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  • 1. Baeyens, Luc
    et al.
    Lemper, Marie
    Leuckx, Gunter
    De Groef, Sofie
    Bonfanti, Paola
    Stange, Geert
    Shemer, Ruth
    Nord, Christoffer
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Scheel, David W
    Pan, Fong C
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (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 mice2014Ingår i: Nature Biotechnology, ISSN 1087-0156, E-ISSN 1546-1696, Vol. 32, nr 1, s. 76-83Artikel i tidskrift (Refereegranskat)
    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.

  • 2.
    Cheddad, Abbas
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Nord, Christoffer
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Hörnblad, Andreas
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (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 universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Georgsson, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för datavetenskap.
    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 universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Improving signal detection in emission optical projection tomography via single source multi-exposure image fusion2013Ingår i: Optics Express, ISSN 1094-4087, E-ISSN 1094-4087, Vol. 21, nr 14, s. 16584-16604Artikel i tidskrift (Refereegranskat)
    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.

  • 3.
    Cheddad, Abbas
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Svensson, Christoffer
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Sharpe, James
    Georgsson, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för datavetenskap.
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Image processing assisted algorithms for optical projection tomography2012Ingår i: IEEE Transactions on Medical Imaging, ISSN 0278-0062, E-ISSN 1558-254X, Vol. 31, nr 1, s. 1-15Artikel i tidskrift (Refereegranskat)
    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.

  • 4.
    Eriksson, Anna U.
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Svensson, Christoffer
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Hörnblad, Andreas
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Cheddad, Abbas
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Kostromina, Elena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Eriksson, Maria
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Norlin, Nils
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (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 universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för datavetenskap.
    Alanentalo, Tomas
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Near infrared optical projection tomography for assessments of beta-cell mass distribution in diabetes research2013Ingår i: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, Vol. 71, artikel-id e50238Artikel i tidskrift (Refereegranskat)
    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.

  • 5. Grong, E.
    et al.
    Nord, Christoffer
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Arbo, I. B.
    Eriksson, M.
    Kulseng, B. E.
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Mårvik, R.
    The effect of hypergastrinemia following sleeve gastrectomy and pantoprazole on type 2 diabetes mellitus and beta-cell mass in Goto-Kakizaki rats2018Ingår i: Journal of Endocrinological Investigation, ISSN 0391-4097, E-ISSN 1720-8386, Vol. 41, nr 6, s. 691-701Artikel i tidskrift (Refereegranskat)
    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.

  • 6. Grong, Eivind
    et al.
    Kulseng, Bård
    Arbo, Ingerid Brænne
    Nord, Christoffer
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Eriksson, Maria
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Mårvik, Ronald
    Sleeve gastrectomy, but not duodenojejunostomy, preserves total beta-cell mass in Goto-Kakizaki rats evaluated by three-dimensional optical projection tomography2016Ingår i: Surgical Endoscopy, ISSN 0930-2794, E-ISSN 1432-2218, Vol. 30, nr 2, s. 532-542Artikel i tidskrift (Refereegranskat)
    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.

  • 7.
    Hörnblad, Andreas
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Nord, Christoffer
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Parween, Saba
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Ahnfelt-Rønne, J
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    The pancreas2015Ingår i: 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, s. 85-94Kapitel i bok, del av antologi (Refereegranskat)
    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.

  • 8.
    Jones, Iwan
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Hägglund, Anna-Carin
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Törnqvist, Gunilla
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Nord, Christoffer
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Carlsson, Leif
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    A novel mouse model of tuberous sclerosis complex (TSC): eye-specific Tsc1-ablation disrupts visual-pathway development2015Ingår i: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 8, nr 12, s. 1517-1529Artikel i tidskrift (Refereegranskat)
    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.

  • 9.
    Nord, Christoffer
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    The Colours of Diabetes: advances and novel applications of molecular optical techniques for studies of the pancreas2016Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Diabetes is a rapidly increasing health problem. In a global perspective,approximately 415 million people suffered from diabetes in 2015 and this number ispredicted to increase to 640 million by 2040. To tackle this pandemic there is a needfor better analytical tools by which we can increase our understanding of the disease.One discipline that has already provided much needed insight to diabetes etiology isoptical molecular imaging. Using various forms of light it is possible to create animage of the analysed sample that can provide information about molecularmechanistic aspects of the disease and to follow spatial and temporal dynamics.

    The overall aim of this thesis is to improve and adapt existing andnovel optical imaging approaches for their specific use in diabetes research. Hereby,we have focused on three techniques: (I) Optical projection tomography (OPT),which can be described as the optical equivalent of x-ray computed tomography(CT), and two vibrational microspectroscopic (VMS) techniques, which records theunique vibrational signatures of molecules building up the sample: (II) Fouriertransforminfrared vibrational microspectroscopy (FT-IR) and (III) Ramanvibrational microspectroscopy (Raman).

    The computational tools and hardware applications presented here generallyimprove OPT data quality, processing speed, sample size and channel capacity.Jointly, these developments enable OPT as a routine tool in diabetes research,facilitating aspects of e.g. pancreatic β-cell generation, proliferation,reprogramming, destruction and preservation to be studied throughout the pancreaticvolume and in large cohorts of experimental animals. Further, a novel application ofmultivariate analysis of VMS data derived from pancreatic tissues is introduced.This approach enables detection of novel biochemical alterations in the pancreasduring diabetes disease progression and can be used to confirm previously reportedbiochemical alterations, but at an earlier stage. Finally, our studies indicate thatRaman imaging is applicable to in vivo studies of grafted islets of Langerhans,allowing for longitudinal studies of pancreatic islet biochemistry.viIn summary, presented here are new and improved methods by which opticalimaging techniques can be utilised to study 3D-spatial, quantitative andmolecular/biochemical alterations of the normal and diseased pancreas.

  • 10.
    Nord, Christoffer
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Eriksson, Maria
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Dicker, Andrea
    Eriksson, Anna
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Grong, Eivind
    Ilegems, Erwin
    Marvik, Ronald
    Kulseng, Bard
    Berggren, Per-Olof
    Gorzsas, Andras
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Biochemical profiling of diabetes disease progression by multivariate vibrational microspectroscopy of the pancreas2017Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikel-id 6646Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Despite the dramatic increase in the prevalence of diabetes, techniques for in situ studies of the underlying pancreatic biochemistry are lacking. Such methods would facilitate obtaining mechanistic understanding of diabetes pathophysiology and aid in prognostic and/or diagnostic assessments. In this report we demonstrate how a multivariate imaging approach (orthogonal projections to latent structures - discriminant analysis) can be applied to generate full vibrational microspectroscopic profiles of pancreatic tissues. These profiles enable extraction of known and previously unrecorded biochemical alterations in models of diabetes, and allow for classification of the investigated tissue with regards to tissue type, strain and stage of disease progression. Most significantly, the approach provided evidence for dramatic alterations of the pancreatic biochemistry at the initial onset of immune-infiltration in the Non Obese Diabetic model for type 1 diabetes. Further, it enabled detection of a previously undocumented accumulation of collagen fibrils in the leptin deficient ob/ob mouse islets. By generating high quality spectral profiles through the tissue capsule of hydrated human pancreata and by in vivo Raman imaging of pancreatic islets transplanted to the anterior chamber of the eye, we provide critical feasibility studies for the translation of this technique to diagnostic assessments of pancreatic biochemistry in vivo.

  • 11.
    Nord, Christoffer
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Eriksson, Maria
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Dicker, Andrea
    The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Sweden.
    Eriksson, Anna
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Grong, Eivind
    Dept. of Gastrointestinal Surgery, St. Olavs Hospital, Trondheim University Hospital, Norway; Dept. of Cancer Research and Molecular Medicine, NTNU, Norway.
    Ilegems, Erwin
    The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Sweden.
    Mårvik, Ronald
    Dept. of Gastrointestinal Surgery, St. Olavs Hospital, Trondheim University Hospital, Norway; Dept. of Cancer Research and Molecular Medicine, NTNU, Norway.
    Kulseng, Bård
    Dept. of Cancer Research and Molecular Medicine, NTNU, Norway.
    Berggren, Per‐Olof
    The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Sweden.
    Gorzsás, András
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Multivariate image analysis facilitates label‐free, biochemicalprofiling of the diabetic pancreasManuskript (preprint) (Övrigt vetenskapligt)
  • 12.
    Nord, Hanna
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Burguiere, Anne-Cecile
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Muck, Joscha
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Nord, Christoffer
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    von Hofsten, Jonas
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Differential regulation of myosin heavy chains defines new muscle domains in zebrafish2014Ingår i: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 25, nr 8, s. 1384-1395Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Numerous muscle lineages are formed during myogenesis within both slow-and fast-specific cell groups. In this study, we show that six fast muscle-specific myosin heavy chain genes have unique expression patterns in the zebrafish embryo. The expression of tail-specific myosin heavy chain (fmyhc2.1) requires wnt signaling and is essential for fast muscle organization within the tail. Retinoic acid treatment results in reduced wnt signaling, which leads to loss of the fmyhc2.1 domain. Retinoic acid treatment also results in a shift of muscle identity within two trunk domains defined by expression of fmyhc1.2 and fmyhc1.3 in favor of the anteriormost myosin isoform, fmyhc1.2. In summary, we identify new muscle domains along the anteroposterior axis in the zebrafish that are defined by individual nonoverlapping, differentially regulated expression of myosin heavy chain isoforms.

  • 13.
    Parween, Saba
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Eriksson, Maria
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Nord, Christoffer
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Kostromina, Elena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Spatial and quantitative datasets of the pancreatic beta-cell mass distribution in lean and obese mice2017Ingår i: Scientific Data, E-ISSN 2052-4463, Vol. 4, artikel-id 170031Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A detailed understanding of pancreatic β-cell mass distribution is a key element to fully appreciate the pathophysiology of models of diabetes and metabolic stress. Commonly, such assessments have been performed by stereological approaches that rely on the extrapolation of two-dimensional data and provide very limited topological information. We present ex vivo optical tomographic data sets of the full β-cell mass distribution in cohorts of obese ob/ob mice and their lean controls, together with information about individual islet β-cell volumes, their three-dimensional coordinates and shape throughout the volume of the pancreas between 4 and 52 weeks of age. These data sets offer the currently most comprehensive public record of the β-cell mass distribution in the mouse. As such, they may serve as a quantitative and topological reference for the planning of a variety of in vivo or ex vivo experiments including computational modelling and statistical analyses. By shedding light on intra- and inter-lobular variations in β-cell mass distribution, they further provide a powerful tool for the planning of stereological sampling assessments.

  • 14.
    Parween, Saba
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Kostromina, Elena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Nord, Christoffer
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Eriksson, Maria
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Lindström, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Intra-islet lesions and lobular variations in β-cell mass expansion in ob/ob mice revealed by 3D imaging of intact pancreas2016Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikel-id 34885Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The leptin deficient ob/ob mouse is a widely used model for studies on initial aspects of metabolic disturbances leading to type 2 diabetes, including insulin resistance and obesity. Although it is generally accepted that ob/ob mice display a dramatic increase in β-cell mass to compensate for increased insulin demand, the spatial and quantitative dynamics of β-cell mass distribution in this model has not been assessed by modern optical 3D imaging techniques. We applied optical projection tomography and ultramicroscopy imaging to extract information about individual islet β-cell volumes throughout the volume of ob/ob pancreas between 4 and 52 weeks of age. Our data show that cystic lesions constitute a significant volume of the hyperplastic ob/ob islets. We propose that these lesions are formed by a mechanism involving extravasation of red blood cells/plasma due to increased islet vessel blood flow and vessel instability. Further, our data indicate that the primary lobular compartments of the ob/ob pancreas have different potentials for expanding their β-cell population. Unawareness of the characteristics of β-cell expansion in ob/ob mice presented in this report may significantly influence ex vivo and in vivo assessments of this model in studies of β-cell adaptation and function.

  • 15. Van de Casteele, M.
    et al.
    Leuckx, G.
    Baeyens, L.
    Cai, Y.
    Yuchi, Y.
    Coppens, V.
    De Groef, S.
    Eriksson, Maria
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Svensson, Christoffer
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Ahnfelt-Ronne, J.
    Madsen, O. D.
    Waisman, A.
    Dor, Y.
    Jensen, J. N.
    Heimberg, H.
    Neurogenin 3(+) cells contribute to beta-cell neogenesis and proliferation in injured adult mouse pancreas2013Ingår i: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 4, s. e523-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We previously showed that injury by partial duct ligation (PDL) in adult mouse pancreas activates Neurogenin 3 (Ngn3)(+) progenitor cells that can differentiate to beta cells ex vivo. Here we evaluate the role of Ngn3(+) cells in beta cell expansion in situ. PDL not only induced doubling of the beta cell volume but also increased the total number of islets. beta cells proliferated without extended delay (the so-called 'refractory' period), their proliferation potential was highest in small islets, and 86% of the beta cell expansion was attributable to proliferation of pre-existing beta cells. At sufficiently high Ngn3 expression level, upto 14% of all beta cells and 40% of small islet beta cells derived from non-beta cells. Moreover, beta cell proliferation was blunted by a selective ablation of Ngn3(+) cells but not by conditional knockout of Ngn3 in pre-existing beta cells supporting a key role for Ngn3(+) insulin(-) cells in beta cell proliferation and expansion. We conclude that Ngn3(+) cell-dependent proliferation of pre-existing and newly-formed beta cells as well as reprogramming of non-beta cells contribute to in vivo beta cell expansion in the injured pancreas of adult mice.

  • 16.
    Witek, Barbara
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    El Wakil, Abeer
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Nord, Christoffer
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Eriksson, Maria
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Vernersson-Lindahl, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Helland, Aslaug
    Alexeyev, Oleg A.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hallberg, Bengt
    Palmer, Ruth H.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg.
    Targeted Disruption of ALK Reveals a Potential Role in Hypogonadotropic Hypogonadism2015Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 5, artikel-id e0123542Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mice lacking ALK activity have previously been reported to exhibit subtle behavioral phenotypes. In this study of ALK of loss of function mice we present data supporting a role for ALK in hypogonadotropic hypogonadism in male mice. We observed lower level of serum testosterone at P40 in ALK knock-out males, accompanied by mild disorganization of seminiferous tubules exhibiting decreased numbers of GATA4 expressing cells. These observations highlight a role for ALK in testis function and are further supported by experiments in which chemical inhibition of ALK activity with the ALK TKI crizotinib was employed. Oral administration of crizotinib resulted in a decrease of serum testosterone levels in adult wild type male mice, which reverted to normal levels after cessation of treatment. Analysis of GnRH expression in neurons of the hypothalamus revealed a significant decrease in the number of GnRH positive neurons in ALK knock-out mice at P40 when compared with control littermates. Thus, ALK appears to be involved in hypogonadotropic hypogonadism by regulating the timing of pubertal onset and testis function at the upper levels of the hypothalamic-pituitary gonadal axis.

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