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Publikationer (10 of 23) Visa alla publikationer
Nord, C., Jones, I., Garcia-Maestre, M., Hägglund, A.-C. & Carlsson, L. (2024). Reduced mTORC1-signaling in progenitor cells leads to retinal lamination deficits. Developmental Dynamics
Öppna denna publikation i ny flik eller fönster >>Reduced mTORC1-signaling in progenitor cells leads to retinal lamination deficits
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2024 (Engelska)Ingår i: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177Artikel i tidskrift (Refereegranskat) Epub ahead of print
Abstract [en]

Background: Neuronal lamination is a hallmark of the mammalian central nervous system (CNS) and underlies connectivity and function. Initial formation of this tissue architecture involves the integration of various signaling pathways that regulate the differentiation and migration of neural progenitor cells.

Results: Here, we demonstrate that mTORC1 mediates critical roles during neuronal lamination using the mouse retina as a model system. Down-regulation of mTORC1-signaling in retinal progenitor cells by conditional deletion of Rptor led to decreases in proliferation and increased apoptosis during embryogenesis. These developmental deficits preceded aberrant lamination in adult animals which was best exemplified by the fusion of the outer and inner nuclear layer and the absence of an outer plexiform layer. Moreover, ganglion cell axons originating from each Rptor-ablated retina appeared to segregate to an equal degree at the optic chiasm with both contralateral and ipsilateral projections displaying overlapping termination topographies within several retinorecipient nuclei. In combination, these visual pathway defects led to visually mediated behavioral deficits.

Conclusions: This study establishes a critical role for mTORC1-signaling during retinal lamination and demonstrates that this pathway regulates diverse developmental mechanisms involved in driving the stratified arrangement of neurons during CNS development.

Ort, förlag, år, upplaga, sidor
John Wiley & Sons, 2024
Nyckelord
Chx10, dLGN, lamination, mTORC1, retina, Rptor
Nationell ämneskategori
Neurovetenskaper Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-223249 (URN)10.1002/dvdy.707 (DOI)001193263800001 ()38546215 (PubMedID)2-s2.0-85189534154 (Scopus ID)
Tillgänglig från: 2024-04-18 Skapad: 2024-04-18 Senast uppdaterad: 2024-04-18
Hahn, M., Nord, C., van Krieken, P. P., Berggren, P.-O., Ilegems, E., Cheddad, A. & Ahlgren, U. (2022). Quantitative 3D OPT and LSFM datasets of pancreata from mice with streptozotocin-induced diabetes. Scientific Data, 9, Article ID 558.
Öppna denna publikation i ny flik eller fönster >>Quantitative 3D OPT and LSFM datasets of pancreata from mice with streptozotocin-induced diabetes
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2022 (Engelska)Ingår i: Scientific Data, E-ISSN 2052-4463, Vol. 9, artikel-id 558Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
Nature Publishing Group, 2022
Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
urn:nbn:se:umu:diva-193538 (URN)10.1038/s41597-022-01546-5 (DOI)000852384000002 ()36088402 (PubMedID)2-s2.0-85138129001 (Scopus ID)
Forskningsfinansiär
DiabetesförbundetUmeå universitetFamiljen Erling-Perssons StiftelseEU, FP7, Sjunde ramprogrammet, 289932EU, FP7, Sjunde ramprogrammet, 613879Knut och Alice Wallenbergs StiftelseVetenskapsrådetNovo Nordisk
Anmärkning

Originally included in thesis in manuscript form.

Tillgänglig från: 2022-04-06 Skapad: 2022-04-06 Senast uppdaterad: 2022-10-03Bibliografiskt granskad
Hahn, M., Nord, C., Eriksson, M., Morini, F., Alanentalo, T., Korsgren, O. & Ahlgren, U. (2021). 3D imaging of human organs with micrometer resolution - applied to the endocrine pancreas. Communications Biology, 4(1), Article ID 1063.
Öppna denna publikation i ny flik eller fönster >>3D imaging of human organs with micrometer resolution - applied to the endocrine pancreas
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2021 (Engelska)Ingår i: Communications Biology, E-ISSN 2399-3642, Vol. 4, nr 1, artikel-id 1063Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
Springer Nature, 2021
Nationell ämneskategori
Cell- och molekylärbiologi Endokrinologi och diabetes
Identifikatorer
urn:nbn:se:umu:diva-187770 (URN)10.1038/s42003-021-02589-x (DOI)000694906000003 ()2-s2.0-85114856810 (Scopus ID)
Tillgänglig från: 2021-09-22 Skapad: 2021-09-22 Senast uppdaterad: 2023-03-24Bibliografiskt granskad
Davies, W. I. L., Sghari, S., Upton, B. A., Nord, C., Hahn, M., Ahlgren, U., . . . Gunhaga, L. (2021). Distinct opsin 3 (Opn3) expression in the developing nervous system during mammalian embryogenesis. eNeuro, 8(5), Article ID ENEURO.0141-21.2021.
Öppna denna publikation i ny flik eller fönster >>Distinct opsin 3 (Opn3) expression in the developing nervous system during mammalian embryogenesis
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2021 (Engelska)Ingår i: eNeuro, E-ISSN 2373-2822, Vol. 8, nr 5, artikel-id ENEURO.0141-21.2021Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
Society for Neuroscience, 2021
Nyckelord
Brain, Development, Encephalopsin, Nervous system, Opn3, OPT
Nationell ämneskategori
Neurovetenskaper Utvecklingsbiologi
Identifikatorer
urn:nbn:se:umu:diva-187852 (URN)10.1523/ENEURO.0141-21.2021 (DOI)000704430100013 ()34417283 (PubMedID)2-s2.0-85114912713 (Scopus ID)
Forskningsfinansiär
Vetenskapsrådet, 2017-01430Kempestiftelserna, SMK-1763Vetenskapsrådet, 2017-01307
Tillgänglig från: 2021-09-23 Skapad: 2021-09-23 Senast uppdaterad: 2023-09-05Bibliografiskt granskad
Quilichini, E., Fabre, M., Nord, C., Dirami, T., Le Marec, A., Cereghini, S., . . . Haumaitre, C. (2021). Insights into the etiology and physiopathology of MODY5/HNF1B pancreatic phenotype with a mouse model of the human disease. Journal of Pathology, 254(1), 31-45
Öppna denna publikation i ny flik eller fönster >>Insights into the etiology and physiopathology of MODY5/HNF1B pancreatic phenotype with a mouse model of the human disease
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2021 (Engelska)Ingår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 254, nr 1, s. 31-45Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Maturity‐onset diabetes of the young type 5 (MODY5) is due to heterozygous mutations or deletion of HNF1B. No mouse models are currently available to recapitulate the human MODY5 disease. Here, we investigate the pancreatic phenotype of a unique MODY5 mouse model generated by heterozygous insertion of a human HNF1B splicing mutation at the intron‐2 splice donor site in the mouse genome. This Hnf1bsp2/+ model generated with targeted mutation of Hnf1b mimicking the c.544+1G>T (<IVS2nt+1G>T) mutation identified in humans, results in alternative transcripts and a 38% decrease of native Hnf1b transcript levels. As a clinical feature of MODY5 patients, the hypomorphic mouse model Hnf1bsp2/+ displays glucose intolerance. Whereas Hnf1bsp2/+ isolated islets showed no altered insulin secretion, we found a 65% decrease in pancreatic insulin content associated with a 30% decrease in total large islet volume and a 20% decrease in total β‐cell volume. These defects were associated with a 30% decrease in expression of the pro‐endocrine gene Neurog3 that we previously identified as a direct target of Hnf1b, showing a developmental etiology. As another clinical feature of MODY5 patients, the Hnf1bsp2/+ pancreases display exocrine dysfunction with hypoplasia. We observed chronic pancreatitis with loss of acinar cells, acinar‐to‐ductal metaplasia, and lipomatosis, with upregulation of signaling pathways and impaired acinar cell regeneration. This was associated with ductal cell deficiency characterized by shortened primary cilia. Importantly, the Hnf1bsp2/+ mouse model reproduces the pancreatic features of the human MODY5/HNF1B disease, providing a unique in vivo tool for molecular studies of the endocrine and exocrine defects and to advance basic and translational research.

Ort, förlag, år, upplaga, sidor
John Wiley & Sons, 2021
Nyckelord
exocrine dysfunction, glucose intolerance, haploinsufficiency, HNF1B, maturity-onset diabetes of the young (MODY), optical projection tomography (OPT), pancreatic hypoplasia, pancreatitis, primary cilia, β-cells
Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
urn:nbn:se:umu:diva-181833 (URN)10.1002/path.5629 (DOI)000630230000001 ()33527355 (PubMedID)2-s2.0-85102621816 (Scopus ID)
Tillgänglig från: 2021-04-06 Skapad: 2021-04-06 Senast uppdaterad: 2022-04-19Bibliografiskt granskad
Hahn, M., Nord, C., Franklin, O., Alanentalo, T., Isaksson Mettävainio, M., Morini, F., . . . Ahlgren, U. (2020). Mesoscopic 3D imaging of pancreatic cancer and Langerhans islets based on tissue autofluorescence. Scientific Reports, 10(1), Article ID 18246.
Öppna denna publikation i ny flik eller fönster >>Mesoscopic 3D imaging of pancreatic cancer and Langerhans islets based on tissue autofluorescence
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2020 (Engelska)Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 10, nr 1, artikel-id 18246Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
Springer Nature, 2020
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:umu:diva-180639 (URN)10.1038/s41598-020-74616-6 (DOI)000615370300001 ()33106532 (PubMedID)2-s2.0-85094218464 (Scopus ID)
Tillgänglig från: 2021-02-25 Skapad: 2021-02-25 Senast uppdaterad: 2022-09-15Bibliografiskt granskad
Hahn, M., van Krieken, P. P., Nord, C., Alanentalo, T., Morini, F., Xiong, Y., . . . Ahlgren, U. (2020). Topologically selective islet vulnerability and self-sustained downregulation of markers for β-cell maturity in streptozotocin-induced diabetes. Communications Biology, 3(1), Article ID 541.
Öppna denna publikation i ny flik eller fönster >>Topologically selective islet vulnerability and self-sustained downregulation of markers for β-cell maturity in streptozotocin-induced diabetes
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2020 (Engelska)Ingår i: Communications Biology, E-ISSN 2399-3642, Vol. 3, nr 1, artikel-id 541Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
Nature Publishing Group, 2020
Nationell ämneskategori
Endokrinologi och diabetes Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-176312 (URN)10.1038/s42003-020-01243-2 (DOI)000576947100003 ()32999405 (PubMedID)2-s2.0-85091723089 (Scopus ID)
Tillgänglig från: 2020-10-29 Skapad: 2020-10-29 Senast uppdaterad: 2023-03-24Bibliografiskt granskad
Grong, E., Nord, C., Arbo, I. B., Eriksson, M., Kulseng, B. E., Ahlgren, U. & Mårvik, R. (2018). The effect of hypergastrinemia following sleeve gastrectomy and pantoprazole on type 2 diabetes mellitus and beta-cell mass in Goto-Kakizaki rats. Journal of Endocrinological Investigation, 41(6), 691-701
Öppna denna publikation i ny flik eller fönster >>The effect of hypergastrinemia following sleeve gastrectomy and pantoprazole on type 2 diabetes mellitus and beta-cell mass in Goto-Kakizaki rats
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2018 (Engelska)Ingår i: Journal of Endocrinological Investigation, ISSN 0391-4097, E-ISSN 1720-8386, Vol. 41, nr 6, s. 691-701Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
Springer, 2018
Nyckelord
sleeve gastrectomy, pantoprazole, gastrin, optical projection tomography, beta-cell mass, glycosylated hemoglobin
Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
urn:nbn:se:umu:diva-148827 (URN)10.1007/s40618-017-0793-9 (DOI)000432236400008 ()29168078 (PubMedID)2-s2.0-85034636636 (Scopus ID)
Tillgänglig från: 2018-06-13 Skapad: 2018-06-13 Senast uppdaterad: 2021-09-22Bibliografiskt granskad
Nord, C., Eriksson, M., Dicker, A., Eriksson, A., Grong, E., Ilegems, E., . . . Ahlgren, U. (2017). Biochemical profiling of diabetes disease progression by multivariate vibrational microspectroscopy of the pancreas. Scientific Reports, 7, Article ID 6646.
Öppna denna publikation i ny flik eller fönster >>Biochemical profiling of diabetes disease progression by multivariate vibrational microspectroscopy of the pancreas
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2017 (Engelska)Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 7, artikel-id 6646Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
Nature Publishing Group, 2017
Nationell ämneskategori
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Identifikatorer
urn:nbn:se:umu:diva-138420 (URN)10.1038/s41598-017-07015-z (DOI)000406366000004 ()2-s2.0-85026213692 (Scopus ID)
Tillgänglig från: 2017-08-23 Skapad: 2017-08-23 Senast uppdaterad: 2023-03-23Bibliografiskt granskad
Parween, S., Eriksson, M., Nord, C., Kostromina, E. & Ahlgren, U. (2017). Spatial and quantitative datasets of the pancreatic beta-cell mass distribution in lean and obese mice. Scientific Data, 4, Article ID 170031.
Öppna denna publikation i ny flik eller fönster >>Spatial and quantitative datasets of the pancreatic beta-cell mass distribution in lean and obese mice
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2017 (Engelska)Ingår i: Scientific Data, E-ISSN 2052-4463, Vol. 4, artikel-id 170031Artikel i tidskrift (Refereegranskat) Published
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.

Nationell ämneskategori
Biomedicinsk laboratorievetenskap/teknologi
Identifikatorer
urn:nbn:se:umu:diva-133764 (URN)10.1038/sdata.2017.31 (DOI)000396109500001 ()2-s2.0-85015444491 (Scopus ID)
Tillgänglig från: 2017-05-03 Skapad: 2017-05-03 Senast uppdaterad: 2023-03-24Bibliografiskt granskad
Organisationer
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0001-9401-6844

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