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Carlsson, Leif
Publications (10 of 23) Show all publications
Jones, I., Yelhekar, T. D., Wiberg, R., Kingham, P. J., Johansson, S., Wiberg, M. & Carlsson, L. (2018). Development and validation of an in vitro model system to study peripheral sensory neuron development and injury. Scientific Reports, 8, Article ID 15961.
Open this publication in new window or tab >>Development and validation of an in vitro model system to study peripheral sensory neuron development and injury
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 15961Article in journal (Refereed) Published
Abstract [en]

The ability to discriminate between diverse types of sensation is mediated by heterogeneous populations of peripheral sensory neurons. Human peripheral sensory neurons are inaccessible for research and efforts to study their development and disease have been hampered by the availability of relevant model systems. The in vitro differentiation of peripheral sensory neurons from human embryonic stem cells therefore provides an attractive alternative since an unlimited source of biological material can be generated for studies that specifically address development and injury. The work presented in this study describes the derivation of peripheral sensory neurons from human embryonic stem cells using small molecule inhibitors. The differentiated neurons express canonical- and modality-specific peripheral sensory neuron markers with subsets exhibiting functional properties of human nociceptive neurons that include tetrodotoxin-resistant sodium currents and repetitive action potentials. Moreover, the derived cells associate with human donor Schwann cells and can be used as a model system to investigate the molecular mechanisms underlying neuronal death following peripheral nerve injury. The quick and efficient derivation of genetically diverse peripheral sensory neurons from human embryonic stem cells offers unlimited access to these specialised cell types and provides an invaluable in vitro model system for future studies.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-153701 (URN)10.1038/s41598-018-34280-3 (DOI)000448589200037 ()30374154 (PubMedID)
Funder
Swedish Research Council, 22292Gunvor och Josef Anérs stiftelseVästerbotten County Council
Available from: 2018-12-05 Created: 2018-12-05 Last updated: 2018-12-05Bibliographically approved
Jones, I., Novikova, L. N., Novikov, L. N., Renardy, M., Ullrich, A., Wiberg, M., . . . Kingham, P. J. (2018). Regenerative effects of human embryonic stem cell-derived neural crest cells for treatment of peripheral nerve injury. Journal of Tissue Engineering and Regenerative Medicine, 12(4), E2099-E2109
Open this publication in new window or tab >>Regenerative effects of human embryonic stem cell-derived neural crest cells for treatment of peripheral nerve injury
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2018 (English)In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 12, no 4, p. E2099-E2109Article in journal (Refereed) Published
Abstract [en]

Surgical intervention is the current gold standard treatment following peripheral nerve injury. However, this approach has limitations, and full recovery of both motor and sensory modalities often remains incomplete. The development of artificial nerve grafts that either complement or replace current surgical procedures is therefore of paramount importance. An essential component of artificial grafts is biodegradable conduits and transplanted cells that provide trophic support during the regenerative process. Neural crest cells are promising support cell candidates because they are the parent population to many peripheral nervous system lineages. In this study, neural crest cells were differentiated from human embryonic stem cells. The differentiated cells exhibited typical stellate morphology and protein expression signatures that were comparable with native neural crest. Conditioned media harvested from the differentiated cells contained a range of biologically active trophic factors and was able to stimulate in vitro neurite outgrowth. Differentiated neural crest cells were seeded into a biodegradable nerve conduit, and their regeneration potential was assessed in a rat sciatic nerve injury model. A robust regeneration front was observed across the entire width of the conduit seeded with the differentiated neural crest cells. Moreover, the up-regulation of several regeneration-related genes was observed within the dorsal root ganglion and spinal cord segments harvested from transplanted animals. Our results demonstrate that the differentiated neural crest cells are biologically active and provide trophic support to stimulate peripheral nerve regeneration. Differentiated neural crest cells are therefore promising supporting cell candidates to aid in peripheral nerve repair.

Keywords
artificial nerve graft, human embryonic stem cells, neural crest cells, peripheral nerve injuries, ripheral nervous system, VELOPMENTAL EVOLUTION, V314B, P95 e Gabsang, 2007, NATURE BIOTECHNOLOGY, V25, P1468
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-147466 (URN)10.1002/term.2642 (DOI)000430395400024 ()29327452 (PubMedID)
Funder
Swedish Research Council, 2014-2306
Available from: 2018-05-28 Created: 2018-05-28 Last updated: 2018-06-09Bibliographically approved
Hagglund, A.-C., Jones, I. & Carlsson, L. (2017). A novel mouse model of anterior segment dysgenesis (ASD): conditional deletion of Tsc1 disrupts ciliary body and iris development. Disease Models and Mechanisms, 10(3), 245-257
Open this publication in new window or tab >>A novel mouse model of anterior segment dysgenesis (ASD): conditional deletion of Tsc1 disrupts ciliary body and iris development
2017 (English)In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 10, no 3, p. 245-257Article in journal (Refereed) Published
Abstract [en]

Development of the cornea, lens, ciliary body and iris within the anterior segment of the eye involves coordinated interaction between cells originating from the ciliary margin of the optic cup, the overlying periocular mesenchyme and the lens epithelium. Anterior segment dysgenesis (ASD) encompasses a spectrum of developmental syndromes that affect these anterior segment tissues. ASD conditions arise as a result of dominantly inherited genetic mutations and result in both ocular-specific and systemic forms of dysgenesis that are best exemplified by aniridia and Axenfeld-Rieger syndrome, respectively. Extensive clinical overlap in disease presentation amongst ASD syndromes creates challenges for correct diagnosis and classification. The use of animal models has therefore proved to be a robust approach for unravelling this complex genotypic and phenotypic heterogeneity. However, despite these successes, it is clear that additional genes that underlie several ASD syndromes remain unidentified. Here, we report the characterisation of a novel mouse model of ASD. Conditional deletion of Tsc1 during eye development leads to a premature upregulation of mTORC1 activity within the ciliary margin, periocular mesenchyme and lens epithelium. This aberrant mTORC1 signalling within the ciliary margin in particular leads to a reduction in the number of cells that express Pax6, Bmp4 and Msx1. Sustained mTORC1 signalling also induces a decrease in ciliary margin progenitor cell proliferation and a consequent failure of ciliary body and iris development in postnatal animals. Our study therefore identifies Tsc1 as a novel candidate ASD gene. Furthermore, the Tsc1-ablated mouse model also provides a valuable resource for future studies concerning the molecular mechanisms underlying ASD and acts as a platform for evaluating therapeutic approaches for the treatment of visual disorders.

Keywords
Tsc1, mTORC1, Pax6, Ciliary body, Iris, Anterior segment dysgenesis
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-133816 (URN)10.1242/dmm.028605 (DOI)000395717100005 ()28250050 (PubMedID)
Available from: 2017-04-18 Created: 2017-04-18 Last updated: 2018-06-09Bibliographically approved
Nilsson, J., Ericsson, M., Joibari, M. M., Anderson, F., Carlsson, L., Nilsson, S. K., . . . Burén, J. (2016). A low-carbohydrate high-fat diet decreases lean mass and impairs cardiac function in pair-fed female C57BL/6J mice. Nutrition & Metabolism, 13, Article ID 79.
Open this publication in new window or tab >>A low-carbohydrate high-fat diet decreases lean mass and impairs cardiac function in pair-fed female C57BL/6J mice
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2016 (English)In: Nutrition & Metabolism, ISSN 1743-7075, E-ISSN 1743-7075, Vol. 13, article id 79Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Excess body fat is a major health issue and a risk factor for the development of numerous chronic diseases. Low-carbohydrate diets like the Atkins Diet are popular for rapid weight loss, but the long-term consequences remain the subject of debate. The Scandinavian low-carbohydrate high-fat (LCHF) diet, which has been popular in Scandinavian countries for about a decade, has very low carbohydrate content (~5 E %) but is rich in fat and includes a high proportion of saturated fatty acids. Here we investigated the metabolic and physiological consequences of a diet with a macronutrient composition similar to the Scandinavian LCHF diet and its effects on the organs, tissues, and metabolism of weight stable mice.

METHODS: Female C57BL/6J mice were iso-energetically pair-fed for 4 weeks with standard chow or a LCHF diet. We measured body composition using echo MRI and the aerobic capacity before and after 2 and 4 weeks on diet. Cardiac function was assessed by echocardiography before and after 4 weeks on diet. The metabolic rate was measured by indirect calorimetry the fourth week of the diet. Mice were sacrificed after 4 weeks and the organ weight, triglyceride levels, and blood chemistry were analyzed, and the expression of key ketogenic, metabolic, hormonal, and inflammation genes were measured in the heart, liver, and adipose tissue depots of the mice using real-time PCR.

RESULTS: The increase in body weight of mice fed a LCHF diet was similar to that in controls. However, while control mice maintained their body composition throughout the study, LCHF mice gained fat mass at the expense of lean mass after 2 weeks. The LCHF diet increased cardiac triglyceride content, impaired cardiac function, and reduced aerobic capacity. It also induced pronounced alterations in gene expression and substrate metabolism, indicating a unique metabolic state.

CONCLUSIONS: Pair-fed mice eating LCHF increased their percentage of body fat at the expense of lean mass already after 2 weeks, and after 4 weeks the function of the heart deteriorated. These findings highlight the urgent need to investigate the effects of a LCHF diet on health parameters in humans.

Place, publisher, year, edition, pages
BioMed Central, 2016
Keywords
Low-carbohydrate diet, Heart, Mouse
National Category
Clinical Medicine Physiology Nutrition and Dietetics Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-128938 (URN)10.1186/s12986-016-0132-8 (DOI)000388140200001 ()27891164 (PubMedID)
Available from: 2016-12-20 Created: 2016-12-20 Last updated: 2018-06-09Bibliographically approved
Jones, I., Hägglund, A.-C., Törnqvist, G., Nord, C., Ahlgren, U. & Carlsson, L. (2015). A novel mouse model of tuberous sclerosis complex (TSC): eye-specific Tsc1-ablation disrupts visual-pathway development. Disease Models and Mechanisms, 8(12), 1517-1529
Open this publication in new window or tab >>A novel mouse model of tuberous sclerosis complex (TSC): eye-specific Tsc1-ablation disrupts visual-pathway development
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2015 (English)In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 8, no 12, p. 1517-1529Article in journal (Refereed) Published
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.

National Category
Other Basic Medicine
Identifiers
urn:nbn:se:umu:diva-120197 (URN)10.1242/dmm.021972 (DOI)000368905300004 ()26449264 (PubMedID)
Available from: 2016-05-11 Created: 2016-05-11 Last updated: 2018-06-07Bibliographically approved
Berghard, A., Hägglund, A.-C., Bohm, S. & Carlsson, L. (2012). Lhx2-dependent specification of olfactory sensory neurons is required for successful integration of olfactory, vomeronasal, and GnRH neurons. The FASEB Journal, 26(8), 3464-3472
Open this publication in new window or tab >>Lhx2-dependent specification of olfactory sensory neurons is required for successful integration of olfactory, vomeronasal, and GnRH neurons
2012 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, no 8, p. 3464-3472Article in journal (Refereed) Published
Abstract [en]

Inactivation of the LIM-homeodomain 2 gene (Lhx2) results in a severe defect in specification of olfactory sensory neurons (OSNs). However, the ramifications of lack of Lhx2-dependent OSN specification for formation of the primary olfactory pathway have not been addressed, since mutant mice die in utero. We have analyzed prenatal and postnatal consequences of conditionally inactivating Lhx2 selectively in OSNs. A cell-autonomous effect is that OSN axons cannot innervate their target, the olfactory bulb. Moreover, the lack of Lhx2 in OSNs causes unpredicted, non-cell-autonomous phenotypes. First, the olfactory bulb shows pronounced hypoplasia in adults, and the data suggest that innervation by correctly specified OSNs is necessary for adult bulb size and organization. Second, absence of an olfactory nerve in the conditional mutant reveals that the vomeronasal nerve is dependent on olfactory nerve formation. Third, the lack of a proper vomeronasal nerve prevents migration of gonadotropin-releasing hormone (GnRH) cells the whole distance to their final positions in the hypothalamus during embryo development. As adults, the conditional mutants do not pass puberty, and these findings support the view of an exclusive nasal origin of GnRH neurons in the mouse. Thus, Lhx2 in OSNs is required for functional development of three separate systems.—Berghard, A., Hägglund, A.-C., Bohm, S., and Carlsson, L. Lhx2-dependent specification of olfactory sensory neurons is required for successful integration of olfactory, vomeronasal, and GnRH neurons.

Place, publisher, year, edition, pages
Federation of American Society of Experimental Biology (FASEB), 2012
Keywords
mouse embryo development, gonadotropin-releasing hormone neurons, puberty phenotype
National Category
Neurosciences Developmental Biology
Identifiers
urn:nbn:se:umu:diva-55206 (URN)10.1096/fj.12-206193 (DOI)
Funder
Swedish Research Council
Available from: 2012-05-13 Created: 2012-05-13 Last updated: 2018-06-08Bibliographically approved
Marcos-Mondejar, P., Peregrin, S., Li, J. Y., Carlsson, L., Tole, S. & Lopez-Bendito, G. (2012). The Lhx2 transcription factor controls Thalamocortical Axonal guidance by specific regulation of Robo1 and Robo2 receptors. Journal of Neuroscience, 32(13), 4372-4385
Open this publication in new window or tab >>The Lhx2 transcription factor controls Thalamocortical Axonal guidance by specific regulation of Robo1 and Robo2 receptors
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2012 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 32, no 13, p. 4372-4385Article in journal (Refereed) Published
Abstract [en]

The assembly of neural circuits is dependent upon the generation of specific neuronal subtypes, each subtype displaying unique properties that direct the formation of selective connections with appropriate target cells. Actions of transcription factors in neural progenitors and postmitotic cells are key regulators in this process. LIM-homeodomain transcription factors control crucial aspects of neuronal differentiation, including subtype identity and axon guidance. Nonetheless, their regulation during development is poorly understood and the identity of the downstream molecular effectors of their activity remains largely unknown. Here, we demonstrate that the Lhx2 transcription factor is dynamically regulated in distinct pools of thalamic neurons during the development of thalamocortical connectivity in mice. Indeed, overexpression of Lhx2 provokes defective thalamocortical axon guidance in vivo, while specific conditional deletion of Lhx2 in the thalamus produces topographic defects that alter projections from the medial geniculate nucleus and from the caudal ventrobasal nucleus in particular. Moreover, we demonstrate that Lhx2 influences axon guidance and the topographical sorting of axons by regulating the expression of Robo1 and Robo2 guidance receptors, which are essential for these axons to establish correct connections in the cerebral cortex. Finally, augmenting Robo1 function restores normal axon guidance in Lhx2-overexpressing neurons. By regulating axon guidance receptors, such as Robo1 and Robo2, Lhx2 differentially regulates the axon guidance program of distinct populations of thalamic neurons, thus enabling the establishment of specific neural connections.

Place, publisher, year, edition, pages
Washington, DC, USA: Social Neuroscience, 2012
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-54326 (URN)10.1523/JNEUROSCI.5851-11.2012 (DOI)000302159400005 ()
Available from: 2012-04-24 Created: 2012-04-24 Last updated: 2018-06-08Bibliographically approved
Hägglund, A.-C., Dahl, L. & Carlsson, L. (2011). Lhx2 is required for patterning and expansion of a distinct progenitor cell population committed to eye development. PLoS ONE, 6(8), e23387
Open this publication in new window or tab >>Lhx2 is required for patterning and expansion of a distinct progenitor cell population committed to eye development
2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8, p. e23387-Article in journal (Refereed) Published
Abstract [en]

Progenitor cells committed to eye development become specified in the prospective forebrain and develop subsequently into the optic vesicle and the optic cup. The optic vesicle induces formation of the lens placode in surface ectoderm from which the lens develops. Numerous transcription factors are involved in this process, including the eye-field transcription factors. However, many of these transcription factors also regulate the patterning of the anterior neural plate and their specific role in eye development is difficult to discern since eye-committed progenitor cells are poorly defined. By using a specific part of the Lhx2 promoter to regulate Cre recombinase expression in transgenic mice we have been able to define a distinct progenitor cell population in the forebrain solely committed to eye development. Conditional inactivation of Lhx2 in these progenitor cells causes an arrest in eye development at the stage when the optic vesicle induces lens placode formation in the surface ectoderm. The eye-committed progenitor cell population is present in the Lhx2(-/-) embryonic forebrain suggesting that commitment to eye development is Lhx2-independent. However, re-expression of Lhx2 in Lhx2(-/-) progenitor cells only promotes development of retinal pigment epithelium cells, indicating that Lhx2 promotes the acquisition of the oligopotent fate of these progenitor cells. This approach also allowed us to identify genes that distinguish Lhx2 function in eye development from that in the forebrain. Thus, we have defined a distinct progenitor cell population in the forebrain committed to eye development and identified genes linked to Lhx2’s function in the expansion and patterning of these progenitor cells.

Place, publisher, year, edition, pages
San Francisco, CA: Public Library of Science, 2011
National Category
Other Biological Topics
Identifiers
urn:nbn:se:umu:diva-46681 (URN)10.1371/journal.pone.0023387 (DOI)21886788 (PubMedID)
Available from: 2011-09-13 Created: 2011-09-09 Last updated: 2018-06-08Bibliographically approved
Törnqvist, G., Sandberg, A., Hägglund, A.-C. & Carlsson, L. (2010). Cyclic expression of lhx2 regulates hair formation.. PLoS genetics, 6(4), e1000904
Open this publication in new window or tab >>Cyclic expression of lhx2 regulates hair formation.
2010 (English)In: PLoS genetics, ISSN 1553-7404, Vol. 6, no 4, p. e1000904-Article in journal (Refereed) Published
Abstract [en]

Hair is important for thermoregulation, physical protection, sensory activity, seasonal camouflage, and social interactions. Hair is generated in hair follicles (HFs) and, following morphogenesis, HFs undergo cyclic phases of active growth (anagen), regression (catagen), and inactivity (telogen) throughout life. The transcriptional regulation of this process is not well understood. We show that the transcription factor Lhx2 is expressed in cells of the outer root sheath and a subpopulation of matrix cells during both morphogenesis and anagen. As the HFs enter telogen, expression becomes undetectable and reappears prior to initiation of anagen in the secondary hair germ. In contrast to previously published results, we find that Lhx2 is primarily expressed by precursor cells outside of the bulge region where the HF stem cells are located. This developmental, stage- and cell-specific expression suggests that Lhx2 regulates the generation and regeneration of hair. In support of this hypothesis, we show that Lhx2 is required for anagen progression and HF morphogenesis. Moreover, transgenic expression of Lhx2 in postnatal HFs is sufficient to induce anagen. Thus, our results reveal an alternative interpretation of Lhx2 function in HFs compared to previously published results, since Lhx2 is periodically expressed, primarily in precursor cells distinct from those in the bulge region, and is an essential positive regulator of hair formation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-33655 (URN)10.1371/journal.pgen.1000904 (DOI)000277354200021 ()20386748 (PubMedID)
Available from: 2010-04-30 Created: 2010-04-30 Last updated: 2018-06-08Bibliographically approved
Carlsson, L. (2010). Periodiskt uttryck av genen Lhx2 reglerar hårväxten. Läkartidningen, 107(24-25), 1616
Open this publication in new window or tab >>Periodiskt uttryck av genen Lhx2 reglerar hårväxten
2010 (Swedish)In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 24-25, p. 1616-Article in journal (Other academic) Published
Keywords
Hår, LHX2 protein, human, Hårsäck, Genuttryck
Identifiers
urn:nbn:se:umu:diva-42854 (URN)
Available from: 2011-04-14 Created: 2011-04-14 Last updated: 2018-06-08Bibliographically approved
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