Article in journal (Refereed)
    Abstract [en]

    Reprogramming of pancreatic exocrine cells into cells resembling beta cells may provide a strategy for treating diabetes. Here we show that transient administration of epidermal growth factor and ciliary neurotrophic factor to adult mice with chronic hyperglycemia efficiently stimulates the conversion of terminally differentiated acinar cells to beta-like cells. Newly generated beta-like cells are epigenetically reprogrammed, functional and glucose responsive, and they reinstate normal glycemic control for up to 248 d. The regenerative process depends on Stat3 signaling and requires a threshold number of Neurogenin 3 (Ngn3)-expressing acinar cells. In contrast to previous work demonstrating in vivo conversion of acinar cells to beta-like cells by viral delivery of exogenous transcription factors, our approach achieves acinar-to-beta-cell reprogramming through transient cytokine exposure rather than genetic modification.

  • 13.
    Cheddad, Abbas
    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).
    Hörnblad, Andreas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Prunskaite-Hyyryläinen, Renata
    Oulu Center for Cell-Matrix Research, Biocenter Oulu, Laboratory of Developmental Biology and Department of Medical Biochemistry and Molecular Biology, Institute of Biomedicine, University of Oulu, Finland.
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Georgsson, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Computing Science.
    Vainio, Seppo
    Oulu Center for Cell-Matrix Research, Biocenter Oulu, Laboratory of Developmental Biology and Department of Medical Biochemistry and Molecular Biology, Institute of Biomedicine, University of Oulu, Finland.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Improving signal detection in emission optical projection tomography via single source multi-exposure image fusion2013In: Optics Express, E-ISSN 1094-4087, Vol. 21, no 14, p. 16584-16604Article in journal (Refereed)
    Abstract [en]

    We demonstrate a technique to improve structural data obtained from Optical Projection Tomography (OPT) using Image Fusion (IF) and contrast normalization. This enables the visualization of molecular expression patterns in biological specimens with highly variable contrast values. In the approach, termed IF-OPT, different exposures are fused by assigning weighted contrasts to each. When applied to projection images from mouse organs and digital phantoms our results demonstrate the capability of IF-OPT to reveal high and low signal intensity details in challenging specimens. We further provide measurements to highlight the benefits of the new algorithm in comparison to other similar methods.

  • 14.
    Cheddad, Abbas
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Svensson, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Sharpe, James
    Georgsson, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Computing Science.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Image processing assisted algorithms for optical projection tomography2012In: IEEE Transactions on Medical Imaging, ISSN 0278-0062, E-ISSN 1558-254X, Vol. 31, no 1, p. 1-15Article in journal (Refereed)
    Abstract [en]

    Since it was first presented in 2002, optical projection tomography (OPT) has emerged as a powerful tool for the study of biomedical specimen on the mm to cm scale. In this paper, we present computational tools to further improve OPT image acquisition and tomographic reconstruction. More specifically, these methods provide: semi-automatic and precise positioning of a sample at the axis of rotation and a fast and robust algorithm for determination of postalignment values throughout the specimen as compared to existing methods. These tools are easily integrated for use with current commercial OPT scanners and should also be possible to implement in "home made" or experimental setups for OPT imaging. They generally contribute to increase acquisition speed and quality of OPT data and thereby significantly simplify and improve a number of three-dimensional and quantitative OPT based assessments.

  • 15.
    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.

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  • 16.
    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.

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  • 17.
    Eriksson, Anna U.
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Svensson, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Hörnblad, Andreas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Cheddad, Abbas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Kostromina, Elena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Norlin, Nils
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Pileggi, Antonello
    Cell Transplants Center, Diabetes Research Institute, University of Miami.
    Sharpe, James
    EMBL-CRG Systems Biology Program, Centre for Genomic Regulation, Catalan Institute of Research and Advance Studies.
    Georgsson, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Computing Science.
    Alanentalo, Tomas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Near infrared optical projection tomography for assessments of beta-cell mass distribution in diabetes research2013In: Journal of Visualized Experiments, E-ISSN 1940-087X, Vol. 71, article id e50238Article in journal (Refereed)
    Abstract [en]

    By adapting OPT to include the capability of imaging in the near infrared (NIR) spectrum, we here illustrate the possibility to image larger bodies of pancreatic tissue, such as the rat pancreas, and to increase the number of channels (cell types) that may be studied in a single specimen. We further describe the implementation of a number of computational tools that provide: 1/ accurate positioning of a specimen's (in our case the pancreas) centre of mass (COM) at the axis of rotation (AR)2; 2/ improved algorithms for post-alignment tuning which prevents geometric distortions during the tomographic reconstruction2 and 3/ a protocol for intensity equalization to increase signal to noise ratios in OPT-based BCM determinations3. In addition, we describe a sample holder that minimizes the risk for unintentional movements of the specimen during image acquisition. Together, these protocols enable assessments of BCM distribution and other features, to be performed throughout the volume of intact pancreata or other organs (e.g. in studies of islet transplantation), with a resolution down to the level of individual islets of Langerhans.

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  • 18.
    Eriksson, Maria
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Litwak, Sara A.
    St Vincent's Institute of Medical Research, 9 Princes Street, Melbourne, Australia.
    Yun, Yan
    Charles Perkins Centre, Discipline of Physiology, School of Medical Sciences, University of Sydney, Johns Hopkins Dr, Sydney, Australia.
    Stanley, William J.
    St Vincent's Institute of Medical Research, 9 Princes Street, Melbourne, Australia; Department of Medicine, The University of Melbourne, Parkville, Melbourne, Australia.
    Thorn, Peter
    Charles Perkins Centre, Discipline of Physiology, School of Medical Sciences, University of Sydney, Johns Hopkins Dr, Sydney, Australia.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gurzov, Esteban N.
    Department of Medicine, The University of Melbourne, Parkville, Melbourne, Australia; Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université libre de Bruxelles, Route de Lennik 808, Brussels, Belgium.
    Insulin-Binding Peptide Probes Provide a Novel Strategy for Pancreatic β-Cell Imaging2021In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 18, no 12, p. 4428-4436Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes develops in childhood and adolescence, with peak incidence in the early teenage years. There is an urgent need for an accurate method to detect insulin-producing β-cells in patients that is not affected by alterations in β-cell function. As part of our research program to design specific probes to measure β-cell mass, we recently developed a novel insulin-binding peptide probe (IBPP) for the detection of β-cells in vivo. Here, we applied our innovative method to show specific labeling of this IBPP to human and mouse fixed β-cells in pancreatic islets. Importantly, we showed staining of human and mouse islets in culture without any negative functional or cell viability impact. Moreover, the IBPP-stained mouse islets after tail vein injection in vivo, albeit with batch differences in staining efficiency. In conclusion, we provide evidence showing that the IBPP can be used for future accurate detection of β-cell mass in a variety of preclinical models of diabetes.

  • 19. Eter, Wael A.
    et al.
    Parween, Saba
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Joosten, Lieke
    Frielink, Cathelijne
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Brom, Maarten
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gotthardt, Martin
    SPECT-OPT multimodal imaging enables accurate evaluation of radiotracers for beta-cell mass assessments2016In: Scientific Reports, E-ISSN 2045-2322, Vol. 6, article id 24576Article in journal (Refereed)
    Abstract [en]

    Single Photon Emission Computed Tomography (SPECT) has become a promising experimental approach to monitor changes in beta-cell mass (BCM) during diabetes progression. SPECT imaging of pancreatic islets is most commonly cross-validated by stereological analysis of histological pancreatic sections after insulin staining. Typically, stereological methods do not accurately determine the total beta-cell volume, which is inconvenient when correlating total pancreatic tracer uptake with BCM. Alternative methods are therefore warranted to cross-validate beta-cell imaging using radiotracers. In this study, we introduce multimodal SPECT - optical projection tomography (OPT) imaging as an accurate approach to cross-validate radionuclide-based imaging of beta-cells. Uptake of a promising radiotracer for beta-cell imaging by SPECT, In-111-exendin-3, was measured by ex vivo-SPECT and cross evaluated by 3D quantitative OPT imaging as well as with histology within healthy and alloxan-treated Brown Norway rat pancreata. SPECT signal was in excellent linear correlation with OPT data as compared to histology. While histological determination of islet spatial distribution was challenging, SPECT and OPT revealed similar distribution patterns of In-111-exendin-3 and insulin positive beta-cell volumes between different pancreatic lobes, both visually and quantitatively. We propose ex vivo SPECT-OPT multimodal imaging as a highly accurate strategy for validating the performance of beta-cell radiotracers.

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  • 20. Grong, E.
    et al.
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Arbo, I. B.
    Eriksson, M.
    Kulseng, B. E.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Mårvik, R.
    The effect of hypergastrinemia following sleeve gastrectomy and pantoprazole on type 2 diabetes mellitus and beta-cell mass in Goto-Kakizaki rats2018In: Journal of Endocrinological Investigation, ISSN 0391-4097, E-ISSN 1720-8386, Vol. 41, no 6, p. 691-701Article in journal (Refereed)
    Abstract [en]

    Purpose: Metabolic surgery alters the secretion of gastrointestinal hormones that influence glycemic control. Elevated gastrin has been suggested to benefit patients with type 2 diabetes and has been reported following sleeve gastrectomy in rats. The present study compares the effect of hypergastrinemia following sleeve gastrectomy with proton-pump inhibitor therapy on glycemic control and beta-cell mass in lean, diabetic animals.

    Methods: Thirty-three diabetic Goto-Kakizaki rats were randomized into pantoprazole + sham operation (GK-PPI), sleeve gastrectomy (GK-SG) and vehicle + sham operation (GK-V). Body weight, glucose parameters, HbA1c, glucagon-like peptide 1, gastrin, insulin and lipids were evaluated for eighteen postoperative weeks. Total beta-cell mass was quantified by optical projection tomography.

    Results: After surgery, body weight development was equal among groups (Pg = 0.75). Fasting and stimulated gastrin increased for GK-PPI and GK-SG vs. GK-V (p < 0.05 for all). Fasting blood glucose was decreased for GK-PPI and GK-SG vs. GK-V (p < 0.05 and p = 0.052). HbA1c was lower for GK-SG vs. GK-V at 6 weeks and for GK-PPI vs. GK-V at twelve- and eighteen weeks postoperative (p < 0.05 for all); a borderline difference was observed for GK-SG vs. GK-V at 18 weeks (p = 0.054). Total- and LDL cholesterol was elevated for GK-PPI compared to the other two groups (p < 0.05 for all). Beta-cell mass did not differ among groups (p = 0.35).

    Conclusions: Hypergastrinemia following sleeve gastrectomy and pantoprazole has a similar, modest effect on glycemic control in Goto-Kakizaki rats but does not enhance beta-cell mass after 18 weeks. Hypergastrinemia in the setting of T2DM might be of clinical relevance.

  • 21. Grong, Eivind
    et al.
    Kulseng, Bård
    Arbo, Ingerid Brænne
    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).
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Mårvik, Ronald
    Sleeve gastrectomy, but not duodenojejunostomy, preserves total beta-cell mass in Goto-Kakizaki rats evaluated by three-dimensional optical projection tomography2016In: Surgical Endoscopy, ISSN 0930-2794, E-ISSN 1432-2218, Vol. 30, no 2, p. 532-542Article in journal (Refereed)
    Abstract [en]

    Background In type 2 diabetes mellitus, there is a progressive loss of beta-cell mass. Bariatric surgery has in recent investigations showed promising results in terms of diabetes remission, but little is established regarding the effect of surgery on the survival or regeneration of pancreatic beta-cells. In this study, we aim to explore how bariatric surgery with its subsequent hormonal alterations affects the islets of Langerhans.

    Methods Twenty-four Goto-Kakizaki rats were operated with duodenojejunostomy (DJ), sleeve gastrectomy (SG) or sham operation. From the 38th week after surgery, body weight, fasting blood glucose, glycosylated hemoglobin, mixed meal tolerance with repeated measures of insulin, glucagon-like peptide 1, gastrin and total ghrelin were evaluated. Forty-six weeks after surgery, the animals were euthanized and the total beta-cell mass in all animals was examined by three-dimensional volume quantification by optical projection tomography based on the signal from insulin-specific antibody staining.

    Results Body weight did not differ between groups (Pg = 0.37). SG showed lower fasting blood glucose compared to DJ and sham (Pg = 0.037); HbA1c levels in SG were lower compared to DJ only (p\0.05). GLP-1 levels were elevated for DJ compared to SG and sham (Pg = 0.001), whereas gastrin levels were higher in SG compared to the two other groups (Pg = 0.002). Beta-cell mass was significantly greater in animals operated with SG compared to both DJ and sham (p = 0.036).

    Conclusion Sleeve gastrectomy is superior to duodenojejunostomy and sham operation when comparing the preservation of beta-cell mass 46 weeks after surgery in Goto-Kakizaki rats. This could be related to both the increased gastrin levels and the long-term improvement in glycemic parameters observed after this procedure.

  • 22. Gurzov, Esteban N.
    et al.
    Ke, Pu Chun
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Garcia Ribeiro, Rita S.
    Gotthardt, Martin
    Novel Strategies to Protect and Visualize Pancreatic beta Cells in Diabetes2020In: Trends in endocrinology and metabolism, ISSN 1043-2760, E-ISSN 1879-3061, Vol. 31, no 12, p. 905-917Article, review/survey (Refereed)
    Abstract [en]

    A common feature in the pathophysiology of different types of diabetes is the reduction of beta cell mass and/or impairment of beta cell function. Diagnosis and treatment of type 1 and type 2 diabetes is currently hampered by a lack of reliable techniques to restore beta cell survival, to improve insulin secretion, and to quantify beta cell mass in patients. Current new approaches may allow us to precisely and specifically visualize beta cells in vivo and provide viable therapeutic strategies to preserve, recover, and regenerate beta cells. In this review, we discuss recent protective approaches for beta cells and the advantages and limitations of current imaging probes in the field.

  • 23.
    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.

  • 24.
    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.

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  • 25.
    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.

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  • 26.
    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.

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  • 27.
    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.

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  • 28. Hecksher-Sørensen, Jacob
    et al.
    Watson, Robert P
    Lettice, Laura A
    Serup, Palle
    Eley, Lorraine
    De Angelis, Carlo
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Hill, Robert E
    The splanchnic mesodermal plate directs spleen and pancreatic laterality, and is regulated by Bapx1/Nkx3.2.2004In: Development, ISSN 0950-1991, Vol. 131, no 19, p. 4665-75Article in journal (Refereed)
  • 29.
    Holmberg, Dan
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Imaging the pancreas: from ex vivo to non-invasive technology.2008In: Diabetologia, ISSN 0012-186X, Vol. 51, no 12, p. 2148-2154Article in journal (Other academic)
  • 30.
    Hörnblad, Andreas
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Cheddad, Abbas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    An improved protocol for optical projection tomography imaging reveals lobular heterogeneities in pancreatic islet and β-cell mass distribution2011In: Islets, ISSN 1938-2014, Vol. 3, no 4, p. 204-208Article in journal (Refereed)
    Abstract [en]

    Optical projection tomography (OPT) imaging is a powerful tool for three-dimensional imaging of gene and protein distribution patterns in biomedical specimens. We have previously demonstrated the possibility, by this technique, to extract information of the spatial and quantitative distribution of the islets of Langerhans in the intact mouse pancreas. In order to further increase the sensitivity of OPT imaging for this type of assessment, we have developed a protocol implementing a computational statistical approach: contrast limited adaptive histogram equalization (CLAHE). We demonstrate that this protocol significantly increases the sensitivity of OPT imaging for islet detection, helps preserve islet morphology and diminish subjectivity in thresholding for tomographic reconstruction. When applied to studies of the pancreas from healthy C57BL/6 mice, our data reveal that, at least in this strain, the pancreas harbors substantially more islets than has previously been reported. Further, we provide evidence that the gastric, duodenal and splenic lobes of the pancreas display dramatic differences in total and relative islet and β-cell mass distribution. This includes a 75% higher islet density in the gastric lobe as compared to the splenic lobe and a higher relative volume of insulin producing cells in the duodenal lobe as compared to the other lobes. Altogether, our data show that CLAHE substantially improves OPT based assessments of the islets of Langerhans and that lobular origin must be taken into careful consideration in quantitative and spatial assessments of the pancreas.

  • 31.
    Hörnblad, Andreas
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Eriksson, Anna
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Sock, Elisabeth
    Hill, Robert
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Impaired spleen formation perturbs morphogenesis of the gastric lobe of the pancreas2011In: PLOS ONE, E-ISSN 1932-6203, Vol. 6, no 6, p. e21753-Article in journal (Refereed)
    Abstract [en]

    Despite the extensive use of the mouse as a model for studies of pancreas development and disease, the development of the gastric pancreatic lobe has been largely overlooked. In this study we use optical projection tomography to provide a detailed three-dimensional and quantitative description of pancreatic growth dynamics in the mouse. Hereby, we describe the epithelial and mesenchymal events leading to the formation of the gastric lobe of the pancreas. We show that this structure forms by perpendicular growth from the dorsal pancreatic epithelium into a distinct lateral domain of the dorsal pancreatic mesenchyme. Our data support a role for spleen organogenesis in the establishment of this mesenchymal domain and in mice displaying perturbed spleen development, including Dh +/-, Bapx1-/- and Sox11-/-, gastric lobe development is disturbed. We further show that the expression profile of markers for multipotent progenitors is delayed in the gastric lobe as compared to the splenic and duodenal pancreatic lobes. Altogether, this study provides new information regarding the developmental dynamics underlying the formation of the gastric lobe of the pancreas and recognizes lobular heterogeneities regarding the time course of pancreatic cellular differentiation. Collectively, these data are likely to constitute important elements in future interpretations of the developing and/or diseased pancreas.

  • 32.
    Hörnblad, Andreas
    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).
    Parween, Saba
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ahnfelt-Rønne, J.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    The pancreas2015In: Kaufman's atlas of mouse development supplement: with coronal sections / [ed] Richard Baldock, Jonathan Bard, Duncan R. Davidson and Gillian Morriss-Kay, Elsevier, 2015, 1, p. 85-94Chapter in book (Refereed)
    Abstract [en]

    This chapter aims to provide a three-dimensional description of the key morphological events, through which a discrete region of the early gut epithelium, as well as its associated mesenchyme, gives rise to the adult pancreas. Facilitated by recent advances in optical imaging techniques, including light sheet fluorescence microscopy and optical projection tomography, we present image series illustrating the growth of the organ and the formation of key morphological and anatomical features. Given the close developmental relationship between the pancreas-associated mesenchyme and the spleen anlage, and thus the potential for the developing spleen to influence pancreas morphogenesis, we include a brief section which covers the early development of this organ. Finally, we describe the spatial and quantitative distribution of the pancreatic endocrine (β-cell) component in adult mice and highlight lobular heterogeneities that may affect phenotypical evaluations of the gland.

  • 33. Ilegems, E.
    et al.
    van Krieken, P. P.
    Edlund, P. K.
    Dicker, A.
    Alanentalo, T.
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Mandic, S.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Berggren, P. -O
    Light scattering as an intrinsic indicator for pancreatic islet cell mass and secretion2015In: Scientific Reports, E-ISSN 2045-2322, Vol. 5, article id 10740Article in journal (Refereed)
    Abstract [en]

    The pancreatic islet of Langerhans is composed of endocrine cells producing and releasing hormones from secretory granules in response to various stimuli for maintenance of blood glucose homeostasis. In order to adapt to a variation in functional demands, these islets are capable of modulating their hormone secretion by increasing the number of endocrine cells as well as the functional response of individual cells. A failure in adaptive mechanisms will lead to inadequate blood glucose regulation and thereby to the development of diabetes. It is therefore necessary to develop tools for the assessment of both pancreatic islet mass and function, with the aim of understanding cellular regulatory mechanisms and factors guiding islet plasticity. Although most of the existing techniques rely on the use of artificial indicators, we present an imaging methodology based on intrinsic optical properties originating from mature insulin secretory granules within endocrine cells that reveals both pancreatic islet mass and function. We demonstrate the advantage of using this imaging strategy by monitoring in vivo scattering signal from pancreatic islets engrafted into the anterior chamber of the mouse eye, and how this versatile and noninvasive methodology permits the characterization of islet morphology and plasticity as well as hormone secretory status.

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  • 34. Jo, Junghyo
    et al.
    Hara, Manami
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Sorenson, Robert L.
    Periwal, Vipul
    Mathematical models of pancreatic islet size distributions2012In: Islets, ISSN 1938-2014, Vol. 4, no 1, p. 10-19Article, review/survey (Refereed)
    Abstract [en]

    The islets of Langerhans, ranging in size from clusters of a few cells to several thousand cells, are scattered near large blood vessels. While the beta-cell mass in mammals is proportional to body weight, the size ranges of islets are similar between species with different body sizes, possibly reflecting an optimal functional size. The large range of islet sizes suggests a stochastic developmental process. It is not fully understood how islets develop to reach such size distributions, and how their sizes change under certain physiological and pathological conditions such as development, pregnancy, aging, obesity, and diabetes. The lack of a high-resolution in vivo imaging technique for pancreatic islets implies that the only data available to elucidate the dynamics of islet development are cross-sectional quantifications of islet size distributions. In this review, we infer biological processes affecting islet morphology in the large by examining changes of islet size distributions. Neonatal islet formation and growth is shown as a particular example of developing a mathematical model of islet size distribution. Application of this modeling to elucidate islet changes under other conditions is also discussed.

  • 35. Jo, Junghyo
    et al.
    Hörnblad, Andreas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Kilimnik, German
    Department of Medicine, The University of Chicago, Chicago, IL, USA.
    Hara, Manami
    Department of Medicine, The University of Chicago, Chicago, IL, USA.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Periwal, Vipul
    Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
    The fractal spatial distribution of pancreatic islets in three dimensions: a self-avoiding growth model2013In: Physical Biology, ISSN 1478-3967, E-ISSN 1478-3975, Vol. 10, no 3, p. 036009-Article in journal (Refereed)
    Abstract [en]

    The islets of Langerhans, responsible for controlling blood glucose levels, are dispersed within the pancreas. A universal power law governing the fractal spatial distribution of islets in two-dimensional pancreatic sections has been reported. However, the fractal geometry in the actual three-dimensional pancreas volume, and the developmental process that gives rise to such a self-similar structure, has not been investigated. Here, we examined the three-dimensional spatial distribution of islets in intact mouse pancreata using optical projection tomography and found a power law with a fractal dimension of 2.1. Furthermore, based on two-dimensional pancreatic sections of human autopsies, we found that the distribution of human islets also follows a universal power law with a fractal dimension of 1.5 in adult pancreata, which agrees with the value previously reported in smaller mammalian pancreas sections. Finally, we developed a self-avoiding growth model for the development of the islet distribution and found that the fractal nature of the spatial islet distribution may be associated with the self-avoidance in the branching process of vascularization in the pancreas.

  • 36.
    Jones, Iwan
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Hägglund, Anna-Carin
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Törnqvist, Gunilla
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Carlsson, Leif
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    A novel mouse model of tuberous sclerosis complex (TSC): eye-specific Tsc1-ablation disrupts visual-pathway development2015In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 8, no 12, p. 1517-1529Article in journal (Refereed)
    Abstract [en]

    Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that is best characterised by neurodevelopmental deficits and the presence of benign tumours (called hamartomas) in affected organs. This multi-organ disorder results from inactivating point mutations in either the TSC1 or the TSC2 genes and consequent activation of the canonical mammalian target of rapamycin complex 1 signalling (mTORC1) pathway. Because lesions to the eye are central to TSC diagnosis, we report here the generation and characterisation of the first eye-specific TSC mouse model. We demonstrate that conditional ablation of Tsc1 in eye-committed progenitor cells leads to the accelerated differentiation and subsequent ectopic radial migration of retinal ganglion cells. This results in an increase in retinal ganglion cell apoptosis and consequent regionalised axonal loss within the optic nerve and topographical changes to the contra- and ipsilateral input within the dorsal lateral geniculate nucleus. Eyes from adult mice exhibit aberrant retinal architecture and display all the classic neuropathological hallmarks of TSC, including an increase in organ and cell size, ring heterotopias, hamartomas with retinal detachment, and lamination defects. Our results provide the first major insight into the molecular etiology of TSC within the developing eye and demonstrate a pivotal role for Tsc1 in regulating various aspects of visual-pathway development. Our novel mouse model therefore provides a valuable resource for future studies concerning the molecular mechanisms underlying TSC and also as a platform to evaluate new therapeutic approaches for the treatment of this multi-organ disorder.

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  • 37.
    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.

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  • 38.
    Lorén, Christina E
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Schrader, John W
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    FGF signals induce Caprin2 expression in the vertebrate lens.2009In: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436, Vol. 77, no 4, p. 386-394Article in journal (Refereed)
    Abstract [en]

    The lens of the eye is derived from the non-neural ectoderm situated next to the optic vesicle. Fibroblast growth factor (FGF) signals play a major role at various stages of vertebrate lens development ranging from induction and proliferation to differentiation. Less is however known about the identity of genes that are induced by FGF activity within the lens. We have isolated and characterized mouse cytoplasmic activation/proliferation-associated protein-2 (Caprin2), with domains belonging to both the Caprin family and the C1q and tumour necrosis factor (TNF) super-family. Here we show that Caprin2 is expressed in the developing vertebrate lens in mouse and chick, and that Caprin2 expression is up-regulated in primary lens fiber cells, after the induction of crystallins the earliest known markers for differentiated lens fiber cells. Caprin2 is subsequently down-regulated in the centre of the lens at the time and at the position of the first fiber cell denucleation and terminal differentiation. In vitro analyses of lens fiber cell differentiation provide evidence that FGF activity emanating from neighboring prospective retinal cells is required and that FGF8 activity is sufficient to induce Caprin2 in lens fiber cells. These results not only provide evidence that FGF signals induce the newly characterized protein Caprin2 in the lens, but also support the general idea that FGF signals are required for lens fiber cell differentiation.

  • 39. Medina, Anya
    et al.
    Parween, Saba
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ullsten, Sara
    Vishnu, Neelanjan
    Siu, Yuk Ting
    Quach, My
    Bennet, Hedvig
    Balhuizen, Alexander
    Åkesson, Lina
    Wierup, Nils
    Carlsson, Per Ola
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Lernmark, Åke
    Fex, Malin
    Early deficits in insulin secretion, beta cell mass and islet blood perfusion precede onset of autoimmune type 1 diabetes in BioBreeding rats2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 4, p. 896-905Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: Genetic studies show coupling of genes affecting beta cell function to type 1 diabetes, but hitherto no studies on whether beta cell dysfunction could precede insulitis and clinical onset of type 1 diabetes are available.

    Methods: We used 40-day-old BioBreeding (BB) DRLyp/Lyp rats (a model of spontaneous autoimmune type 1 diabetes) and diabetes-resistant DRLyp/+ and DR+/+ littermates (controls) to investigate beta cell function in vivo, and insulin and glucagon secretion in vitro. Beta cell mass was assessed by optical projection tomography (OPT) and morphometry. Additionally, measurements of intra-islet blood flow were performed using microsphere injections. We also assessed immune cell infiltration, cytokine expression in islets (by immunohistochemistry and qPCR), as well as islet Glut2 expression and ATP/ADP ratio to determine effects on glucose uptake and metabolism in beta cells.

    Results: DRLyp/Lyp rats were normoglycaemic and without traces of immune cell infiltrates. However, IVGTTs revealed a significant decrease in the acute insulin response to glucose compared with control rats (1685.3 +/- 121.3 vs 633.3 +/- 148.7; p < 0.0001). In agreement, insulin secretion was severely perturbed in isolated islets, and both first- and second-phase insulin release were lowered compared with control rats, while glucagon secretion was similar in both groups. Interestingly, after 5-7 days of culture of islets from DRLyp/Lyp rats in normal media, glucose-stimulated insulin secretion (GSIS) was improved; although, a significant decrease in GSIS was still evident compared with islets from control rats at this time (7393.9 +/- 1593.7 vs 4416.8 +/- 1230.5 pg islet-1 h-1; p < 0.0001). Compared with controls, OPT of whole pancreas from DRLyp/Lyp rats revealed significant reductions in medium (4.1 x 109 +/- 9.5 x 107 vs 3.8 x 109 +/- 5.8 x 107 μm3; p = 0.044) and small sized islets (1.6 x 109 +/- 5.1 x 107 vs 1.4 x 109 +/- 4.5 x 107 μm3; p = 0.035). Finally, we found lower intra-islet blood perfusion in vivo (113.1 +/- 16.8 vs 76.9 +/- 11.8 μl min-1 [g pancreas]-1; p = 0.023) and alterations in the beta cell ATP/ADP ratio in DRLyp/Lyp rats vs control rats.

    Conclusions/interpretation: The present study identifies a deterioration of beta cell function and mass, and intra-islet blood flow that precedes insulitis and diabetes development in animals prone to autoimmune type 1 diabetes. These underlying changes in islet function may be previously unrecognised factors of importance in type 1 diabetes development.