Publications by authors named "Jonas Frisén"

112 Publications

Single-cell transcriptomics of human embryos identifies multiple sympathoblast lineages with potential implications for neuroblastoma origin.

Nat Genet 2021 May 8;53(5):694-706. Epub 2021 Apr 8.

Department of Physiology and Pharmacology, Karolinska Institutet, Solna, Sweden.

Characterization of the progression of cellular states during human embryogenesis can provide insights into the origin of pediatric diseases. We examined the transcriptional states of neural crest- and mesoderm-derived lineages differentiating into adrenal glands, kidneys, endothelium and hematopoietic tissue between post-conception weeks 6 and 14 of human development. Our results reveal transitions connecting the intermediate mesoderm and progenitors of organ primordia, the hematopoietic system and endothelial subtypes. Unexpectedly, by using a combination of single-cell transcriptomics and lineage tracing, we found that intra-adrenal sympathoblasts at that stage are directly derived from nerve-associated Schwann cell precursors, similarly to local chromaffin cells, whereas the majority of extra-adrenal sympathoblasts arise from the migratory neural crest. In humans, this process persists during several weeks of development within the large intra-adrenal ganglia-like structures, which may also serve as reservoirs of originating cells in neuroblastoma.
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http://dx.doi.org/10.1038/s41588-021-00818-xDOI Listing
May 2021

The age of adult pilocytic astrocytoma cells.

Oncogene 2021 Apr 17;40(16):2830-2841. Epub 2021 Mar 17.

Group Genome Instability in Tumors, DKFZ, Heidelberg, Germany.

Adult pilocytic astrocytomas (PAs) have been regarded as indistinguishable from pediatric PAs in terms of genome-wide expression and methylation patterns. It has been unclear whether adult PAs arise early in life and remain asymptomatic until adulthood, or whether they develop during adulthood. We sought to determine the age and origin of adult human PAs using two types of "marks" in the genomic DNA. First, we analyzed the DNA methylation patterns of adult and pediatric PAs to distinguish between PAs of different anatomic locations (n = 257 PA and control brain tissues). Second, we measured the concentration of nuclear bomb test-derived C in genomic DNA (n = 14 cases), which indicates the time point of the formation of human cell populations. Our data suggest that adult and pediatric PAs developing in the infratentorial brain are closely related and potentially develop from precursor cells early in life, whereas supratentorial PAs might show age and location-specific differences.
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http://dx.doi.org/10.1038/s41388-021-01738-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062266PMC
April 2021

Spatially resolved transcriptomics adds a new dimension to genomics.

Nat Methods 2021 01;18(1):15-18

Science for Life Laboratory, Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden.

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http://dx.doi.org/10.1038/s41592-020-01038-7DOI Listing
January 2021

Distinct oligodendrocyte populations have spatial preference and different responses to spinal cord injury.

Nat Commun 2020 11 17;11(1):5860. Epub 2020 Nov 17.

Laboratory of Molecular Neurobiology, Department Medical Biochemistry and Biophysics, Karolinska Institutet, Biomedicum, 17177, Stockholm, Sweden.

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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http://dx.doi.org/10.1038/s41467-020-19453-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673029PMC
November 2020

Revisiting remyelination: Towards a consensus on the regeneration of CNS myelin.

Semin Cell Dev Biol 2020 Oct 17. Epub 2020 Oct 17.

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom. Electronic address:

The biology of CNS remyelination has attracted considerable interest in recent years because of its translational potential to yield regenerative therapies for the treatment of chronic and progressive demyelinating diseases such as multiple sclerosis (MS). Critical to devising myelin regenerative therapies is a detailed understanding of how remyelination occurs. The accepted dogma, based on animal studies, has been that the myelin sheaths of remyelination are made by oligodendrocytes newly generated from adult oligodendrocyte progenitor cells in a classical regenerative process of progenitor migration, proliferation and differentiation. However, recent human and a growing number of animal studies have revealed a second mode of remyelination in which mature oligodendrocytes surviving within an area of demyelination are able to regenerate new myelin sheaths. This discovery, while opening up new opportunities for therapeutic remyelination, has also raised the question of whether there are fundamental differences in myelin regeneration between humans and some of the species in which experimental remyelination studies are conducted. Here we review how this second mode of remyelination can be integrated into a wider and revised framework for understanding remyelination in which apparent species differences can be reconciled but that also raises important questions for future research.
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http://dx.doi.org/10.1016/j.semcdb.2020.09.009DOI Listing
October 2020

A latent lineage potential in resident neural stem cells enables spinal cord repair.

Science 2020 10;370(6512)

Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.

Injuries to the central nervous system (CNS) are inefficiently repaired. Resident neural stem cells manifest a limited contribution to cell replacement. We have uncovered a latent potential in neural stem cells to replace large numbers of lost oligodendrocytes in the injured mouse spinal cord. Integrating multimodal single-cell analysis, we found that neural stem cells are in a permissive chromatin state that enables the unfolding of a normally latent gene expression program for oligodendrogenesis after injury. Ectopic expression of the transcription factor OLIG2 unveiled abundant stem cell-derived oligodendrogenesis, which followed the natural progression of oligodendrocyte differentiation, contributed to axon remyelination, and stimulated functional recovery of axon conduction. Recruitment of resident stem cells may thus serve as an alternative to cell transplantation after CNS injury.
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http://dx.doi.org/10.1126/science.abb8795DOI Listing
October 2020

A Widespread Neurogenic Potential of Neocortical Astrocytes Is Induced by Injury.

Cell Stem Cell 2020 10 5;27(4):605-617.e5. Epub 2020 Aug 5.

Department of Cell and Molecular Biology, Karolinska Institute, 171 77 Stockholm, Sweden. Electronic address:

Parenchymal astrocytes have emerged as a potential reservoir for new neurons in non-neurogenic brain regions. It is currently unclear how astrocyte neurogenesis is controlled molecularly. Here we show that Notch signaling-deficient astrocytes can generate new neurons after injury. Using single-cell RNA sequencing, we found that, when Notch signaling is blocked, astrocytes transition to a neural stem cell-like state. However, only after injury do a few of these primed astrocytes unfold a neurogenic program, including a self-amplifying progenitor-like state. Further, reconstruction of the trajectories of individual cells allowed us to uncouple astrocyte neurogenesis from reactive gliosis, which occur along independent branches. Finally, we show that cortical neurogenesis molecularly recapitulates canonical subventricular zone neurogenesis with remarkable fidelity. Our study supports a widespread potential of parenchymal astrocytes to function as dormant neural stem cells.
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http://dx.doi.org/10.1016/j.stem.2020.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534841PMC
October 2020

Activation of a neural stem cell transcriptional program in parenchymal astrocytes.

Elife 2020 08 3;9. Epub 2020 Aug 3.

Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.

Adult neural stem cells, located in discrete brain regions, generate new neurons throughout life. These stem cells are specialized astrocytes, but astrocytes in other brain regions do not generate neurons under physiological conditions. After stroke, however, striatal astrocytes undergo neurogenesis in mice, triggered by decreased Notch signaling. We used single-cell RNA sequencing to characterize neurogenesis by Notch-depleted striatal astrocytes in vivo. Striatal astrocytes were located upstream of neural stem cells in the neuronal lineage. As astrocytes initiated neurogenesis, they became transcriptionally very similar to subventricular zone stem cells, progressing through a near-identical neurogenic program. Surprisingly, in the non-neurogenic cortex, Notch-depleted astrocytes also initiated neurogenesis. Yet, these cortical astrocytes, and many striatal ones, stalled before entering transit-amplifying divisions. Infusion of epidermal growth factor enabled stalled striatal astrocytes to resume neurogenesis. We conclude that parenchymal astrocytes are latent neural stem cells and that targeted interventions can guide them through their neuronal differentiation.
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http://dx.doi.org/10.7554/eLife.59733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7440914PMC
August 2020

Blocking Notch-Signaling Increases Neurogenesis in the Striatum after Stroke.

Cells 2020 07 20;9(7). Epub 2020 Jul 20.

Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden.

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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http://dx.doi.org/10.3390/cells9071732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409130PMC
July 2020

Induction of Leptomeningeal Cells Modification Via Intracisternal Injection.

J Vis Exp 2020 05 7(159). Epub 2020 May 7.

Department of Cell and Molecular Biology, Karolinska Institute;

The protocol outlined here describes how to safely and manually inject solutions through the cisterna magna while eliminating the risk of damage to the underlying parenchyma. Previously published protocols recommend using straight needles that should be lowered to a maximum of 1-2 mm from the dural surface. The sudden drop in resistance once the dural membrane has been punctured makes it difficult to maintain the needle in a steady position. Our method, instead, employs a needle bent at the tip that can be stabilized against the occipital bone of the skull, thus preventing the syringe from penetrating into the tissue after perforation of the dural membrane. The procedure is straightforward, reproducible, and does not cause long-lasting discomfort in the operated animals. We describe the intracisternal injection strategy in the context of genetic fate mapping of vascular leptomeningeal cells. The same technique can, furthermore, be utilized to address a wide range of research questions, such as probing the role of leptomeninges in neurodevelopment and the spreading of bacterial meningitis, through genetic ablation of genes putatively implicated in these phenomena. Additionally, the procedure can be combined with an automatized infusion system for a constant delivery and used for tracking cerebrospinal fluid movement via injection of fluorescently labelled molecules.
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http://dx.doi.org/10.3791/61009DOI Listing
May 2020

Cell generation dynamics underlying naive T-cell homeostasis in adult humans.

PLoS Biol 2019 10 29;17(10):e3000383. Epub 2019 Oct 29.

Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.

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 14C 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 κB (NF-κB) phosphorylation positively correlated with CD31 expression and thus is decreased in peripherally expanded naive T-cell clones. Functionally, we found that NF-κB signaling was essential for naive T-cell proliferation to the homeostatic growth factor interleukin (IL)-7, and reduced NF-κB 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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http://dx.doi.org/10.1371/journal.pbio.3000383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818757PMC
October 2019

High-definition spatial transcriptomics for in situ tissue profiling.

Nat Methods 2019 10 9;16(10):987-990. Epub 2019 Sep 9.

Science for Life Laboratory, Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden.

Spatial and molecular characteristics determine tissue function, yet high-resolution methods to capture both concurrently are lacking. Here, we developed high-definition spatial transcriptomics, which captures RNA from histological tissue sections on a dense, spatially barcoded bead array. Each experiment recovers several hundred thousand transcript-coupled spatial barcodes at 2-μm resolution, as demonstrated in mouse brain and primary breast cancer. This opens the way to high-resolution spatial analysis of cells and tissues.
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http://dx.doi.org/10.1038/s41592-019-0548-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765407PMC
October 2019

Disruption of the Extracellular Matrix Progressively Impairs Central Nervous System Vascular Maturation Downstream of β-Catenin Signaling.

Arterioscler Thromb Vasc Biol 2019 07 9;39(7):1432-1447. Epub 2019 May 9.

Department of Physiology and Pharmacology (B.H., V.M.L., J.K.), Karolinska Institutet, Stockholm, Sweden.

Objective- The Wnt/β-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/β-catenin signaling by induced overexpression of Axin1, an inhibitor of β-catenin signaling, specifically in endothelial cells ( Axin1 - ). AOE (Axin1 overexpression) in Axin1 - 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/β-catenin driven CNS vascular development in zebrafish also suggested that Axin1 - led to CNS vascular regression and impaired maturation but not inhibition of ongoing angiogenesis within the CNS. Transcriptomic profiling of isolated, β-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 β-catenin-responsive ECM signature was also repressed in Axin1 - and endothelial cell-specific β-catenin-knockout mice ( Ctnnb1-KO) during initial blood-brain barrier maturation (E14.5), consistent with an important role of Wnt/β-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-β-catenin that impact spatiotemporally on blood-brain barrier differentiation during forebrain vessel development. Visual Overview- An online visual overview is available for this article.
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http://dx.doi.org/10.1161/ATVBAHA.119.312388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597191PMC
July 2019

Conbase: a software for unsupervised discovery of clonal somatic mutations in single cells through read phasing.

Genome Biol 2019 04 1;20(1):68. Epub 2019 Apr 1.

Department of Cell and Molecular Biology, Karolinska Institutet, Solna, Sweden.

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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http://dx.doi.org/10.1186/s13059-019-1673-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444814PMC
April 2019

A fresh look at adult neurogenesis.

Nat Med 2019 04;25(4):542-543

Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.

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http://dx.doi.org/10.1038/s41591-019-0408-4DOI Listing
April 2019

Regenerating the field of cardiovascular cell therapy.

Nat Biotechnol 2019 03 18;37(3):232-237. Epub 2019 Feb 18.

Institute for Stem Cell Biology and Regenerative Medicine; Ludwig Center for Cancer Stem Cell Biology and Medicine; Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA.

The retraction of >30 falsified studies by Anversa et al. has had a disheartening impact on the cardiac cell therapeutics field. The premise of heart muscle regeneration by the transdifferentiation of bone marrow cells or putative adult resident cardiac progenitors has been largely disproven. Over the past 18 years, a generation of physicians and scientists has lost years chasing these studies, and patients have been placed at risk with little scientific grounding. Funding agencies invested hundreds of millions of dollars in irreproducible work, and both academic institutions and the scientific community ignored troubling signals over a decade of questionable work. Our collective retrospective analysis identifies preventable problems at the level of the editorial and peer-review process, funding agencies and academic institutions. This Perspective provides a chronology of the forces that led to this scientific debacle, integrating direct knowledge of the process. We suggest a science-driven path forward that includes multiple novel approaches to the problem of heart muscle regeneration.
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http://dx.doi.org/10.1038/s41587-019-0042-1DOI Listing
March 2019

Publisher Correction: Dynamics of oligodendrocyte generation in multiple sclerosis.

Nature 2019 02;566(7744):E9

Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.

In this Letter, the vertical error bars were missing from Fig. 3b and 3c. This figure has been corrected online.
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http://dx.doi.org/10.1038/s41586-019-0935-7DOI Listing
February 2019

Dynamics of oligodendrocyte generation in multiple sclerosis.

Nature 2019 02 23;566(7745):538-542. Epub 2019 Jan 23.

Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.

Oligodendrocytes wrap nerve fibres in the central nervous system with layers of specialized cell membrane to form myelin sheaths. Myelin is destroyed by the immune system in multiple sclerosis, but myelin is thought to regenerate and neurological function can be recovered. In animal models of demyelinating disease, myelin is regenerated by newly generated oligodendrocytes, and remaining mature oligodendrocytes do not seem to contribute to this process. Given the major differences in the dynamics of oligodendrocyte generation and adaptive myelination between rodents and humans, it is not clear how well experimental animal models reflect the situation in multiple sclerosis. Here, by measuring the integration of C derived from nuclear testing in genomic DNA, we assess the dynamics of oligodendrocyte generation in patients with multiple sclerosis. The generation of new oligodendrocytes was increased several-fold in normal-appearing white matter in a subset of individuals with very aggressive multiple sclerosis, but not in most subjects with the disease, demonstrating an inherent potential to substantially increase oligodendrocyte generation that fails in most patients. Oligodendrocytes in shadow plaques-thinly myelinated lesions that are thought to represent remyelinated areas-were old in patients with multiple sclerosis. The absence of new oligodendrocytes in shadow plaques suggests that remyelination of lesions occurs transiently or not at all, or that myelin is regenerated by pre-existing, and not new, oligodendrocytes in multiple sclerosis. We report unexpected oligodendrocyte generation dynamics in multiple sclerosis, and this should guide the use of current, and the development of new, therapies.
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http://dx.doi.org/10.1038/s41586-018-0842-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420067PMC
February 2019

Limits to human neurogenesis-really?

Mol Psychiatry 2020 10 7;25(10):2207-2209. Epub 2019 Jan 7.

Netherlands Institute for Neurosciences, Meibergdreef, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1038/s41380-018-0337-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515796PMC
October 2020

Barcoded solid-phase RNA capture for Spatial Transcriptomics profiling in mammalian tissue sections.

Nat Protoc 2018 11;13(11):2501-2534

Science for Life Laboratory, Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden.

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 ~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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http://dx.doi.org/10.1038/s41596-018-0045-2DOI Listing
November 2018

The hippocampus in multiple sclerosis.

Lancet Neurol 2018 10 18;17(10):918-926. Epub 2018 Sep 18.

Neuroimaging Research Unit and Department of Neurology, Institute of Experimental Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy. Electronic address:

Some of the clinical manifestations of multiple sclerosis, such as memory impairment and depression, are, at least partly, related to involvement of the hippocampus. Pathological studies have shown extensive demyelination, neuronal damage, and synaptic abnormalities in the hippocampus of patients with multiple sclerosis, and improvements in MRI technology have provided novel ways to assess hippocampal involvement in vivo. It is now accepted that clinical manifestations related to the hippocampus are due not only to focal hippocampal damage, but also to disconnection of the hippocampus from several brain networks. Evidence suggests anatomical and functional subspecialisation of the different hippocampal subfields, resulting in variability between regions in the extent to which damage and repair occur. The hippocampus also has important roles in plasticity and neurogenesis, both of which potentially contribute to functional preservation and restoration. These findings underline the importance of evaluation of the hippocampus not only to improve understanding of the clinical manifestations of multiple sclerosis, but also as a potential future target for treatment.
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http://dx.doi.org/10.1016/S1474-4422(18)30309-0DOI Listing
October 2018

Human Adult Neurogenesis: Evidence and Remaining Questions.

Cell Stem Cell 2018 Jul 19;23(1):25-30. Epub 2018 Apr 19.

Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden. Electronic address:

Renewed discussion about whether or not adult neurogenesis exists in the human hippocampus, and the nature and strength of the supporting evidence, has been reignited by two prominently published reports with opposite conclusions. Here, we summarize the state of the field and argue that there is currently no reason to abandon the idea that adult-generated neurons make important functional contributions to neural plasticity and cognition across the human lifespan.
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http://dx.doi.org/10.1016/j.stem.2018.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035081PMC
July 2018

Reducing Pericyte-Derived Scarring Promotes Recovery after Spinal Cord Injury.

Cell 2018 03 1;173(1):153-165.e22. Epub 2018 Mar 1.

Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Electronic address:

CNS injury often severs axons. Scar tissue that forms locally at the lesion site is thought to block axonal regeneration, resulting in permanent functional deficits. We report that inhibiting the generation of progeny by a subclass of pericytes led to decreased fibrosis and extracellular matrix deposition after spinal cord injury in mice. Regeneration of raphespinal and corticospinal tract axons was enhanced and sensorimotor function recovery improved following spinal cord injury in animals with attenuated pericyte-derived scarring. Using optogenetic stimulation, we demonstrate that regenerated corticospinal tract axons integrated into the local spinal cord circuitry below the lesion site. The number of regenerated axons correlated with improved sensorimotor function recovery. In conclusion, attenuation of pericyte-derived fibrosis represents a promising therapeutic approach to facilitate recovery following CNS injury.
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http://dx.doi.org/10.1016/j.cell.2018.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871719PMC
March 2018

Meningioma growth dynamics assessed by radiocarbon retrospective birth dating.

EBioMedicine 2018 Jan 19;27:176-181. Epub 2017 Dec 19.

Department of Cell and Molecular Biology, Karolinska Institute, Sweden. Electronic address:

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 C, 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±6.5years, whereas atypical WHO grade II meningiomas originated 1.5±0.1years 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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http://dx.doi.org/10.1016/j.ebiom.2017.12.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828546PMC
January 2018

The Lifespan and Turnover of Microglia in the Human Brain.

Cell Rep 2017 07;20(4):779-784

Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden. Electronic address:

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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http://dx.doi.org/10.1016/j.celrep.2017.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540680PMC
July 2017

Cardiomyocyte Regeneration: A Consensus Statement.

Circulation 2017 08 6;136(7):680-686. Epub 2017 Jul 6.

From Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg Eppendorf, Hamburg, Germany (T.E.); DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany (T.E.) and partner site Rhein/Main, Bad Nauheim, Germany (T.B.); Institute of Molecular Cardiology, University of Louisville, Louisville, KY (R.B.); Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (T.B.); Department of Internal Medicine II, University of Giessen, Germany (T.B.); German Center for Lung Research (DZHL), Giessen/Marburg Bad Nauheim, Bad Nauheim, Germany (T.B.); Krannert Institute of Cardiology and Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis (L.J.F.); Institute of Physiology I, Life and Brain Center, Medical Faculty, University of Bonn, Germany (B.K.F.); Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden (J.F.); International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy (M.G.); Donald Soffer Endowed Program in Regenerative Medicine, Miller School of Medicine, Miami, FL (J.M.H.); Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (J.M.H.); Department of Physiology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA (S.H.); Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA (R.T.L.); Cedars-Sinai Heart Institute, Los Angeles, CA (E.M.); Cardiomyocyte Renewal Laboratory, Texas Heart Institute, Houston (J.F.M.); Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX (J.F.M.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (J.D.M.); Departments of Pathology, Bioengineering, and Medicine/Cardiology, Institute for Stem Cell and Regenerative Medicine, and Center for Cardiovascular Biology, University of Washington, Seattle (C.E.M.); University of Oxford, Department of Physiology, Anatomy and Genetics, United Kingdom (P.R.R.) Regencor, Inc, Los Altos, CA (P.R.-L.); Departments of Internal Medicine (Division of Cardiology) and Molecular Biology, UT Southwestern Medical Center, Dallas, TX (H.A.S., J.A.H.); and Heart Institute, Integrated Regenerative Research Institute, and Biology Department, San Diego State University, CA (M.S.A.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.029343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557671PMC
August 2017

Comparison of whole genome amplification techniques for human single cell exome sequencing.

PLoS One 2017 16;12(2):e0171566. Epub 2017 Feb 16.

Scilifelab, Division of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden.

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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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0171566PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5313163PMC
August 2017

Antibody-secreting plasma cells persist for decades in human intestine.

J Exp Med 2017 02 19;214(2):309-317. Epub 2017 Jan 19.

Department of Pathology, Centre for Immune Regulation, Oslo University Hospital-Rikshospitalet and The University of Oslo, 0372 Oslo, Norway

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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http://dx.doi.org/10.1084/jem.20161590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294861PMC
February 2017

Analysis of allelic expression patterns in clonal somatic cells by single-cell RNA-seq.

Nat Genet 2016 11 26;48(11):1430-1435. Epub 2016 Sep 26.

Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.

Cellular heterogeneity can emerge from the expression of only one parental allele. However, it has remained controversial whether, or to what degree, random monoallelic expression of autosomal genes (aRME) is mitotically inherited (clonal) or stochastic (dynamic) in somatic cells, particularly in vivo. Here we used allele-sensitive single-cell RNA-seq on clonal primary mouse fibroblasts and freshly isolated human CD8 T cells to dissect clonal and dynamic monoallelic expression patterns. Dynamic aRME affected a considerable portion of the cells' transcriptomes, with levels dependent on the cells' transcriptional activity. Notably, clonal aRME was detected, but it was surprisingly scarce (<1% of genes) and mainly affected the most weakly expressed genes. Consequently, the overwhelming majority of aRME occurs transiently within individual cells, and patterns of aRME are thus primarily scattered throughout somatic cell populations rather than, as previously hypothesized, confined to patches of clonally related cells.
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http://dx.doi.org/10.1038/ng.3678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5117254PMC
November 2016