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Lekholm, Emilia
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Hoeber, J., König, N., Trolle, C., Lekholm, E., Zhou, C., Pankratova, S., . . . Kozlova, E. (2017). A Combinatorial Approach to Induce Sensory Axon Regeneration into the Dorsal Root Avulsed Spinal Cord. Stem Cells and Development, 26(14), 1065-1077
Åpne denne publikasjonen i ny fane eller vindu >>A Combinatorial Approach to Induce Sensory Axon Regeneration into the Dorsal Root Avulsed Spinal Cord
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2017 (engelsk)Inngår i: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 26, nr 14, s. 1065-1077Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Spinal root injuries result in newly formed glial scar formation, which prevents regeneration of sensory axons causing permanent sensory loss. Previous studies showed that delivery of trophic factors or implantation of human neural progenitor cells supports sensory axon regeneration and partly restores sensory functions. In this study, we elucidate mechanisms underlying stem cell-mediated ingrowth of sensory axons after dorsal root avulsion (DRA). We show that human spinal cord neural stem/progenitor cells (hscNSPC), and also, mesoporous silica particles loaded with growth factor mimetics (MesoMIM), supported sensory axon regeneration. However, when hscNSPC and MesoMIM were combined, sensory axon regeneration failed. Morphological and tracing analysis showed that sensory axons grow through the newly established glial scar along "bridges" formed by migrating stem cells. Coimplantation of MesoMIM prevented stem cell migration, "bridges" were not formed, and sensory axons failed to enter the spinal cord. MesoMIM applied alone supported sensory axons ingrowth, but without affecting glial scar formation. In vitro, the presence of MesoMIM significantly impaired migration of hscNSPC without affecting their level of differentiation. Our data show that (1) the ability of stem cells to migrate into the spinal cord and organize cellular "bridges" in the newly formed interface is crucial for successful sensory axon regeneration, (2) trophic factor mimetics delivered by mesoporous silica may be a convenient alternative way to induce sensory axon regeneration, and (3) a combinatorial approach of individually beneficial components is not necessarily additive, but can be counterproductive for axonal growth.

Emneord
biomimetics, neural stem cells, spinal cord regeneration, stem cell transplantation
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-328587 (URN)10.1089/scd.2017.0019 (DOI)000405071200005 ()28562227 (PubMedID)
Forskningsfinansiär
Stiftelsen Olle Engkvist ByggmästareSwedish Research Council, 20716
Merknad

De två första författarna delar förstaförfattarskapet.

Tilgjengelig fra: 2017-08-28 Laget: 2017-08-28 Sist oppdatert: 2018-01-13bibliografisk kontrollert
Lekholm, E., Perland, E., Eriksson, M. M., Hellsten, S. V., Lindberg, F. A., Rostami, J. & Fredriksson, R. (2017). Putative Membrane-Bound Transporters MFSD14A and MFSD14B Are Neuronal and Affected by Nutrient Availability. Frontiers in Molecular Neuroscience, 10, Article ID 11.
Åpne denne publikasjonen i ny fane eller vindu >>Putative Membrane-Bound Transporters MFSD14A and MFSD14B Are Neuronal and Affected by Nutrient Availability
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2017 (engelsk)Inngår i: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 10, artikkel-id 11Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Characterization of orphan transporters is of importance due to their involvement in cellular homeostasis but also in pharmacokinetics and pharmacodynamics. The tissue and cellular localization, as well as function, is still unknown for many of the solute carriers belonging to the major facilitator superfamily (MFS) Pfam clan. Here, we have characterized two putative novel transporters MFSD14A (HIAT1) and MFSD14B (HIATL1) in the mouse central nervous system and found protein staining throughout the adult mouse brain. Both transporters localized to neurons and MFSD14A co-localized with the Golgi marker Giantin in primary embryonic cortex cultures, while MFSD14B staining co-localized with an endoplasmic retention marker, KDEL. Based on phylogenetic clustering analyses, we predict both to have organic substrate profiles, and possible involvement in energy homeostasis. Therefore, we monitored gene regulation changes in mouse embryonic primary cultures after amino acid starvations and found both transporters to be upregulated after 3 h of starvation. Interestingly, in mice subjected to 24 h of food starvation, both transporters were downregulated in the hypothalamus, while Mfsdl4a was also downregulated in the brainstem. In addition, in mice fed a high fat diet (HFD), upregulation of both transporters was seen in the striatum. Both MFSD14A and MFSD14B were intracellular neuronal membrane bound proteins, expressed in the Golgi and Endoplasmic reticulum, affected by both starvation and HFD to varying degree in the mouse brain.

Emneord
MFSD14A, HIAT1, MFSD14B, HIATL1, SLC, MFSD, transporter protein
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-316413 (URN)10.3389/fnmol.2017.00011 (DOI)000392751300001 ()28179877 (PubMedID)
Forskningsfinansiär
Swedish Research CouncilThe Swedish Brain FoundationSwedish Society for Medical Research (SSMF)Novo NordiskMagnus Bergvall Foundation
Tilgjengelig fra: 2017-03-02 Laget: 2017-03-02 Sist oppdatert: 2017-11-29bibliografisk kontrollert
Lekholm, E. (2017). Solute Carriers in Metabolism: Regulation of known and putative solute carriers in the central nervous system. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Åpne denne publikasjonen i ny fane eller vindu >>Solute Carriers in Metabolism: Regulation of known and putative solute carriers in the central nervous system
2017 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Solute carriers (SLCs) are membrane-bound transporter proteins, important for nutrient, ion, drug and metabolite transport across membranes. A quarter of the human genome codes for membrane-bound proteins, and SLCs make up the largest group of transporter proteins. Due to their ability to transport a large repertoire of substances across, not just the plasma membrane, but also the membrane of internal organelles, they hold a key position in maintaining homeostasis affecting metabolic pathways. Unfortunately, some of the more than 400 identified SLCs are still not fully characterized, even though a quarter of these are associated with human disease. In addition, there are about 30 membrane-bound proteins with strong resemblance to SLCs, of which very little is known. The aim of this thesis is to characterize some of these putative SLCs, focusing on their localization and function in the central nervous system. Since many of the known SLCs play a vital part in metabolism and related pathways, the response to different nutritional conditions has been used as a key method. MFSD14A and MFSD14B, characterized in Paper I, are putative SLCs belonging to the Major Facilitator Superfamily (MFS) and found to be neuronal, differentially expressed in the mouse central nervous system and transiently upregulated in mouse embryonic cortex cultures due to amino acid deprivation. They were also altered in areas of the mouse brain after starvation as well as after high fat diet. In Paper II, the effect on gene regulation due to complete amino acid starvation was monitored in a mouse hypothalamic cell line and 47 different genes belonging to SLCs, or putative SLCs, were found to be affected. Of these, 15 genes belonged to already known amino acid transporters, whereas 32 were putative SLCs with no known function or SLCs not known to react to amino acids. The three SV2 proteins, SV2A, SV2B and SV2C, were studied in Paper III using human neuroblastoma cell lines. The high metabolic state of cancers often result in an upregulation and alteration of transporter proteins, and alterations of the SV2 proteins were found following different treatments performed in this study. Paper IV focused on putative SLCs of MFS type and their role in glucose metabolism. Mouse embryonic cortex cultures were subjected to glucose starvation and the gene expression of 19 putative transporters were analyzed. All but four of the putative transporters were affected either at 3h or 12h of glucose deprivation. In conclusion, several SLCs and putative SLCs studied in this thesis are strongly affected by alteration in metabolism, either due to amino acids or glucose or both. This makes the putative SLCs dynamic membrane-bound proteins, possibly transporters, highly affected by nutritional status and most likely regulated to maintain homeostasis.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2017. s. 44
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1380
Emneord
Solute Carriers, transporter, amino acid starvation, glucose metabolism, MFS, SV2
HSV kategori
Forskningsprogram
Medicinsk vetenskap
Identifikatorer
urn:nbn:se:uu:diva-331328 (URN)978-91-513-0104-4 (ISBN)
Disputas
2017-11-30, B21, Biomedicinskt Centrum (BMC), Husargatan 3, Uppsala, 09:30 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2017-11-07 Laget: 2017-10-12 Sist oppdatert: 2018-01-13
Hellsten, S. V., Lekholm, E., Ahmad, T. & Fredriksson, R. (2017). The gene expression of numerous SLC transporters is altered in the immortalized hypothalamic cell line N25/2 following amino acid starvation. FEBS Open Bio, 7(2), 249-264
Åpne denne publikasjonen i ny fane eller vindu >>The gene expression of numerous SLC transporters is altered in the immortalized hypothalamic cell line N25/2 following amino acid starvation
2017 (engelsk)Inngår i: FEBS Open Bio, E-ISSN 2211-5463, Vol. 7, nr 2, s. 249-264Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Amino acids are known to play a key role in gene expression regulation,and in mammalian cells, amino acid signaling is mainly mediated via twopathways, the mammalian target of rapamycin complex 1 (mTORC1) pathwayand the amino acid responsive (AAR) pathway. It is vital for cells tohave a system to sense amino acid levels, in order to control protein andamino acid synthesis and catabolism. Amino acid transporters are crucialin these pathways, due to both their sensing and transport functions. Inthis large-scale study, an immortalized mouse hypothalamic cell line (N25/2)was used to study the gene expression changes following 1, 2, 3, 5 or 16 hof amino acid starvation. We focused on genes encoding solute carriers(SLCs) and putative SLCs, more specifically on amino acid transporters.The microarray contained 28 270 genes and 86.2% of the genes wereexpressed in the cell line. At 5 h of starvation, 1001 genes were upregulatedand 848 genes were downregulated, and among these, 47 genes from theSLC superfamily or atypical SLCs were found. Of these, 15 were genesencoding amino acid transporters and 32 were genes encoding other SLCsor atypical SLCs. Increased expression was detected for genes encodingamino acid transporters from system A, ASC, L, N, T, xc-, and y+. UsingGO annotations, genes involved in amino acid transport and amino acidtransmembrane transporter activity were found to be most upregulated at3 h and 5 h of starvation.

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-331260 (URN)10.1002/2211-5463.12181 (DOI)000397220400011 ()28174690 (PubMedID)
Forskningsfinansiär
Swedish Research CouncilNovo NordiskStiftelsen Olle Engkvist ByggmästareMagnus Bergvall Foundation
Tilgjengelig fra: 2017-10-12 Laget: 2017-10-12 Sist oppdatert: 2018-09-07bibliografisk kontrollert
Hellsten, S. V., Eriksson, M., Lekholm, E., Arapi, V., Perland, E. & Fredriksson, R. (2017). The gene expression of the neuronal protein, SLC38A9, changes in mouse brain after in vivo starvation and high-fat diet. PLoS ONE, 12(2), Article ID e0172917.
Åpne denne publikasjonen i ny fane eller vindu >>The gene expression of the neuronal protein, SLC38A9, changes in mouse brain after in vivo starvation and high-fat diet
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2017 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 2, artikkel-id e0172917Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

SLC38A9 is characterized as a lysosomal component of the amino acid sensing RagulatorRAG GTPase complex, controlling the mechanistic target of rapamycin complex 1 (mTORC1). Here, immunohistochemistry was used to map SLC38A9 in mouse brain and staining was detected throughout the brain, in cortex, hypothalamus, thalamus, hippocampus, brainstem and cerebellum. More specifically, immunostaining was found in areas known to be involved in amino acid sensing and signaling pathways e.g. piriform cortex and hypothalamus. SLC38A9 immunoreactivity co-localized with both GABAergic and glutamatergic neurons, but not with astrocytes. SLC38A9 play a key role in the mTORC1 pathway, and therefore we performed in vivo starvation and high-fat diet studies, to measure gene expression alterations in specific brain tissues and in larger brain regions. Following starvation, Slc38a9 was upregulated in brainstem and cortex, and in anterior parts of the brain (Bregma 3.2 to -2.1mm). After high-fat diet, Slc38a9 was specifically upregulated in hypothalamus, while overall downregulation was noticed throughout the brain (Bregma 3.2 to -8.6mm).

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-318954 (URN)10.1371/journal.pone.0172917 (DOI)000394688200168 ()
Forskningsfinansiär
Swedish Research CouncilThe Swedish Brain FoundationNovo NordiskMagnus Bergvall Foundation
Tilgjengelig fra: 2017-03-30 Laget: 2017-03-30 Sist oppdatert: 2017-11-29bibliografisk kontrollert
Eriksson, M., Lekholm, E., Hellsten, S. V., Perland, E. & Fredriksson, R. (2017). The Neuronal and Peripheral Expressed Membrane-Bound UNC93A Respond to Nutrient Availability in Mice. Frontiers in Molecular Neuroscience, 10, Article ID 351.
Åpne denne publikasjonen i ny fane eller vindu >>The Neuronal and Peripheral Expressed Membrane-Bound UNC93A Respond to Nutrient Availability in Mice
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2017 (engelsk)Inngår i: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 10, artikkel-id 351Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Many transporters such as the solute carriers belonging to the Major facilitator superfamily Pfam clan are orphans in that their tissue and cellular localization as well as substrate profile and function are still unknown. Here we have characterized the putative solute carrier UNC93A. We aimed to investigate the expression profile on both protein and mRNA level of UNC93A in mouse since it has not been clarified. UNC93A staining was found in cortex, hippocampus and cerebellum. It was found to be expressed in many neurons, but not all, with staining located in close proximity to the plasma membrane. Furthermore, we aimed to extend the starvation data available for Unc93a in hypothalamic cell cultures from mouse. We investigated the Unc93a alterations with focus on amino acid deprivation in embryonic cortex cells from mice as well as 24 h starvation in adult male mice and compared it to recently studied putative and known solute carriers. Unc93a expression was found both in the brain and peripheral organs, in low to moderate levels in the adult mice and was affected by amino acid deprivation in embryonic cortex cultures and starvation in in vivo samples. In conclusion, the membrane-bound UNC93A is expressed in both the brain and peripheral tissues and responds to nutrient availability in mice.

sted, utgiver, år, opplag, sider
FRONTIERS MEDIA SA, 2017
Emneord
UNC93A, SLC, MFS, MFSD, transporter protein, starvation
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-340711 (URN)10.3389/fnmol.2017.00351 (DOI)000414018600001 ()29163028 (PubMedID)
Forskningsfinansiär
Swedish Research Council
Tilgjengelig fra: 2018-02-02 Laget: 2018-02-02 Sist oppdatert: 2018-02-02bibliografisk kontrollert
Perland, E., Hellsten, S. V., Lekholm, E., Eriksson, M. M., Arapi, V. & Fredriksson, R. (2017). The Novel Membrane-Bound Proteins MFSD1 and MFSD3 are Putative SLC Transporters Affected by Altered Nutrient Intake. Journal of Molecular Neuroscience, 61(2), 199-214
Åpne denne publikasjonen i ny fane eller vindu >>The Novel Membrane-Bound Proteins MFSD1 and MFSD3 are Putative SLC Transporters Affected by Altered Nutrient Intake
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2017 (engelsk)Inngår i: Journal of Molecular Neuroscience, ISSN 0895-8696, E-ISSN 1559-1166, Vol. 61, nr 2, s. 199-214Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Membrane-bound solute carriers (SLCs) are essential as they maintain several physiological functions, such as nutrient uptake, ion transport and waste removal. The SLC family comprise about 400 transporters, and we have identified two new putative family members, major facilitator superfamily domain containing 1 (MFSD1) and 3 (MFSD3). They cluster phylogenetically with SLCs of MFS type, and both proteins are conserved in chordates, whileMFSD1 is also found in fruit fly. Based on homology modelling, we predict 12 transmembrane regions, a common feature for MFS transporters. The genes are expressed in abundance in mice, with specific protein staining along the plasma membrane in neurons. Deprivingm ouse embryonic primary cortex cells of amino acids resulted in upregulation of Mfsd1, whereas Mfsd3 is unaltered. Furthermore, in vivo, Mfsd1 and Mfsd3 are down-regulated in anterior brain sections in mice subjected to starvation, while upregulated specifically in brainstem. Mfsd3 is also attenuated in cerebellum after starvation. In mice raised on high-fat diet, Mfsd1 was specifically downregulated in brainstem and hypothalamus, while Mfsd3 was reduced consistently throughout the brain.

sted, utgiver, år, opplag, sider
HUMANA PRESS INC, 2017
Emneord
MFSD1, MFSD3, SLC, Protein expression
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-320771 (URN)10.1007/s12031-016-0867-8 (DOI)000396263800008 ()27981419 (PubMedID)
Forskningsfinansiär
Swedish Research CouncilThe Swedish Brain FoundationSwedish Society for Medical Research (SSMF)Novo Nordisk
Tilgjengelig fra: 2017-04-25 Laget: 2017-04-25 Sist oppdatert: 2017-10-12bibliografisk kontrollert
Hellsten, S. V., Perland, E., Lekholm, E., Ahmad, T., Yamskova, O. & Fredriksson, R. (2016). Amino acid deprivation of neuronal cells changes expression levels of numerous transporters from the SLC family, including several members of the SLC38 family.
Åpne denne publikasjonen i ny fane eller vindu >>Amino acid deprivation of neuronal cells changes expression levels of numerous transporters from the SLC family, including several members of the SLC38 family
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2016 (engelsk)Artikkel i tidsskrift (Fagfellevurdert) Submitted
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-275718 (URN)
Tilgjengelig fra: 2016-02-12 Laget: 2016-02-05 Sist oppdatert: 2018-01-10bibliografisk kontrollert
Roshanbin, S., Lindberg, F., Lekholm, E., Perland, E., Eriksson, M., Åhlund, J., . . . Fredriksson, R. (2016). Histological characterization of orphan transporter MCT14 (SLC16A14) shows abundant expression in mouse CNS and kidney. BMC neuroscience (Online), 17, Article ID 43.
Åpne denne publikasjonen i ny fane eller vindu >>Histological characterization of orphan transporter MCT14 (SLC16A14) shows abundant expression in mouse CNS and kidney
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2016 (engelsk)Inngår i: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 17, artikkel-id 43Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Background: MCT14 (SLC16A14) is an orphan member of the monocarboxylate transporter (MCT) family, also known as the SLC16 family of secondary active transmembrane transporters. Available expression data for this transporter is limited, and in this paper we aim to characterize MCT14 with respect to tissue distribution and cellular localization in mouse brain. Results: Using qPCR, we found that Slc16a14 mRNA was highly abundant in mouse kidney and moderately in central nervous system, testis, uterus and liver. Using immunohistochemistry and in situ hybridization, we determined that MCT14 was highly expressed in excitatory and inhibitory neurons as well as epithelial cells in the mouse brain. The expression was exclusively localized to the soma of neurons. Furthermore, we showed with our phylogenetic analysis that MCT14 most closely relate to the aromatic amino acid- and thyroid-hormone transporters MCT8 (SLC16A2) and MCT10 (SLC16A10), in addition to the carnitine transporter MCT9 (SLC16A9). Conclusions: We provide here the first histological mapping of MCT14 in the brain and our data are consistent with the hypothesis that MCT14 is a neuronal aromatic-amino-acid transporter.

Emneord
Monocarboxylate; Transporter; Mouse; Amino acid
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-282951 (URN)10.1186/s12868-016-0274-7 (DOI)000379823100001 ()27364523 (PubMedID)
Forskningsfinansiär
Swedish Research CouncilThe Swedish Brain FoundationSwedish Society for Medical Research (SSMF)Novo Nordisk
Tilgjengelig fra: 2016-04-10 Laget: 2016-04-08 Sist oppdatert: 2017-11-30bibliografisk kontrollert
Perland, E., Lekholm, E., Eriksson, M. M., Bagchi, S., Arapi, V. & Fredriksson, R. (2016). The Putative SLC Transporters Mfsd5 and Mfsd11 Are Abundantly Expressed in the Mouse Brain and Have a Potential Role in Energy Homeostasis. PLoS ONE, 11(6), Article ID e0156912.
Åpne denne publikasjonen i ny fane eller vindu >>The Putative SLC Transporters Mfsd5 and Mfsd11 Are Abundantly Expressed in the Mouse Brain and Have a Potential Role in Energy Homeostasis
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2016 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 6, artikkel-id e0156912Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Background Solute carriers (SLCs) are membrane bound transporters responsible for the movement of soluble molecules such as amino acids, ions, nucleotides, neurotransmitters and oligopeptides over cellular membranes. At present, there are 395 SLCs identified in humans, where about 40% are still uncharacterized with unknown expression and/or function(s). Here we have studied two uncharacterized atypical SLCs that belong to the Major Facilitator Superfamily Pfam clan, Major facilitator superfamily domain 5 (MFSD5) and Major facilitator superfamily domain 11 (MFSD11). We provide fundamental information about the histology in mice as well as data supporting their disposition to regulate expression levels to keep the energy homeostasis. Results In mice subjected to starvation or high-fat diet, the mRNA expression of Mfsd5 was significantly down-regulated (P<0.001) in food regulatory brain areas whereas Mfsd11 was significantly up-regulated in mice subjected to either starvation (P<0.01) or high-fat diet (P< 0.001). qRT-PCR analysis on wild type tissues demonstrated that both Mfsd5 and Mfsd11 have a wide central and peripheral mRNA distribution, and immunohistochemistry was utilized to display the abundant protein expression in the mouse embryo and the adult mouse brain. Both proteins are expressed in excitatory and inhibitory neurons, but not in astrocytes. Conclusions Mfsd5 and Mfsd11 are both affected by altered energy homeostasis, suggesting plausible involvement in the energy regulation. Moreover, the first histological mapping of MFSD5 and MFSD11 shows ubiquitous expression in the periphery and the central nervous system of mice, where the proteins are expressed in excitatory and inhibitory mouse brain neurons.

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-299580 (URN)10.1371/journal.pone.0156912 (DOI)000377561000047 ()27272503 (PubMedID)
Forskningsfinansiär
Swedish Research CouncilThe Swedish Brain FoundationNovo Nordisk
Tilgjengelig fra: 2016-07-22 Laget: 2016-07-22 Sist oppdatert: 2018-01-10bibliografisk kontrollert
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