| 1. |
- Butwicka, Agnieszka, et al.
(författare)
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Association of Childhood-Onset Inflammatory Bowel Disease With Risk of Psychiatric Disorders and Suicide Attempt
- 2019
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Ingår i: JAMA pediatrics. - : American Medical Association. - 2168-6203 .- 2168-6211. ; 173:10, s. 969-978
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Inflammatory bowel disease (IBD) has been associated with psychiatric morbidity in adults, although previous studies have not accounted for familial confounding. In children, IBD has an even more severe course, but the association between childhood-onset IBD and psychiatric morbidity remains unclear.Objective: To examine the risk of psychiatric morbidity in individuals with childhood-onset IBD, controlling for potential confounding shared between siblings.Design, Setting, and Participants: A population-based cohort study was conducted using data from the Swedish national health care and population registers of all children younger than 18 years born from 1973 to 2013. The study included 6464 individuals with a diagnosis of childhood-onset IBD (3228 with ulcerative colitis, 2536 with Crohn disease, and 700 with IBD unclassified) who were compared with 323 200 matched reference individuals from the general population and 6999 siblings of patients with IBD. Cox proportional hazards regression was used to estimate hazard ratios (HRs) with 95% CIs. Statistical analysis was performed from January 1, 1973, to December 1, 2013.Main Outcomes and Measures: The primary outcome was any psychiatric disorder and suicide attempt. Secondary outcomes were the following specific psychiatric disorders: psychotic, mood, anxiety, eating, personality, and behavioral disorders; substance misuse; attention-deficit/hyperactivity disorder; autism spectrum disorders; and intellectual disability.Results: The study included 6464 individuals with a diagnosis of childhood-onset IBD (2831 girls and 3633 boys; mean [SD] age at diagnosis of IBD, 13 [4] years). During a median follow-up time of 9 years, 1117 individuals with IBD (17.3%) received a diagnosis of any psychiatric disorder (incidence rate, 17.1 per 1000 person-years), compared with 38 044 of 323 200 individuals (11.8%) in the general population (incidence rate, 11.2 per 1000 person-years), corresponding to an HR of 1.6 (95% CI, 1.5-1.7), equaling 1 extra case of any psychiatric disorder per 170 person-years. Inflammatory bowel disease was significantly associated with suicide attempt (HR, 1.4; 95% CI, 1.2-1.7) as well as mood disorders (HR, 1.6; 95% CI, 1.4-1.7), anxiety disorders (HR, 1.9; 95% CI, 1.7-2.0) eating disorders (HR, 1.6; 95% CI, 1.3-2.0), personality disorders (HR, 1.4; 95% CI, 1.1-1.8), attention-deficit/hyperactivity disorder (HR, 1.2; 95% CI, 1.1-1.4), and autism spectrum disorders (HR, 1.4; 95% CI, 1.1-1.7) Results were similar for boys and girls. Hazard ratios for any psychiatric disorder were highest in the first year of follow-up but remained statistically significant after more than 5 years. Psychiatric disorders were particularly common for patients with very early-onset IBD (<6 years) and for patients with a parental psychiatric history. Results were largely confirmed by sibling comparison, with similar estimates noted for any psychiatric disorder (HR, 1.6; 95% CI, 1.5-1.8) and suicide attempt (HR, 1.7; 95% CI, 1.2-2.3).Conclusions and Relevance: Overall, childhood-onset IBD was associated with psychiatric morbidity, confirmed by between-sibling results. Particularly concerning is the increased risk of suicide attempt, suggesting that long-term psychological support be considered for patients with childhood-onset IBD.
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| 2. |
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| 3. |
- Ryden, Mikael, et al.
(författare)
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Transplanted Bone Marrow-Derived Cells Contribute to Human Adipogenesis
- 2015
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 22:3, s. 408-417
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Tidskriftsartikel (refereegranskat)abstract
- Because human white adipocytes display a high turnover throughout adulthood, a continuous supply of precursor cells is required to maintain adipogenesis. Bone marrow (BM)-derived progenitor cells may contribute to mammalian adipogenesis; however, results in animal models are conflicting. Here we demonstrate in 65 subjects who underwent allogeneic BM or peripheral blood stem cell (PBSC) transplantation that, over the entire lifespan, BM/PBSC-derived progenitor cells contribute similar to 10% to the subcutaneous adipocyte population. While this is independent of gender, age, and different transplantation-related parameters, body fat mass exerts a strong influence, with up to 2.5-fold increased donor cell contribution in obese individuals. Exome and whole-genome sequencing of single adipocytes suggests that BM/PBSC-derived progenitors contribute to adipose tissue via both differentiation and cell fusion. Thus, at least in the setting of transplantation, BM serves as a reservoir for adipocyte progenitors, particularly in obese subjects.
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| 4. |
- Andersson, Alma, et al.
(författare)
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Spatial deconvolution of HER2-positive breast cancer delineates tumor-associated cell type interactions
- 2021
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- In the past decades, transcriptomic studies have revolutionized cancer treatment and diagnosis. However, tumor sequencing strategies typically result in loss of spatial information, critical to understand cell interactions and their functional relevance. To address this, we investigate spatial gene expression in HER2-positive breast tumors using Spatial Transcriptomics technology. We show that expression-based clustering enables data-driven tumor annotation and assessment of intra- and interpatient heterogeneity; from which we discover shared gene signatures for immune and tumor processes. By integration with single cell data, we spatially map tumor-associated cell types to find tertiary lymphoid-like structures, and a type I interferon response overlapping with regions of T-cell and macrophage subset colocalization. We construct a predictive model to infer presence of tertiary lymphoid-like structures, applicable across tissue types and technical platforms. Taken together, we combine different data modalities to define a high resolution map of cellular interactions in tumors and provide tools generalizing across tissues and diseases. While transcriptomics have enhanced our understanding for cancer, spatial transcriptomics enable the characterisation of cellular interactions. Here, the authors integrate single cell data with spatial information for HER2 + tumours and develop tools for the prediction of interactions between tumour-infiltrating cells.
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| 5. |
- Andersson, Alma, et al.
(författare)
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Spatial Deconvolution of HER2-positive Breast Tumors Reveals Novel Intercellular Relationships
- 2020
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- In the past decades, transcriptomic studies have revolutionized cancer treatment and diagnosis. However, tumor sequencing strategies typically result in loss of spatial information, critical to understand cell interactions and their functional relevance. To address this, we investigate spatial gene expression in HER2-positive breast tumors using Spatial Transcriptomics technology. We show that expression-based clustering enables data-driven tumor annotation and assessment of intra-and interpatient heterogeneity; from which we discover shared gene signatures for immune and tumor processes. We integrate and spatially map tumor-associated types from single cell data to find: segregated epithelial cells, interactions between B and T-cells and myeloid cells, co-localization of macrophage and T-cell subsets. A model is constructed to infer presence of tertiary lymphoid structures, applicable across tissue types and technical platforms. Taken together, we combine different data modalities to define novel interactions between tumor-infiltrating cells in breast cancer and provide tools generalizing across tissues and diseases.
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| 6. |
- Arner, Erik, et al.
(författare)
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Adipocyte Turnover : Relevance to Human Adipose Tissue Morphology
- 2010
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 59:1, s. 105-109
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-Adipose tissue may contain few large adipocytes (hypertrophy) or many small adipocytes (hyperplasia). We investigated factors of putative importance for adipose tissue morphology. RESEARCH DESIGN AND METHODS-Subcutaneous adipocyte size and total fat mass were compared in 764 subjects with BMI 18-60 kg/m(2). A morphology value was defined as tire difference between the measured adipocyte volume and the expected volume given by a curved-line fit for a given body fat mass and was related to insulin values. In 35 subjects, in vivo adipocyte turnover was measured by exploiting incorporation of atmospheric C-14 into DNA. RESULTS-Occurrence of hyperplasia (negative morphology value) or hypertrophy (positive morphology value) was independent of sex and body weight but con-elated with fasting plasma insulin levels and insulin sensitivity, independent of adipocyte volume (beta-coefficient = 0.3, P < 0.0001). Total adipocyte number and morphology were negatively related (r = -0.66); i.e., the total adipocyte number was greatest in pronounced hyperplasia and smallest in pronounced hypertrophy. The absolute number of new adipocytes generated each year was 70% lower (P < 0.001) in hypertrophy than in hyperplasia, and individual values for adipocyte generation and morphology were strongly related (r = 0.7, P < 0.001). The relative death rate (similar to 10% per year) or mean age of adipocytes (similar to 10 years) was not correlated with morphology. CONCLUSIONS-Adipose tissue morphology correlates with insulin measures and is linked to the total adipocyte number independently of sex and body fat level. Low generation rates of adipocytes associate with adipose tissue hypertrophy, whereas high generation rates associate with adipose hyperplasia. Diabetes 59:105-109, 2010
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| 7. |
- Bergmann, Olaf, et al.
(författare)
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Cardiomyocyte Renewal in Humans
- 2012
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Ingår i: Circulation Research. - 0009-7330 .- 1524-4571. ; 110:1, s. 17-18
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 8. |
- Bergmann, Olaf, et al.
(författare)
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Dynamics of Cell Generation and Turnover in the Human Heart.
- 2015
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Ingår i: Cell. - : Elsevier BV. - 1097-4172 .- 0092-8674. ; 161:7, s. 1566-1575
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Tidskriftsartikel (refereegranskat)abstract
- The contribution of cell generation to physiological heart growth and maintenance in humans has been difficult to establish and has remained controversial. We report that the full complement of cardiomyocytes is established perinataly and remains stable over the human lifespan, whereas the numbers of both endothelial and mesenchymal cells increase substantially from birth to early adulthood. Analysis of the integration of nuclear bomb test-derived (14)C revealed a high turnover rate of endothelial cells throughout life (>15% per year) and more limited renewal of mesenchymal cells (<4% per year in adulthood). Cardiomyocyte exchange is highest in early childhood and decreases gradually throughout life to <1% per year in adulthood, with similar turnover rates in the major subdivisions of the myocardium. We provide an integrated model of cell generation and turnover in the human heart. VIDEO ABSTRACT.
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| 9. |
- Bergmann, Olaf, et al.
(författare)
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Evidence for Cardiomyocyte Renewal in Humans
- 2009
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 324:5923, s. 98-102
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Tidskriftsartikel (refereegranskat)abstract
- It has been difficult to establish whether we are limited to the heart muscle cells we are born with or if cardiomyocytes are generated also later in life. We have taken advantage of the integration of carbon-14, generated by nuclear bomb tests during the Cold War, into DNA to establish the age of cardiomyocytes in humans. We report that cardiomyocytes renew, with a gradual decrease from 1% turning over annually at the age of 25 to 0.45% at the age of 75. Fewer than 50% of cardiomyocytes are exchanged during a normal life span. The capacity to generate cardiomyocytes in the adult human heart suggests that it may be rational to work toward the development of therapeutic strategies aimed at stimulating this process in cardiac pathologies.
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| 10. |
- Bergmann, Olaf, et al.
(författare)
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Turnover of Human Cardiomyocytes
- 2008
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Ingår i: Circulation Research. - 0009-7330. ; 103:12, s. 1494-1495
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Konferensbidrag (refereegranskat)
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| 11. |
- Bhardwaj, R. D., et al.
(författare)
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Neocortical neurogenesis in humans is restricted to development.
- 2006
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 103:33, s. 12564-8
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Tidskriftsartikel (refereegranskat)abstract
- Stem cells generate neurons in discrete regions in the postnatal mammalian brain. However, the extent of neurogenesis in the adult human brain has been difficult to establish. We have taken advantage of the integration of (14)C, generated by nuclear bomb tests during the Cold War, in DNA to establish the age of neurons in the major areas of the human cerebral neocortex. Together with the analysis of the neocortex from patients who received BrdU, which integrates in the DNA of dividing cells, our results demonstrate that, whereas nonneuronal cells turn over, neurons in the human cerebral neocortex are not generated in adulthood at detectable levels but are generated perinatally.
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| 12. |
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| 13. |
- Borgström, Erik, et al.
(författare)
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Comparison of whole genome amplification techniques for human single cell exome sequencing
- 2017
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 12:2
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Tidskriftsartikel (refereegranskat)abstract
- Background Whole genome amplification (WGA) is currently a prerequisite for single cell whole genome or exome sequencing. Depending on the method used the rate of artifact formation, allelic dropout and sequence coverage over the genome may differ significantly. Results The largest difference between the evaluated protocols was observed when analyzing the target coverage and read depth distribution. These differences also had impact on the downstream variant calling. Conclusively, the products from the AMPLI1 and MALBAC kits were shown to be most similar to the bulk samples and are therefore recommended for WGA of single cells. Discussion In this study four commercial kits for WGA (AMPLI1, MALBAC, Repli-G and PicoPlex) were used to amplify human single cells. The WGA products were exome sequenced together with non-amplified bulk samples from the same source. The resulting data was evaluated in terms of genomic coverage, allelic dropout and SNP calling.
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| 14. |
- Butwicka, Agnieszka, et al.
(författare)
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Celiac disease is associated with childhood psychiatric disorders : A Population-Based Study
- 2017
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Ingår i: Journal of Pediatrics. - : Elsevier. - 0022-3476 .- 1097-6833. ; 184, s. 87-93.e1
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To determine the risk of future childhood psychiatric disorders in celiac disease, assess the association between previous psychiatric disorders and celiac disease in children, and investigate the risk of childhood psychiatric disorders in siblings of celiac disease probands.STUDY DESIGN: This was a nationwide registry-based matched cohort study in Sweden with 10 903 children (aged <18 years) with celiac disease and 12 710 of their siblings. We assessed the risk of childhood psychiatric disorders (any psychiatric disorder, psychotic disorder, mood disorder, anxiety disorder, eating disorder, psychoactive substance misuse, behavioral disorder, attention-deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and intellectual disability). HRs of future psychiatric disorders in children with celiac disease and their siblings was estimated by Cox regression. The association between previous diagnosis of a psychiatric disorder and current celiac disease was assessed using logistic regression.RESULTS: Compared with the general population, children with celiac disease had a 1.4-fold greater risk of future psychiatric disorders. Childhood celiac disease was identified as a risk factor for mood disorders, anxiety disorders, eating disorders, behavioral disorders, ADHD, ASD, and intellectual disability. In addition, a previous diagnosis of a mood, eating, or behavioral disorder was more common before the diagnosis of celiac disease. In contrast, siblings of celiac disease probands were at no increased risk of any of the investigated psychiatric disorders.CONCLUSIONS: Children with celiac disease are at increased risk for most psychiatric disorders, apparently owing to the biological and/or psychological effects of celiac disease.
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| 15. |
- Carlen, Marie, et al.
(författare)
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Forebrain ependymal cells are Notch-dependent and generate neuroblasts and astrocytes after stroke
- 2009
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Ingår i: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1546-1726 .- 1097-6256. ; 12:3, s. 259-267
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Tidskriftsartikel (refereegranskat)abstract
- Neurons are continuously generated from stem cells in discrete regions in the adult mammalian brain. We found that ependymal cells lining the lateral ventricles were quiescent and did not contribute to adult neurogenesis under normal conditions in mice but instead gave rise to neuroblasts and astrocytes in response to stroke. Ependymal cell quiescence was actively maintained by canonical Notch signaling. Inhibition of this pathway in uninjured animals allowed ependymal cells to enter the cell cycle and produce olfactory bulb neurons, whereas forced Notch signaling was sufficient to block the ependymal cell response to stroke. Ependymal cells were depleted by stroke and failed to self-renew sufficiently to maintain their own population. Thus, although ependymal cells act as primary cells in the neural lineage to produce neurons and glial cells after stroke, they do not fulfill defining criteria for stem cells under these conditions and instead serve as a reservoir that is recruited by injury.
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| 16. |
- Curtis, Maurice A, et al.
(författare)
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Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension.
- 2007
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Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 315:5816, s. 1243-9
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Tidskriftsartikel (refereegranskat)abstract
- The rostral migratory stream (RMS) is the main pathway by which newly born subventricular zone cells reach the olfactory bulb (OB) in rodents. However, the RMS in the adult human brain has been elusive. We demonstrate the presence of a human RMS, which is unexpectedly organized around a lateral ventricular extension reaching the OB, and illustrate the neuroblasts in it. The RMS ensheathing the lateral olfactory ventricular extension, as seen by magnetic resonance imaging, cell-specific markers, and electron microscopy, contains progenitor cells with migratory characteristics and cells that incorporate 5-bromo-2'-deoxyuridine and become mature neurons in the OB.
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| 17. |
- Dias, David O., et al.
(författare)
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Pericyte-derived fibrotic scarring is conserved across diverse central nervous system lesions
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Fibrotic scar tissue limits central nervous system regeneration in adult mammals. The extent of fibrotic tissue generation and distribution of stromal cells across different lesions in the brain and spinal cord has not been systematically investigated in mice and humans. Furthermore, it is unknown whether scar-forming stromal cells have the same origin throughout the central nervous system and in different types of lesions. In the current study, we compared fibrotic scarring in human pathological tissue and corresponding mouse models of penetrating and non-penetrating spinal cord injury, traumatic brain injury, ischemic stroke, multiple sclerosis and glioblastoma. We show that the extent and distribution of stromal cells are specific to the type of lesion and, in most cases, similar between mice and humans. Employing in vivo lineage tracing, we report that in all mouse models that develop fibrotic tissue, the primary source of scar-forming fibroblasts is a discrete subset of perivascular cells, termed type A pericytes. Perivascular cells with a type A pericyte marker profile also exist in the human brain and spinal cord. We uncover type A pericyte-derived fibrosis as a conserved mechanism that may be explored as a therapeutic target to improve recovery after central nervous system lesions.
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| 18. |
- Djelloul, Mehdi, et al.
(författare)
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Alpha-Synuclein Expression in the Oligodendrocyte Lineage: an In Vitro and In Vivo Study Using Rodent and Human Models.
- 2015
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Ingår i: Stem Cell Reports. - : Elsevier BV. - 2213-6711. ; 5:2, s. 174-184
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we sought evidence for alpha-synuclein (ASYN) expression in oligodendrocytes, as a possible endogenous source of ASYN to explain its presence in glial inclusions found in multiple system atrophy (MSA) and Parkinson's disease (PD). We identified ASYN in oligodendrocyte lineage progenitors isolated from the rodent brain, in oligodendrocytes generated from embryonic stem cells, and in induced pluripotent stem cells produced from fibroblasts of a healthy individual and patients diagnosed with MSA or PD, in cultures in vitro. Notably, we observed a significant decrease in ΑSYN during oligodendrocyte maturation. Additionally, we show the presence of transcripts in PDGFRΑ/CD140a(+) cells and SOX10(+) oligodendrocyte lineage nuclei isolated by FACS from rodent and human healthy and diseased brains, respectively. Our work identifies ASYN in oligodendrocyte lineage cells, and it offers additional in vitro cellular models that should provide significant insights of the functional implication of ASYN during oligodendrocyte development and disease.
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| 19. |
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| 20. |
- Engblom, Camilla, et al.
(författare)
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Spatial transcriptomics of B cell and T cell receptors reveals lymphocyte clonal dynamics
- 2023
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 382:6675, s. 8486-
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Tidskriftsartikel (refereegranskat)abstract
- The spatial distribution of lymphocyte clones within tissues is critical to their development, selection, and expansion. We have developed spatial transcriptomics of variable, diversity, and joining (VDJ) sequences (Spatial VDJ), a method that maps B cell and T cell receptor sequences in human tissue sections. Spatial VDJ captures lymphocyte clones that match canonical B and T cell distributions and amplifies clonal sequences confirmed by orthogonal methods. We found spatial congruency between paired receptor chains, developed a computational framework to predict receptor pairs, and linked the expansion of distinct B cell clones to different tumor-associated gene expression programs. Spatial VDJ delineates B cell clonal diversity and lineage trajectories within their anatomical niche. Thus, Spatial VDJ captures lymphocyte spatial clonal architecture across tissues, providing a platform to harness clonal sequences for therapy.
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| 21. |
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| 22. |
- Ernst, Aurélie, et al.
(författare)
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Neurogenesis in the Striatum of the Adult Human Brain
- 2014
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Ingår i: Cell. - Cambridge, MA 02139, USA : Elsevier. - 0092-8674 .- 1097-4172. ; 156:5, s. 1072-1083
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Tidskriftsartikel (refereegranskat)abstract
- Neurons are added throughout life in the hippocampus and olfactory bulb in most mammals, although humans represent an exception without detectable olfactory bulb neurogenesis. Nevertheless, neuroblasts are generated in the lateral ventricle wall in humans, the neurogenic niche for olfactory bulb neurons in other mammals. We show that, in humans, new neurons integrate adjacent to this neurogenic niche, in the striatum. The neuronal turnover in the striatum appears restricted to interneurons and we show that postnatally generated striatal neurons are preferentially depleted in Huntington’s disease. This demonstrates a unique pattern of neurogenesis in the adult human brain.
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| 23. |
- Floriddia, Elisa M., et al.
(författare)
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Distinct oligodendrocyte populations have spatial preference and different responses to spinal cord injury
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Mature oligodendrocytes (MOLs) show transcriptional heterogeneity, the functional consequences of which are unclear. MOL heterogeneity might correlate with the local environment or their interactions with different neuron types. Here, we show that distinct MOL populations have spatial preference in the mammalian central nervous system (CNS). We found that MOL type 2 (MOL2) is enriched in the spinal cord when compared to the brain, while MOL types 5 and 6 (MOL5/6) increase their contribution to the OL lineage with age in all analyzed regions. MOL2 and MOL5/6 also have distinct spatial preference in the spinal cord regions where motor and sensory tracts run. OL progenitor cells (OPCs) are not specified into distinct MOL populations during development, excluding a major contribution of OPC intrinsic mechanisms determining MOL heterogeneity. In disease, MOL2 and MOL5/6 present different susceptibility during the chronic phase following traumatic spinal cord injury. Our results demonstrate that the distinct MOL populations have different spatial preference and different responses to disease.
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| 24. |
- Hard, Joanna, et al.
(författare)
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Conbase : a software for unsupervised discovery of clonal somatic mutations in single cells through read phasing
- 2019
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Ingår i: Genome Biology. - : BMC. - 1465-6906 .- 1474-760X. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- Accurate variant calling and genotyping represent major limiting factors for downstream applications of single-cell genomics. Here, we report Conbase for the identification of somatic mutations in single-cell DNA sequencing data. Conbase leverages phased read data from multiple samples in a dataset to achieve increased confidence in somatic variant calls and genotype predictions. Comparing the performance of Conbase to three other methods, we find that Conbase performs best in terms of false discovery rate and specificity and provides superior robustness on simulated data, in vitro expanded fibroblasts and clonal lymphocyte populations isolated directly from a healthy human donor.
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| 25. |
- Hofstetter, Christoph P, et al.
(författare)
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Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome.
- 2005
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Ingår i: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1097-6256 .- 1546-1726. ; 8:3, s. 346-53
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Tidskriftsartikel (refereegranskat)abstract
- Several studies have reported functional improvement after transplantation of neural stem cells into injured spinal cord. We now provide evidence that grafting of adult neural stem cells into a rat thoracic spinal cord weight-drop injury improves motor recovery but also causes aberrant axonal sprouting associated with allodynia-like hypersensitivity of forepaws. Transduction of neural stem cells with neurogenin-2 before transplantation suppressed astrocytic differentiation of engrafted cells and prevented graft-induced sprouting and allodynia. Transduction with neurogenin-2 also improved the positive effects of engrafted stem cells, including increased amounts of myelin in the injured area, recovery of hindlimb locomotor function and hindlimb sensory responses, as determined by functional magnetic resonance imaging. These findings show that stem cell transplantation into injured spinal cord can cause severe side effects and call for caution in the consideration of clinical trials.
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| 26. |
- Holmberg, Johan, et al.
(författare)
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EphB receptors coordinate migration and proliferation in the intestinal stem cell niche.
- 2006
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Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 125:6, s. 1151-63
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Tidskriftsartikel (refereegranskat)abstract
- More than 10(10) cells are generated every day in the human intestine. Wnt proteins are key regulators of proliferation and are known endogenous mitogens for intestinal progenitor cells. The positioning of cells within the stem cell niche in the intestinal epithelium is controlled by B subclass ephrins through their interaction with EphB receptors. We report that EphB receptors, in addition to directing cell migration, regulate proliferation in the intestine. EphB signaling promotes cell-cycle reentry of progenitor cells and accounts for approximately 50% of the mitogenic activity in the adult mouse small intestine and colon. These data establish EphB receptors as key coordinators of migration and proliferation in the intestinal stem cell niche.
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| 27. |
- Huttner, Hagen B., et al.
(författare)
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Meningioma growth dynamics assessed by radiocarbon retrospective birth dating
- 2018
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 27, s. 176-181
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Tidskriftsartikel (refereegranskat)abstract
- It is not known how long it takes from the initial neoplastic transformation of a cell to the detection of a tumor, which would be valuable for understanding tumor growth dynamics. Meningiomas show a broad histological, genetic and clinical spectrum, are usually benign and considered slowly growing. There is an intense debate regarding their age and growth pattern and when meningiomas should be resected. We have assessed the age and growth dynamics of 14 patients with meningiomas (WHO grade I: n = 6 with meningothelial and n = 6 with fibrous subtype, as well as n = 2 atypical WHO grade II meningiomas) by combining retrospective birth-dating of cells by analyzing incorporation of nuclear-bomb-test-derived 14C, analysis of cell proliferation, cell density, MRI imaging and mathematical modeling. We provide an integrated model of the growth dynamics of benign meningiomas. The mean age of WHO grade I meningiomas was 22.1 ± 6.5 years, whereas atypical WHO grade II meningiomas originated 1.5 ± 0.1 years prior to surgery (p < 0.01). We conclude that WHO grade I meningiomas are very slowly growing brain tumors, which are resected in average two decades after time of origination.
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| 28. |
- Huttner, Hagen B, et al.
(författare)
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The age and genomic integrity of neurons after cortical stroke in humans
- 2014
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Ingår i: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1097-6256 .- 1546-1726. ; 17:6, s. 801-803
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Tidskriftsartikel (refereegranskat)abstract
- It has been unclear whether ischemic stroke induces neurogenesis or neuronal DNA rearrangements in the human neocortex. Using immunohistochemistry; transcriptome, genome and ploidy analyses; and determination of nuclear bomb test-derived (14)C concentration in neuronal DNA, we found neither to be the case. A large proportion of cortical neurons displayed DNA fragmentation and DNA repair a short time after stroke, whereas neurons at chronic stages after stroke showed DNA integrity, demonstrating the relevance of an intact genome for survival.
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| 29. |
- Jensen, Lasse, et al.
(författare)
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Disruption of the Extracellular Matrix Progressively Impairs Central Nervous System Vascular Maturation Downstream of beta-Catenin Signaling
- 2019
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : LIPPINCOTT WILLIAMS & WILKINS. - 1079-5642 .- 1524-4636. ; 39:7, s. 1432-1447
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Tidskriftsartikel (refereegranskat)abstract
- Objective- The Wnt/beta-catenin pathway orchestrates development of the blood-brain barrier, but the downstream mechanisms involved at different developmental windows and in different central nervous system (CNS) tissues have remained elusive. Approach and Results- Here, we create a new mouse model allowing spatiotemporal investigations of Wnt/beta-catenin signaling by induced overexpression of Axin1, an inhibitor of beta-catenin signaling, specifically in endothelial cells (Axin1(iEC)-(OE)). AOE (Axin1 overexpression) in Axin1(iEC)-(OE) mice at stages following the initial vascular invasion of the CNS did not impair angiogenesis but led to premature vascular regression followed by progressive dilation and inhibition of vascular maturation resulting in forebrain-specific hemorrhage 4 days post-AOE. Analysis of the temporal Wnt/beta-catenin driven CNS vascular development in zebrafish also suggested that Axin1(iEC)-(OE) led to CNS vascular regression and impaired maturation but not inhibition of ongoing angiogenesis within the CNS. Transcriptomic profiling of isolated, beta-catenin signaling-deficient endothelial cells during early blood-brain barrier-development (E11.5) revealed ECM (extracellular matrix) proteins as one of the most severely deregulated clusters. Among the 20 genes constituting the forebrain endothelial cell-specific response signature, 8 (Adamtsl2, Apod, Ctsw, Htra3, Pglyrp1, Spock2, Ttyh2, and Wfdc1) encoded bona fide ECM proteins. This specific beta-catenin-responsive ECM signature was also repressed in Axin1(iEC)-(OE) and endothelial cell-specific beta-catenin-knockout mice (Ctnnb1-KOiEC) during initial blood-brain barrier maturation (E14.5), consistent with an important role of Wnt/beta-catenin signaling in orchestrating the development of the forebrain vascular ECM. Conclusions- These results suggest a novel mechanism of establishing a CNS endothelium-specific ECM signature downstream of Wnt-beta-catenin that impact spatiotemporally on blood-brain barrier differentiation during forebrain vessel development.
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| 30. |
- King, Carina, et al.
(författare)
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COVID-19—a very visible pandemic
- 2020
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Ingår i: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 396:10248, s. 15-15
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Tidskriftsartikel (refereegranskat)
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| 31. |
- Landsverk, Ole J. B., et al.
(författare)
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Antibody-secreting plasma cells persist for decades in human intestine
- 2017
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Ingår i: Journal of Experimental Medicine. - NewYork, USA : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 214:2, s. 309-317
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Tidskriftsartikel (refereegranskat)abstract
- Plasma cells (PCs) produce antibodies that mediate immunity after infection or vaccination. In contrast to PCs in the bone marrow, PCs in the gut have been considered short lived. In this study, we studied PC dynamics in the human small intestine by cell-turnover analysis in organ transplants and by retrospective cell birth dating measuring carbon-14 in genomic DNA. We identified three distinct PC subsets: a CD19(+) PC subset was dynamically exchanged, whereas of two CD19(-) PC subsets, CD45(+) PCs exhibited little and CD45(-) PCs no replacement and had a median age of 11 and 22 yr, respectively. Accumulation of CD45(-) PCs during ageing and the presence of rotavirus-specific clones entirely within the CD19(-) PC subsets support selection and maintenance of protective PCs for life in human intestine.
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| 32. |
- Larsson, Ludvig, et al.
(författare)
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Spatially resolved transcriptomics adds a new dimension to genomics
- 2021
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Ingår i: Nature Methods. - : NATURE RESEARCH. - 1548-7091 .- 1548-7105. ; 18:1, s. 15-18
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- As single-cell omics continue to advance, the field of spatially resolved transcriptomics has emerged with a set of experimental and computational methods to map out the positions of cells and their gene expression profiles in space. Here we summarize current transcriptome-wide and sequencing-based methodologies and their applications in genomics research.
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| 33. |
- Lindström, Sara, et al.
(författare)
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High-Density Microwell Chip for Culture and Analysis of Stem Cells
- 2009
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Ingår i: PLos ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:9, s. e6997-
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Tidskriftsartikel (refereegranskat)abstract
- With recent findings on the role of reprogramming factors on stem cells, in vitro screening assays for studying (de)differentiation is of great interest. We developed a miniaturized stem cell screening chip that is easily accessible and provides means of rapidly studying thousands of individual stem/progenitor cell samples, using low reagent volumes. For example, screening of 700,000 substances would take less than two days, using this platform combined with a conventional bio-imaging system. The microwell chip has standard slide format and consists of 672 wells in total. Each well holds 500 nl, a volume small enough to drastically decrease reagent costs but large enough to allow utilization of standard laboratory equipment. Results presented here include weeklong culturing and differentiation assays of mouse embryonic stem cells, mouse adult neural stem cells, and human embryonic stem cells. The possibility to either maintain the cells as stem/progenitor cells or to study cell differentiation of stem/progenitor cells over time is demonstrated. Clonality is critical for stem cell research, and was accomplished in the microwell chips by isolation and clonal analysis of single mouse embryonic stem cells using flow cytometric cell-sorting. Protocols for practical handling of the microwell chips are presented, describing a rapid and user-friendly method for the simultaneous study of thousands of stem cell cultures in small microwells. This microwell chip has high potential for a wide range of applications, for example directed differentiation assays and screening of reprogramming factors, opening up considerable opportunities in the stem cell field.
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| 34. |
- Llorens-Bobadilla, Enric, et al.
(författare)
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Solid-phase capture and profiling of open chromatin by spatial ATAC
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Current methods for epigenomic profiling are limited in the ability to obtain genome wideinformation with spatial resolution. Here we introduce spatial ATAC, a method that integratestransposase-accessible chromatin profiling in tissue sections with barcoded solid-phase captureto perform spatially resolved epigenomics. We show that spatial ATAC enables the discoveryof the regulatory programs underlying spatial gene expression during mouse organogenesis,lineage differentiation and in human pathology.
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| 35. |
- Llorens-Bobadilla, Enric, et al.
(författare)
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Solid-phase capture and profiling of open chromatin by spatial ATAC
- 2023
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Ingår i: Nature Biotechnology. - : Nature Research. - 1087-0156 .- 1546-1696. ; 41:8, s. 1085-1088
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Tidskriftsartikel (refereegranskat)abstract
- Current methods for epigenomic profiling are limited in their ability to obtain genome-wide information with spatial resolution. We introduce spatial ATAC, a method that integrates transposase-accessible chromatin profiling in tissue sections with barcoded solid-phase capture to perform spatially resolved epigenomics. We show that spatial ATAC enables the discovery of the regulatory programs underlying spatial gene expression during mouse organogenesis, lineage differentiation and in human pathology.
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| 36. |
- Magnusson, Jens P, et al.
(författare)
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A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse.
- 2014
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 346:6206, s. 237-241
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Tidskriftsartikel (refereegranskat)abstract
- Neurogenesis is restricted in the adult mammalian brain; most neurons are neither exchanged during normal life nor replaced in pathological situations. We report that stroke elicits a latent neurogenic program in striatal astrocytes in mice. Notch1 signaling is reduced in astrocytes after stroke, and attenuated Notch1 signaling is necessary for neurogenesis by striatal astrocytes. Blocking Notch signaling triggers astrocytes in the striatum and the medial cortex to enter a neurogenic program, even in the absence of stroke, resulting in 850 ± 210 (mean ± SEM) new neurons in a mouse striatum. Thus, under Notch signaling regulation, astrocytes in the adult mouse brain parenchyma carry a latent neurogenic program that may potentially be useful for neuronal replacement strategies.
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| 37. |
- Meletis, Konstantinos, et al.
(författare)
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p53 suppresses the self-renewal of adult neural stem cells
- 2006
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Ingår i: Development. - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 133:2, s. 363-369
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Tidskriftsartikel (refereegranskat)abstract
- There is increasing evidence that tumors are heterogeneous and that a subset of cells act as cancer stem cells. Several proto-oncogenes and tumor suppressors control key aspects of stem cell function, suggesting that similar mechanisms control normal and cancer stem cell properties. We show here that the prototypical tumor suppressor p53, which plays an important role in brain tumor initiation and growth, is expressed in the neural stem cell lineage in the adult brain. p53 negatively regulates proliferation and survival, and thereby self-renewal, of neural stem cells. Analysis of the neural stem cell transcriptome identified the dysregulation of several cell cycle regulators in the absence of p53, most notably a pronounced downregulation of p21 expression. These data implicate p53 as a suppressor of tissue and cancer stem cell self-renewal.
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| 38. |
- Mold, Jeff E., et al.
(författare)
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Cell generation dynamics underlying naive T-cell homeostasis in adult humans
- 2019
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Ingår i: PLoS biology. - : Public Library of Science (PLoS). - 1544-9173 .- 1545-7885. ; 17:10
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Tidskriftsartikel (refereegranskat)abstract
- Thymic involution and proliferation of naive T cells both contribute to shaping the naive T-cell repertoire as humans age, but a clear understanding of the roles of each throughout a human life span has been difficult to determine. By measuring nuclear bomb test-derived C-14 in genomic DNA, we determined the turnover rates of CD4(+) and CD8(+) naive T-cell populations and defined their dynamics in healthy individuals ranging from 20 to 65 years of age. We demonstrate that naive T-cell generation decreases with age because of a combination of declining peripheral division and thymic production during adulthood. Concomitant decline in T-cell loss compensates for decreased generation rates. We investigated putative mechanisms underlying age-related changes in homeostatic regulation of CD4+ naive T-cell turnover, using mass cytometry to profile candidate signaling pathways involved in T-cell activation and proliferation relative to CD31 expression, a marker of thymic proximity for the CD4+ naive T-cell population. We show that basal nuclear factor kappa B (NF-kappa B) phosphorylation positively correlated with CD31 expression and thus is decreased in peripherally expanded naive T-cell clones. Functionally, we found that NF-kappa B signaling was essential for naive T-cell proliferation to the homeostatic growth factor interleukin (IL)-7, and reduced NF-kappa B phosphorylation in CD4(+)CD31(-) naive T cells is linked to reduced homeostatic proliferation potential. Our results reveal an age-related decline in naive T-cell turnover as a putative regulator of naive T-cell diversity and identify a molecular pathway that restricts proliferation of peripherally expanded naive T-cell clones that accumulate with age.
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| 39. |
- Mold, Jeff E., et al.
(författare)
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Clonally heritable gene expression imparts a layer of diversity within cell types
- 2024
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Ingår i: Cell systems. - : Elsevier BV. - 2405-4720. ; 15:2, s. 149-
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Tidskriftsartikel (refereegranskat)abstract
- Cell types can be classified according to shared patterns of transcription. Non-genetic variability among individual cells of the same type has been ascribed to stochastic transcriptional bursting and transient cell states. Using high-coverage single-cell RNA profiling, we asked whether long-term, heritable differences in gene expression can impart diversity within cells of the same type. Studying clonal human lymphocytes and mouse brain cells, we uncovered a vast diversity of heritable gene expression patterns among different clones of cells of the same type in vivo. We combined chromatin accessibility and RNA profiling on different lymphocyte clones to reveal thousands of regulatory regions exhibiting interclonal variation, which could be directly linked to interclonal variation in gene expression. Our findings identify a source of cellular diversity, which may have important implications for how cellular populations are shaped by selective processes in development, aging, and disease. A record of this paper's transparent peer review process is included in the supplemental information.
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| 40. |
- Mold, Jeff E., et al.
(författare)
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Divergent clonal differentiation trajectories establish CD8(+) memory T cell heterogeneity during acute viral infections in humans
- 2021
-
Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 35:8
-
Tidskriftsartikel (refereegranskat)abstract
- The CD8(+) T cell response to an antigen is composed of many T cell clones with unique T cell receptors, together forming a heterogeneous repertoire of effector and memory cells. How individual T cell clones contribute to this heterogeneity throughout immune responses remains largely unknown. In this study, we longitudinally track human CD8(+) T cell clones expanding in response to yellow fever virus (YFV) vaccination at the single-cell level. We observed a drop in clonal diversity in blood from the acute to memory phase, suggesting that clonal selection shapes the circulating memory repertoire. Clones in the memory phase display biased differentiation trajectories along a gradient from stem cell to terminally differentiated effector memory fates. In secondary responses, YFV- and influenza-specific CD8(+) T cell clones are poised to recapitulate skewed differentiation trajectories. Collectively, we show that the sum of distinct clonal phenotypes results in the multifaceted human T cell response to acute viral infections.
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| 41. |
- Passante, Lara, et al.
(författare)
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Temporal regulation of ephrin/Eph signalling is required for the spatial patterning of the mammalian striatum
- 2008
-
Ingår i: Development. - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 135:19, s. 3281-3290
-
Tidskriftsartikel (refereegranskat)abstract
- Brain structures, whether mature or developing, display a wide diversity of pattern and shape, such as layers, nuclei or segments. The striatum in the mammalian forebrain displays a unique mosaic organization (subdivided into two morphologically and functionally defined neuronal compartments: the matrix and the striosomes) that underlies important functional features of the basal ganglia. Matrix and striosome neurons are generated sequentially during embryonic development, and segregate from each other to form a mosaic of distinct compartments. However, the molecular mechanisms that underlie this time-dependent process of neuronal segregation remain largely unknown. Using a novel organotypic assay, we identified ephrin/Eph family members as guidance cues that regulate matrix/striosome compartmentalization. We found that EphA4 and its ephrin ligands displayed specific temporal patterns of expression and function that play a significant role in the spatial segregation of matrix and striosome neurons. Analysis of the striatal patterning in ephrin A5/EphA4 mutant mice further revealed the requirement of EphA4 signalling for the proper sorting of matrix and striosome neuronal populations in vivo. These data constitute the first identification of genes involved in striatal compartmentalization, and reveal a novel mechanism by which the temporal control of guidance cues enables neuronal segregation, and thereby the generation of complex cellular patterns in the brain.
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| 42. |
- Paul-Visse, Gesine, et al.
(författare)
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Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson's disease patients
- 2015
-
Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 125:3, s. 1339-1346
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. Recombinant human PDGF-BB (rhPDGF-BB) reduces Parkinsonian symptoms and increases dopamine transporter (DAT) binding in several animal models of Parkinson's disease (PD). Effects of rhPDGF-BB are the result of proliferation of ventricular wall progenitor cells and reversed by blocking mitosis. Based on these restorative effects, we assessed the safety and tolerability of intracerebroventricular (i.c.v.) rhPDGF-BB administration in individuals with PD. METHODS. We conducted a double-blind, randomized, placebo-controlled phase I/IIa study at two clinical centers in Sweden. Twelve patients with moderate PD received rhPDGF-BB via an implanted drug infusion pump and an investigational i.c.v. catheter. Patients were assigned to a dose cohort (0.2, 1.5, or 5 mu g rhPDGF-BB per day) and then randomized to active treatment or placebo (3:1) for a 12-day treatment period. The primary objective was to assess safety and tolerability of i.c.v.-delivered rhPDGF-BB. Secondary outcome assessments included several clinical rating scales and changes in DAT binding. The follow-up period was 85 days. RESULTS. All patients completed the study. There were no unresolved adverse events. Serious adverse events occurred in three patients; however, these were unrelated to rhPDGF-BB administration. Secondary outcome parameters did not show dose-dependent changes in clinical rating scales, but there was a positive effect on DAT binding in the right putamen. CONCLUSION. At all doses tested, i.c.v. administration of rhPDGF-BB was well tolerated. Results support further clinical development of rhPDGF-BB for patients with PD.
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| 43. |
- Reu, Pedro, et al.
(författare)
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Human T cell lifespan
- 2013
-
Ingår i: Journal of Immunology. - 0022-1767 .- 1550-6606. ; 190, s. P1284-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 44. |
- Reu, Pedro, et al.
(författare)
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The Lifespan and Turnover of Microglia in the Human Brain
- 2017
-
Ingår i: Cell Reports. - Cambridge, MA 02139, USA : Elsevier BV. - 2211-1247. ; 20:4, s. 779-784
-
Tidskriftsartikel (refereegranskat)abstract
- The hematopoietic system seeds the CNS with microglial progenitor cells during the fetal period, but the subsequent cell generation dynamics and maintenance of this population have been poorly understood. We report that microglia, unlike most other hematopoietic lineages, renew slowly at a median rate of 28% per year, and some microglia last for more than two decades. Furthermore, we find no evidence for the existence of a substantial population of quiescent long-lived cells, meaning that the microglia population in the human brain is sustained by continuous slow turnover throughout adult life.
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| 45. |
- Salmén, Fredrik, et al.
(författare)
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Barcoded solid-phase RNA capture for Spatial Transcriptomics profiling in mammalian tissue sections
- 2018
-
Ingår i: Nature Protocols. - : Nature Publishing Group. - 1754-2189 .- 1750-2799. ; 13:11, s. 2501-2534
-
Tidskriftsartikel (refereegranskat)abstract
- Spatial resolution of gene expression enables gene expression events to be pinpointed to a specific location in biological tissue. Spatially resolved gene expression in tissue sections is traditionally analyzed using immunohistochemistry (IHC) or in situ hybridization (ISH). These technologies are invaluable tools for pathologists and molecular biologists; however, their throughput is limited to the analysis of only a few genes at a time. Recent advances in RNA sequencing (RNA-seq) have made it possible to obtain unbiased high-throughput gene expression data in bulk. Spatial Transcriptomics combines the benefits of traditional spatially resolved technologies with the massive throughput of RNA-seq. Here, we present a protocol describing how to apply the Spatial Transcriptomics technology to mammalian tissue. This protocol combines histological staining and spatially resolved RNA-seq data from intact tissue sections. Once suitable tissue-specific conditions have been established, library construction and sequencing can be completed in similar to 5-6 d. Data processing takes a few hours, with the exact timing dependent on the sequencing depth. Our method requires no special instruments and can be performed in any laboratory with access to a cryostat, microscope and next-generation sequencing.
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| 46. |
- Salmén, Fredrik, et al.
(författare)
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Multidimensional transcriptomics provides detailed information about immune cell distribution an identity in HER2+ breast tumors
- 2018
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The comprehensive analysis of tumor tissue heterogeneity is crucial for determining specific disease states and establishing suitable treatment regimes. Here, we analyze tumor tissue sections from ten patients diagnosed with HER2+ breast cancer. We obtain and analyze multidimensional, genome-wide transcriptomics data to resolve spatial immune cell distribution and identity within the tissue sections. Furthermore, we determine the extent of immune cell infiltration in different regions of the tumor tissue, including invasive cancer regions. We combine cross-sectioning and computational alignment to build three-dimensional images of the transcriptional landscape of the tumor and its microenvironment. The three-dimensional data clearly demonstrates the heterogeneous nature of tumor-immune interactions and reveal interpatient differences in immune cell infiltration patterns. Our study shows the potential for an improved stratification and description of the tumor-immune interplay, which is likely to be essential in treatment decisions.
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| 47. |
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| 48. |
- Sandberg, Julia, et al.
(författare)
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Interrogation of polyguaninine nucleotide repeat variability in human T-cells by whole genome sequencing of single cells
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Polyguanine nucleotide repeats exhibit a greater degree of variation than the average for the genome as a whole. This is partly due to polymerase slippage that causes insertions or deletions in these repeat sequence. The high variability of these repeats makes them useful for tracking the differentiation and fate of cells within tissues and organs. However, the same factors that create this variability also give rise to technical difficulties in DNA amplification and massively parallel DNA sequencing. In the study reported herein, we investigated shotgun sequence data from a standard multi-cell sample as well as sequence data for four single cells from the same individual. This was used to assess sequence quality in whole genome amplified single cell material and to investigate variability in homopolymeric regions between individual T-cells. In a more focused study, a selected set of polyG loci in single cells for which the phylogenetic relationship was known, were amplified and sequence determined. Based on the length differences in polyG repeats between the eight cells a phylogenetic tree was constructed, that was very similar to the known tree.
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| 49. |
- Santopolo, Giuseppe, et al.
(författare)
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Blocking Notch-Signaling Increases Neurogenesis in the Striatum after Stroke
- 2020
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 9:7
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Tidskriftsartikel (refereegranskat)abstract
- Stroke triggers neurogenesis in the striatum in mice, with new neurons deriving in part from the nearby subventricular zone and in part from parenchymal astrocytes. The initiation of neurogenesis by astrocytes within the striatum is triggered by reduced Notch-signaling, and blocking this signaling pathway by deletion of the gene encoding the obligate Notch coactivator Rbpj is sufficient to activate neurogenesis by striatal astrocytes in the absence of an injury. Here we report that blocking Notch-signaling in stroke increases the neurogenic response to stroke 3.5-fold in mice. Deletion of Rbpj results in the recruitment of a larger number of parenchymal astrocytes to neurogenesis and over larger areas of the striatum. These data suggest inhibition of Notch-signaling as a potential translational strategy to promote neuronal regeneration after stroke.
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| 50. |
- Seidel, Sascha, et al.
(författare)
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A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha
- 2010
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 133, s. 983-995
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Tidskriftsartikel (refereegranskat)abstract
- Glioma growth and progression depend on a specialized subpopulation of tumour cells, termed tumour stem cells. Thus, tumour stem cells represent a critical therapeutic target, but the molecular mechanisms that regulate them are poorly understood. Hypoxia plays a key role in tumour progression and in this study we provide evidence that the hypoxic tumour microenvironment also controls tumour stem cells. We define a detailed molecular signature of tumour stem cell genes, which are overexpressed by tumour cells in vascular and perinecrotic/hypoxic niches. Mechanistically, we show that hypoxia plays a key role in the regulation of the tumour stem cell phenotype through hypoxia-inducible factor 2 alpha and subsequent induction of specific tumour stem cell signature genes, including mastermind-like protein 3 (Notch pathway), nuclear factor of activated T cells 2 (calcineurin pathway) and aspartate beta-hydroxylase domain-containing protein 2. Notably, a number of these genes belong to pathways regulating the stem cell phenotype. Consistently, tumour stem cell signature genes are overexpressed in newly formed gliomas and are associated with worse clinical prognosis. We propose that tumour stem cells are maintained within a hypoxic niche, providing a functional link between the well-established role of hypoxia in stem cell and tumour biology. The identification of molecular regulators of tumour stem cells in the hypoxic niche points to specific signalling mechanisms that may be used to target the glioblastoma stem cell population.
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