Publications by authors named "Ulrich Pfisterer"

20 Publications

  • Page 1 of 1

Coordinated maintenance of H3K36/K27 methylation by histone demethylases preserves germ cell identity and immortality.

Cell Rep 2021 Nov;37(8):110050

Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes vej 5, Copenhagen DK-2200, Denmark. Electronic address:

Germ cells have evolved unique mechanisms to ensure the transmission of genetically and nongenetically encoded information, whose alteration compromises germ cell immortality. Chromatin factors play fundamental roles in these mechanisms. H3K36 and H3K27 methyltransferases shape and propagate a pattern of histone methylation essential for C. elegans germ cell maintenance, but the role of respective histone demethylases remains unexplored. Here, we show that jmjd-5 regulates H3K36me2 and H3K27me3 levels, preserves germline immortality, and protects germ cell identity by controlling gene expression. The transcriptional and biological effects of jmjd-5 loss can be hindered by the removal of H3K27demethylases, indicating that H3K36/K27 demethylases act in a transcriptional framework and promote the balance between H3K36 and H3K27 methylation required for germ cell immortality. Furthermore, we find that in wild-type, but not in jmjd-5 mutants, alterations of H3K36 methylation and transcription occur at high temperature, suggesting a role for jmjd-5 in adaptation to environmental changes.
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http://dx.doi.org/10.1016/j.celrep.2021.110050DOI Listing
November 2021

Single-cell sequencing in translational cancer research and challenges to meet clinical diagnostic needs.

Genes Chromosomes Cancer 2021 07 15;60(7):504-524. Epub 2021 Mar 15.

Center for Translational Genomics, Lund University, Lund, Sweden.

The ability to capture alterations in the genome or transcriptome by next-generation sequencing has provided critical insight into molecular changes and programs underlying cancer biology. With the rapid technological development in single-cell sequencing, it has become possible to study individual cells at the transcriptional, genetic, epigenetic, and protein level. Using single-cell analysis, an increased resolution of fundamental processes underlying cancer development is obtained, providing comprehensive insights otherwise lost by sequencing of entire (bulk) samples, in which molecular signatures of individual cells are averaged across the entire cell population. Here, we provide a concise overview on the application of single-cell analysis of different modalities within cancer research by highlighting key articles of their respective fields. We furthermore examine the potential of existing technologies to meet clinical diagnostic needs and discuss current challenges associated with this translation.
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http://dx.doi.org/10.1002/gcc.22944DOI Listing
July 2021

Author Correction: Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis.

Nat Commun 2020 Nov 19;11(1):5988. Epub 2020 Nov 19.

Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-19869-5.
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http://dx.doi.org/10.1038/s41467-020-19869-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678822PMC
November 2020

Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis.

Nat Commun 2020 10 7;11(1):5038. Epub 2020 Oct 7.

Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.

Epilepsy is one of the most common neurological disorders, yet its pathophysiology is poorly understood due to the high complexity of affected neuronal circuits. To identify dysfunctional neuronal subtypes underlying seizure activity in the human brain, we have performed single-nucleus transcriptomics analysis of >110,000 neuronal transcriptomes derived from temporal cortex samples of multiple temporal lobe epilepsy and non-epileptic subjects. We found that the largest transcriptomic changes occur in distinct neuronal subtypes from several families of principal neurons (L5-6_Fezf2 and L2-3_Cux2) and GABAergic interneurons (Sst and Pvalb), whereas other subtypes in the same families were less affected. Furthermore, the subtypes with the largest epilepsy-related transcriptomic changes may belong to the same circuit, since we observed coordinated transcriptomic shifts across these subtypes. Glutamate signaling exhibited one of the strongest dysregulations in epilepsy, highlighted by layer-wise transcriptional changes in multiple glutamate receptor genes and strong upregulation of genes coding for AMPA receptor auxiliary subunits. Overall, our data reveal a neuronal subtype-specific molecular phenotype of epilepsy.
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http://dx.doi.org/10.1038/s41467-020-18752-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541486PMC
October 2020

A community-based transcriptomics classification and nomenclature of neocortical cell types.

Nat Neurosci 2020 12;23(12):1456-1468

Vanderbilt University, Nashville, TN, USA.

To understand the function of cortical circuits, it is necessary to catalog their cellular diversity. Past attempts to do so using anatomical, physiological or molecular features of cortical cells have not resulted in a unified taxonomy of neuronal or glial cell types, partly due to limited data. Single-cell transcriptomics is enabling, for the first time, systematic high-throughput measurements of cortical cells and generation of datasets that hold the promise of being complete, accurate and permanent. Statistical analyses of these data reveal clusters that often correspond to cell types previously defined by morphological or physiological criteria and that appear conserved across cortical areas and species. To capitalize on these new methods, we propose the adoption of a transcriptome-based taxonomy of cell types for mammalian neocortex. This classification should be hierarchical and use a standardized nomenclature. It should be based on a probabilistic definition of a cell type and incorporate data from different approaches, developmental stages and species. A community-based classification and data aggregation model, such as a knowledge graph, could provide a common foundation for the study of cortical circuits. This community-based classification, nomenclature and data aggregation could serve as an example for cell type atlases in other parts of the body.
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http://dx.doi.org/10.1038/s41593-020-0685-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683348PMC
December 2020

Complex IV subunit isoform COX6A2 protects fast-spiking interneurons from oxidative stress and supports their function.

EMBO J 2020 09 3;39(18):e105759. Epub 2020 Aug 3.

Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Parvalbumin-positive (PV ) fast-spiking interneurons are essential to control the firing activity of principal neuron ensembles, thereby regulating cognitive processes. The high firing frequency activity of PV interneurons imposes high-energy demands on their metabolism that must be supplied by distinctive machinery for energy generation. Exploring single-cell transcriptomic data for the mouse cortex, we identified a metabolism-associated gene with highly restricted expression to PV interneurons: Cox6a2, which codes for an isoform of a cytochrome c oxidase subunit. Cox6a2 deletion in mice disrupts perineuronal nets and enhances oxidative stress in PV interneurons, which in turn impairs the maturation of their morphological and functional properties. Such dramatic effects were likely due to an essential role of COX6A2 in energy balance of PV interneurons, underscored by a decrease in the ATP-to-ADP ratio in Cox6a2 PV interneurons. Energy disbalance and aberrant maturation likely hinder the integration of PV interneurons into cortical neuronal circuits, leading to behavioral alterations in mice. Additionally, in a human patient bearing mutations in COX6A2, we found a potential association of the mutations with mental/neurological abnormalities.
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http://dx.doi.org/10.15252/embj.2020105759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507454PMC
September 2020

Genetic modification increases the survival and the neuroregenerative properties of transplanted neural stem cells.

JCI Insight 2020 02 27;5(4). Epub 2020 Feb 27.

Biotech Research & Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

Cell therapy raises hopes high for better treatment of brain disorders. However, the majority of transplanted cells often die soon after transplantation, and those that survive initially continue to die in the subacute phase, diminishing the impact of transplantations. In this study, we genetically modified transplanted human neural stem cells (hNSCs), from 2 distant embryonic stem cell lines (H9 and RC17), to express 1 of 4 prosurvival factors - Hif1a, Akt1, Bcl-2, or Bcl-xl - and studied how these modifications improve short- and long-term survival of transplanted hNSCs. All genetic modifications dramatically increased survival of the transplanted hNSCs. Importantly, 3 out of 4 modifications also enhanced the exit of hNSCs from the cell cycle, thus avoiding aberrant growth of the transplants. Bcl-xl expression provided the strongest protection of transplanted cells, reducing both immediate and delayed cell death, and stimulated hNSC differentiation toward neuronal and oligodendroglial lineages. By designing hNSCs with drug-controlled expression of Bcl-xl, we demonstrated that short-term expression of a prosurvival factor can ensure the long-term survival of transplanted cells. Importantly, transplantation of Bcl-xl-expressing hNSCs into mice suffering from stroke improved behavioral outcome and recovery of motor activity in mice.
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http://dx.doi.org/10.1172/jci.insight.126268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101138PMC
February 2020

Maternal inflammation has a profound effect on cortical interneuron development in a stage and subtype-specific manner.

Mol Psychiatry 2020 10 8;25(10):2313-2329. Epub 2019 Oct 8.

Biotech Research and Innovation Centre (BRIC), Faculty of Health, University of Copenhagen, Copenhagen N, Denmark.

Severe infections during pregnancy are one of the major risk factors for cognitive impairment in the offspring. It has been suggested that maternal inflammation leads to dysfunction of cortical GABAergic interneurons that in turn underlies cognitive impairment of the affected offspring. However, the evidence comes largely from studies of adult or mature brains and how the impairment of inhibitory circuits arises upon maternal inflammation is unknown. Here we show that maternal inflammation affects multiple steps of cortical GABAergic interneuron development, i.e., proliferation of precursor cells, migration and positioning of neuroblasts, as well as neuronal maturation. Importantly, the development of distinct subtypes of cortical GABAergic interneurons was discretely impaired as a result of maternal inflammation. This translated into a reduction in cell numbers, redistribution across cortical regions and layers, and changes in morphology and cellular properties. Furthermore, selective vulnerability of GABAergic interneuron subtypes was associated with the stage of brain development. Thus, we propose that maternally derived insults have developmental stage-dependent effects, which contribute to the complex etiology of cognitive impairment in the affected offspring.
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http://dx.doi.org/10.1038/s41380-019-0539-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515848PMC
October 2020

Directly Converted Human Fibroblasts Mature to Neurons and Show Long-Term Survival in Adult Rodent Hippocampus.

Stem Cells Int 2017 26;2017:5718608. Epub 2017 Nov 26.

Epilepsy Centre, Lund University Hospital, Lund, Sweden.

Direct conversion of human somatic cells to induced neurons (iNs), using lineage-specific transcription factors has opened new opportunities for cell therapy in a number of neurological diseases, including epilepsy. In most severe cases of epilepsy, seizures often originate in the hippocampus, where populations of inhibitory interneurons degenerate. Thus, iNs could be of potential use to replace these lost interneurons. It is not known, however, if iNs survive and maintain functional neuronal properties for prolonged time periods in . We transplanted human fibroblast-derived iNs into the adult rat hippocampus and observed a progressive morphological differentiation, with more developed dendritic arborisation at six months as compared to one month. This was accompanied by mature electrophysiological properties and fast high amplitude action potentials at six months after transplantation. This proof-of-principle study suggests that human iNs can be developed as a candidate source for cell replacement therapy in temporal lobe epilepsy.
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http://dx.doi.org/10.1155/2017/5718608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727793PMC
November 2017

Constitutively Active SMAD2/3 Are Broad-Scope Potentiators of Transcription-Factor-Mediated Cellular Reprogramming.

Cell Stem Cell 2017 Dec 22;21(6):791-805.e9. Epub 2017 Nov 22.

MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh BioQuarter, 5 Little France Drive, Edinburgh EH16 4UU, Scotland, UK. Electronic address:

Reprogramming of cellular identity using exogenous expression of transcription factors (TFs) is a powerful and exciting tool for tissue engineering, disease modeling, and regenerative medicine. However, generation of desired cell types using this approach is often plagued by inefficiency, slow conversion, and an inability to produce mature functional cells. Here, we show that expression of constitutively active SMAD2/3 significantly improves the efficiency of induced pluripotent stem cell (iPSC) generation by the Yamanaka factors. Mechanistically, SMAD3 interacts with reprogramming factors and co-activators and co-occupies OCT4 target loci during reprogramming. Unexpectedly, active SMAD2/3 also markedly enhances three other TF-mediated direct reprogramming conversions, from B cells to macrophages, myoblasts to adipocytes, and human fibroblasts to neurons, highlighting broad and general roles for SMAD2/3 as cell-reprogramming potentiators. Our results suggest that co-expression of active SMAD2/3 could enhance multiple types of TF-based cell identity conversion and therefore be a powerful tool for cellular engineering.
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http://dx.doi.org/10.1016/j.stem.2017.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732323PMC
December 2017

Neuronal survival in the brain: neuron type-specific mechanisms.

Cell Death Dis 2017 03 2;8(3):e2643. Epub 2017 Mar 2.

Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.

Neurogenic regions of mammalian brain produce many more neurons that will eventually survive and reach a mature stage. Developmental cell death affects both embryonically produced immature neurons and those immature neurons that are generated in regions of adult neurogenesis. Removal of substantial numbers of neurons that are not yet completely integrated into the local circuits helps to ensure that maturation and homeostatic function of neuronal networks in the brain proceed correctly. External signals from brain microenvironment together with intrinsic signaling pathways determine whether a particular neuron will die. To accommodate this signaling, immature neurons in the brain express a number of transmembrane factors as well as intracellular signaling molecules that will regulate the cell survival/death decision, and many of these factors cease being expressed upon neuronal maturation. Furthermore, pro-survival factors and intracellular responses depend on the type of neuron and region of the brain. Thus, in addition to some common neuronal pro-survival signaling, different types of neurons possess a variety of 'neuron type-specific' pro-survival constituents that might help them to adapt for survival in a certain brain region. This review focuses on how immature neurons survive during normal and impaired brain development, both in the embryonic/neonatal brain and in brain regions associated with adult neurogenesis, and emphasizes neuron type-specific mechanisms that help to survive for various types of immature neurons. Importantly, we mainly focus on in vivo data to describe neuronal survival specifically in the brain, without extrapolating data obtained in the PNS or spinal cord, and thus emphasize the influence of the complex brain environment on neuronal survival during development.
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http://dx.doi.org/10.1038/cddis.2017.64DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386560PMC
March 2017

Small molecules increase direct neural conversion of human fibroblasts.

Sci Rep 2016 12 5;6:38290. Epub 2016 Dec 5.

Department of Experimental Medical Science, Wallenberg Neuroscience Center 221 84, Lund, Sweden.

The generation of human induced neurons (hiNs) via exogenous delivery of neural transcription factors represents a novel technique to obtain disease and patient specific neurons. These cells have the potential to be used for disease modeling, diagnostics and drug screening, and also to be further developed for brain repair. In the present study, we utilized hiNs to develop an unbiased screening assay for small molecules that increase the conversion efficiency. Using this assay, we screened 307 compounds from five annotated libraries and identified six compounds that were very potent in potentiating the reprogramming process. When combined in an optimal combination and dose, these compounds increased the reprogramming efficiency of human fibroblasts more than 6-fold. Global gene expression and CellNet analysis at different timepoints during the reprogramming process revealed that neuron-specific genes and gene regulatory networks (GRNs) became progressively more activated while converting cells shut down fibroblast-specific GRNs. Further bioinformatics analysis revealed that the addition of the six compound resulted in the accelerated upregulation of a subset of neuronal genes, and also increased expression of genes associated with transcriptional activity and mediation of cellular stress response.
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http://dx.doi.org/10.1038/srep38290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137010PMC
December 2016

hESC-derived neural progenitors prevent xenograft rejection through neonatal desensitisation.

Exp Neurol 2016 08 25;282:78-85. Epub 2016 May 25.

Department of Experimental Medical Science, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, Lund University, Lund, Sweden; Lund Stem Cell Center, Lund University, Lund, Sweden. Electronic address:

Stem cell therapies for neurological disorders are rapidly moving towards use in clinical trials. Before initiation of clinical trials, extensive pre-clinical validation in appropriate animal models is essential. However, grafts of human cells into the rodent brain are rejected within weeks after transplantation and the standard methods of immune-suppression for the purpose of studying human xenografts are not always sufficient for the long-term studies needed for transplanted human neurons to maturate, integrate and provide functional benefits in the host brain. Neonatal injections in rat pups using human fetal brain cells have been shown to desensitise the host to accept human tissue grafts as adults, whilst not compromising their immune system. Here, we show that differentiated human embryonic stem cells (hESCs) can be used for desensitisation to achieve long-term graft survival of human stem cell-derived neurons in a xenograft setting, surpassing the time of conventional pharmacological immune-suppressive treatments. The use of hESCs for desensitisation opens up for a widespread use of the technique, which will be of great value when performing pre-clinical evaluation of stem cell-derived neurons in animal models.
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http://dx.doi.org/10.1016/j.expneurol.2016.05.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4920671PMC
August 2016

Highly efficient generation of induced neurons from human fibroblasts that survive transplantation into the adult rat brain.

Sci Rep 2014 Sep 11;4:6330. Epub 2014 Sep 11.

Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, 221 84 Lund, Sweden.

Induced neurons (iNs) offer a novel source of human neurons that can be explored for applications of disease modelling, diagnostics, drug screening and cell replacement therapy. Here we present a protocol for highly efficient generation of functional iNs from fetal human fibroblasts, and also demonstrate the ability of these converted human iNs (hiNs) to survive transplantation and maintain their phenotype in the adult rat brain. The protocol encompasses a delay in transgene activation after viral transduction that resulted in a significant increase in conversion efficiency. Combining this approach with treatment of small molecules that inhibit SMAD signalling and activate WNT signalling provides a further increase in the conversion efficiency and neuronal purity, resulting in a protocol that provides a highly efficient method for the generation of large numbers of functional and transplantable iNs from human fibroblasts without the use of a selection step. When transplanting the converted neurons from different stages of in vitro culture into the brain of adult rats, we observed robust survival and maintenance of neuronal identity four weeks post-transplantation. Interestingly, the positive effect of small molecule treatment observed in vitro did not result in a higher yield of iNs surviving transplantation.
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http://dx.doi.org/10.1038/srep06330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160709PMC
September 2014

The novel MAPT mutation K298E: mechanisms of mutant tau toxicity, brain pathology and tau expression in induced fibroblast-derived neurons.

Acta Neuropathol 2014 Feb 30;127(2):283-95. Epub 2013 Nov 30.

Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, UK.

Frontotemporal lobar degeneration (FTLD) consists of a group of neurodegenerative diseases characterized by behavioural and executive impairment, language disorders and motor dysfunction. About 20-30% of cases are inherited in a dominant manner. Mutations in the microtubule-associated protein tau gene (MAPT) cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T). Here we report a novel MAPT mutation (K298E) in exon 10 in a patient with FTDP-17T. Neuropathological studies of post-mortem brain showed widespread neuronal loss and gliosis and abundant deposition of hyperphosphorylated tau in neurons and glia. Molecular studies demonstrated that the K298E mutation affects both protein function and alternative mRNA splicing. Fibroblasts from a skin biopsy of the proband taken at post-mortem were directly induced into neurons (iNs) and expressed both 3-repeat and 4-repeat tau isoforms. As well as contributing new knowledge on MAPT mutations in FTDP-17T, this is the first example of the successful generation of iNs from skin cells retrieved post-mortem.
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http://dx.doi.org/10.1007/s00401-013-1219-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895181PMC
February 2014

Generation of induced neurons via direct conversion in vivo.

Proc Natl Acad Sci U S A 2013 Apr 25;110(17):7038-43. Epub 2013 Mar 25.

Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, 221 84 Lund, Sweden.

Cellular reprogramming is a new and rapidly emerging field in which somatic cells can be turned into pluripotent stem cells or other somatic cell types simply by the expression of specific combinations of genes. By viral expression of neural fate determinants, it is possible to directly reprogram mouse and human fibroblasts into functional neurons, also known as induced neurons. The resulting cells are nonproliferating and present an alternative to induced pluripotent stem cells for obtaining patient- and disease-specific neurons to be used for disease modeling and for development of cell therapy. In addition, because the cells do not pass a stem cell intermediate, direct neural conversion has the potential to be performed in vivo. In this study, we show that transplanted human fibroblasts and human astrocytes, which are engineered to express inducible forms of neural reprogramming genes, convert into neurons when reprogramming genes are activated after transplantation. Using a transgenic mouse model to specifically direct expression of reprogramming genes to parenchymal astrocytes residing in the striatum, we also show that endogenous mouse astrocytes can be directly converted into neural nuclei (NeuN)-expressing neurons in situ. Taken together, our data provide proof of principle that direct neural conversion can take place in the adult rodent brain when using transplanted human cells or endogenous mouse cells as a starting cell for neural conversion.
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http://dx.doi.org/10.1073/pnas.1303829110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637783PMC
April 2013

Efficient induction of functional neurons from adult human fibroblasts.

Cell Cycle 2011 Oct 1;10(19):3311-6. Epub 2011 Oct 1.

Department of Experimental Medical Science, Lund University, Lund, Sweden.

Cellular reprogramming is a rapidly developing technology by which somatic cells are turned into pluripotent stem cells or other somatic cell types through expression of specific combinations of genes. This allows for the generation of patient-specific cell lines that can serve as tools for understanding disease pathogenesis, for drug screens and, potentially, for cell replacement therapies. Several cellular models of neurological disorders based on induced pluripotent cells (iPS cells) have been developed, and iPS-derived neurons are being explored as candidates for transplantation. Recent findings show that neurons can also be induced directly from embryonic and postnatal somatic cells by expression of defined combinations of genes. This conversion does not occur through a pluripotent stem cell stage, which eliminates the risk for tumor formation. Here, we demonstrate for the first time that functional neurons can be generated via direct conversion of fibroblasts also from adult individuals. Thus, this technology is an attractive alternative to iPS cells for generating patient- and disease-specific neurons suitable for disease modeling and autologous transplantation.
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http://dx.doi.org/10.4161/cc.10.19.17584DOI Listing
October 2011

Direct conversion of human fibroblasts to dopaminergic neurons.

Proc Natl Acad Sci U S A 2011 Jun 6;108(25):10343-8. Epub 2011 Jun 6.

Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, SE-221 84 Lund, Sweden.

Recent reports demonstrate that somatic mouse cells can be directly converted to other mature cell types by using combined expression of defined factors. Here we show that the same strategy can be applied to human embryonic and postnatal fibroblasts. By overexpression of the transcription factors Ascl1, Brn2, and Myt1l, human fibroblasts were efficiently converted to functional neurons. We also demonstrate that the converted neurons can be directed toward distinct functional neurotransmitter phenotypes when the appropriate transcriptional cues are provided together with the three conversion factors. By combining expression of the three conversion factors with expression of two genes involved in dopamine neuron generation, Lmx1a and FoxA2, we could direct the phenotype of the converted cells toward dopaminergic neurons. Such subtype-specific induced neurons derived from human somatic cells could be valuable for disease modeling and cell replacement therapy.
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http://dx.doi.org/10.1073/pnas.1105135108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121829PMC
June 2011
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