Lorenz Studer

Cornell University, Итак, New York, United States

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Publications (136)1687.27 Total impact

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    ABSTRACT: Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the accumulation of protein aggregates comprised of α-synuclein (α-syn). A major barrier in treatment discovery for PD is the lack of identifiable therapeutic pathways capable of reducing aggregates in human neuronal model systems. Mutations in key components of protein trafficking and cellular degradation machinery represent important risk factors for PD; however, their precise role in disease progression and interaction with α-syn remains unclear. Here, we find that α-syn accumulation reduced lysosomal degradation capacity in human midbrain dopamine models of synucleinopathies through disrupting hydrolase trafficking. Accumulation of α-syn at the cell body resulted in aberrant association with cis-Golgi-tethering factor GM130 and disrupted the endoplasmic reticulum-Golgi localization of rab1a, a key mediator of vesicular transport. Overexpression of rab1a restored Golgi structure, improved hydrolase trafficking and activity, and reduced pathological α-syn in patient neurons. Our work suggests that enhancement of lysosomal hydrolase trafficking may prove beneficial in synucleinopathies and indicates that human midbrain disease models may be useful for identifying critical therapeutic pathways in PD and related disorders.
    No preview · Article · Feb 2016 · Proceedings of the National Academy of Sciences
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    Full-text · Dataset · Jan 2016
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    ABSTRACT: Capturing the full potential of human pluripotent stem cell (PSC)-derived neurons in disease modeling and regenerative medicine requires analysis in complex functional systems. Here we establish optogenetic control in human PSC-derived spinal motorneurons and show that co-culture of these cells with human myoblast-derived skeletal muscle builds a functional all-human neuromuscular junction that can be triggered to twitch upon light stimulation. To model neuromuscular disease we incubated these co-cultures with IgG from myasthenia gravis patients and active complement. Myasthenia gravis is an autoimmune disorder that selectively targets neuromuscular junctions. We saw a reversible reduction in the amplitude of muscle contractions, representing a surrogate marker for the characteristic loss of muscle strength seen in this disease. The ability to recapitulate key aspects of disease pathology and its symptomatic treatment suggests that this neuromuscular junction assay has significant potential for modeling of neuromuscular disease and regeneration.
    Full-text · Article · Jan 2016 · Cell Stem Cell
  • Nadja Zeltner · Lorenz Studer
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    ABSTRACT: Human induced pluripotent stem cells (hiPSCs) can yield unlimited numbers of patient-specific cells of any type and may be an important tool in efforts to overcome current shortcomings in biomedical research. In vitro disease models based on the use of hiPSCs have been proposed for various applications. Those include drug discovery and validation, efficacy, safety and toxicity assays, the elucidation of previously unknown disease mechanisms, the enhancement of animal based assays, the promise of conducting clinical trials in the dish and the identification of cell types and stages suitable for cell replacement therapies. Here, we provide an overview of the current state of hiPSC-based disease modeling and discuss recent progress and remaining challenges on the road to realizing the full potential of this novel technology.
    No preview · Article · Dec 2015 · Current opinion in cell biology
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    ABSTRACT: As a group, we met to discuss the current challenges for creating meaningful patient-specific in vitro models to study brain disorders. Although the convergence of findings between laboratories and patient cohorts provided us confidence and optimism that hiPSC-based platforms will inform future drug discovery efforts, a number of critical technical challenges remain. This opinion piece outlines our collective views on the current state of hiPSC-based disease modeling and discusses what we see to be the critical objectives that must be addressed collectively as a field.
    Full-text · Article · Nov 2015 · Stem Cell Reports
  • Daniela Cornacchia · Lorenz Studer
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    ABSTRACT: The advent of induced pluripotent stem cells (iPSC) has transformed the classic approach of studying human disease, providing in vitro access to disease-relevant cells from patients for the study of disease pathogenesis and for drug screening. However, in spite of the broad repertoire of iPSC-based disease models developed in recent years, increasing evidence suggests that this technology might not be fully suitable for the study of conditions of old age, such as neurodegeneration. The difficulty in recapitulating late-stage features of disease in cells of pluripotent origin is believed to be a discrepancy between the fetal-like nature of iPSC-progeny and the advanced age of onset of neurodegenerative syndromes. In parallel to the issue of functional immaturity known to affect derivatives of pluripotent cells, latest findings suggest that reprogramming also subjects cells to a process of "rejuvenation", giving rise to cells that are too "young" to manifest phenotypes of age-related diseases. Thus, following the significant progress in manipulating cellular fate, the stem cell field will now have to face the new challenge of controlling cellular age, in order to fully harness the potential of iPSC-technology to advance the research and cure of diseases of the aging brain. This article is part of a Special Issue entitled SI: Exploiting human neurons.
    No preview · Article · Nov 2015 · Brain research
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    Full-text · Dataset · Oct 2015
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    ABSTRACT: Translating new cell-based therapies to the clinic for patients with neurodegenerative disorders is complex. It involves pre-clinical testing of the cellular product and discussions with several regulatory agencies, as well as ethical debates. In an attempt to support efforts around the world, we set up a global consortium that brings together the major funded teams working on developing a stem cell-derived neural transplantation therapy for Parkinson’s disease (PD). This consortium, G-Force PD, involves teams from Europe, USA, and Japan, and has already met on two occasions to discuss common problems, solutions, and the roadmap to the clinic. In this short review, we lay out the brief history and rationale for this initiative and discuss some of the issues that arose in our most recent meeting (May 2015) as we consider undertaking first-in-human clinical trials with stem cell-derived neurons for PD.
    Preview · Article · Sep 2015
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    Elsa Vera · Lorenz Studer
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    ABSTRACT: In contrast to the successful modeling of early-onset disorders using patient-specific cells, modeling of late-onset neurodegenerative diseases such as Parkinson's disease remains a challenge. This might be related to the often ignored fact that current induced pluripotent stem cell (iPSC) differentiation protocols yield cells that typically show the behavior of fetal stage cells. Acknowledging aging as a contributing factor in late-onset neurodegenerative disorders represents an important step on the road towards faithfully recreating these diseases in vitro. Here, we summarize progress in the field and review the strategies and challenges for triggering late-onset disease phenotypes.
    Full-text · Article · Sep 2015 · Development
  • Faranak Fattahi · Lorenz Studer · Mark J Tomishima
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    ABSTRACT: Neural crest (NC) cells are migratory multipotent progenitors that delaminate from the neural tube during embryonic development and give rise to various cell types in different organs. These cells are a transient embryonic cell population and therefore difficult to obtain from primary sources. Deriving NC from human pluripotent stem cells offers an alternative way to provide large-scale human NC cells for developmental and disease-related studies. In recent years, the protocols to make these cells have matured, incorporating the efficient conversion of pluripotent stem cells to neural cells through dual SMAD inhibition and early Wnt activation to increase the yield of NC cells. Here, we provide a minor variation to this NC protocol that has been successful for many in our laboratories. © 2015 by John Wiley & Sons, Inc.
    No preview · Article · Sep 2015 · Current protocols in stem cell biology
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    ABSTRACT: The derivation of somatic motoneurons (MNs) from ES cells (ESCs) after exposure to sonic hedgehog (SHH) and retinoic acid (RA) is one of the best defined, directed differentiation strategies to specify fate in pluripotent lineages. In mouse ESCs,MNyield is particularly high after RA + SHH treatment, whereas human ESC (hESC) protocols have been generally less efficient. In an effort to optimize yield, we observe that functional MNs can be derived from hESCs at high efficiencies if treated with patterning molecules at very early differentiation steps before neural induction. Remarkably, under these conditions, equal numbers of human MNs were obtained in the presence or absence of SHH exposure. Using pharmacological and genetic strategies, we demonstrate that early RA treatment directsMNdifferentiation independently of extrinsicSHHactivation by suppressing the induction of GLI3.We further demonstrate that neural induction triggers a switch from a poised to an active chromatin state at GLI3. Early RA treatment prevents this switch by direct binding of the RA receptor at the GLI3 promoter. Furthermore, GLI3 knock-out hESCs can bypass the requirement for early RA patterning to yield MNs efficiently. Our data demonstrate that RAmediated suppression of GLI3 is sufficient to generate MNs in an SHH-independent manner and that temporal changes in exposure to patterning factors such as RA affect chromatin state and competency of hESC-derived lineages to adopt specific neuronal fates. Finally, our work presents a streamlined platform for the highly efficient derivation of human MNs from ESCs and induced pluripotent stem cells.
    Full-text · Article · Aug 2015 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: Mammalian NOTCH1-4 receptors are all associated with human malignancy, although exact roles remain enigmatic. Here we employ glp-1(ar202), a temperature-sensitive gain-of-function C. elegans NOTCH mutant, to delineate NOTCH-driven tumor responses to radiotherapy. At ≤20°C, glp-1(ar202) is wild-type, whereas at 25°C it forms a germline stem cell⁄progenitor cell tumor reminiscent of human cancer. We identify a NOTCH tumor phenotype in which all tumor cells traffic rapidly to G2⁄M post-irradiation, attempt to repair DNA strand breaks exclusively via homology-driven repair, and when this fails die by mitotic death. Homology-driven repair inactivation is dramatically radiosensitizing. We show that these concepts translate directly to human cancer models.
    Full-text · Article · Jun 2015 · PLoS ONE
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    Lorenz Studer · Elsa Vera · Daniela Cornacchia
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    ABSTRACT: The ability to reprogram adult somatic cells back to pluripotency presents a powerful tool for studying cell-fate identity and modeling human disease. However, the reversal of cellular age during reprogramming results in an embryonic-like state of induced pluripotent stem cells (iPSCs) and their derivatives, which presents specific challenges for modeling late onset disease. This age reset requires novel methods to mimic age-related changes but also offers opportunities for studying cellular rejuvenation in real time. Here, we discuss how iPSC research may transform studies of aging and enable the precise programming of cellular age in parallel to cell-fate specification. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Jun 2015 · Cell stem cell
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    ABSTRACT: Herpes simplex virus 1 (HSV-1) is a common virus that can rarely invade the human central nervous system (CNS), causing devastating encephalitis. The permissiveness to HSV-1 of the various relevant cell types of the CNS, neurons, astrocytes, oligodendrocytes, and microglia cells, as well as their response to viral infection, has been extensively studied in humans and other animals. Nevertheless, human CNS cell-based models of anti-HSV-1 immunity are of particular importance, as responses to any given neurotropic virus may differ between humans and other animals. Human CNS neuron cell lines as well as primary human CNS neurons, astrocytes, and microglia cells cultured/isolated from embryos or cadavers, have enabled the study of cell-autonomous anti-HSV-1 immunity in vitro. However, the paucity of biological samples and their lack of purity have hindered progress in the field, which furthermore suffers from the absence of testable primary human oligodendrocytes. Recently, the authors have established a human induced pluripotent stem cells (hiPSCs)-based model of anti-HSV-1 immunity in neurons, oligodendrocyte precursor cells, astrocytes, and neural stem cells, which has widened the scope of possible in vitro studies while permitting in-depth explorations. This mini-review summarizes the available data on human primary and iPSC-derived CNS cells for anti-HSV-1 immunity. The hiPSC-mediated study of anti-viral immunity in both healthy individuals and patients with viral encephalitis will be a powerful tool in dissecting the disease pathogenesis of CNS infections with HSV-1 and other neurotropic viruses.
    Full-text · Article · May 2015 · Frontiers in Immunology
  • Julius A Steinbeck · Lorenz Studer
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    ABSTRACT: Stem cell-based therapies hold considerable promise for many currently devastating neurological disorders. Substantial progress has been made in the derivation of disease-relevant human donor cell populations. Behavioral data in relevant animal models of disease have demonstrated therapeutic efficacy for several cell-based approaches. Consequently, cGMP grade cell products are currently being developed for first in human clinical trials in select disorders. Despite the therapeutic promise, the presumed mechanism of action of donor cell populations often remains insufficiently validated. It depends greatly on the properties of the transplanted cell type and the underlying host pathology. Several new technologies have become available to probe mechanisms of action in real time and to manipulate in vivo cell function and integration to enhance therapeutic efficacy. Results from such studies generate crucial insight into the nature of brain repair that can be achieved today and push the boundaries of what may be possible in the future. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Apr 2015 · Neuron
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    ABSTRACT: Epigenetic regulation of key transcriptional programs is a critical mechanism that controls hematopoietic development, and, thus, aberrant expression patterns or mutations in epigenetic regulators occur frequently in hematologic malignancies. We demonstrate that the Polycomb protein L3MBTL1, which is monoallelically deleted in 20q- myeloid malignancies, represses the ability of stem cells to drive hematopoietic-specific transcriptional programs by regulating the expression of SMAD5 and impairing its recruitment to target regulatory regions. Indeed, knockdown of L3MBTL1 promotes the development of hematopoiesis and impairs neural cell fate in human pluripotent stem cells. We also found a role for L3MBTL1 in regulating SMAD5 target gene expression in mature hematopoietic cell populations, thereby affecting erythroid differentiation. Taken together, we have identified epigenetic priming of hematopoietic-specific transcriptional networks, which may assist in the development of therapeutic approaches for patients with anemia. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Mar 2015 · Stem Cell Reports
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    ABSTRACT: Hypothalamic neurons orchestrate many essential physiological and behavioral processes via secreted neuropeptides, and are relevant to human diseases such as obesity, narcolepsy and infertility. We report the differentiation of human pluripotent stem cells into many of the major types of neuropeptidergic hypothalamic neurons, including those producing pro-opiolemelanocortin, agouti-related peptide, hypocretin/orexin, melanin-concentrating hormone, oxytocin, arginine vasopressin, corticotropin-releasing hormone (CRH) or thyrotropin-releasing hormone. Hypothalamic neurons can be generated using a 'self-patterning' strategy that yields a broad array of cell types, or via a more reproducible directed differentiation approach. Stem cell-derived human hypothalamic neurons share characteristic morphological properties and gene expression patterns with their counterparts in vivo, and are able to integrate into the mouse brain. These neurons could form the basis of cellular models, chemical screens or cellular therapies to study and treat common human diseases. © 2015. Published by The Company of Biologists Ltd.
    Full-text · Article · Feb 2015 · Development
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    ABSTRACT: Recent studies have shown evidence of behavioral recovery after transplantation of human pluripotent stem cell (PSC)-derived neural cells in animal models of neurological disease. However, little is known about the mechanisms underlying graft function. Here we use optogenetics to modulate in real time electrophysiological and neurochemical properties of mesencephalic dopaminergic (mesDA) neurons derived from human embryonic stem cells (hESCs). In mice that had recovered from lesion-induced Parkinsonian motor deficits, light-induced selective silencing of graft activity rapidly and reversibly re-introduced the motor deficits. The re-introduction of motor deficits was prevented by the dopamine agonist apomorphine. These results suggest that functionality depends on graft neuronal activity and dopamine release. Combining optogenetics, slice electrophysiology and pharmacological approaches, we further show that mesDA-rich grafts modulate host glutamatergic synaptic transmission onto striatal medium spiny neurons in a manner reminiscent of endogenous mesDA neurons. Thus, application of optogenetics in cell therapy can link transplantation, animal behavior and postmortem analysis to enable the identification of mechanisms that drive recovery.
    Full-text · Article · Jan 2015 · Nature Biotechnology
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    ABSTRACT: The long-term risk of malignancy associated with stem cell therapies is a significant concern in the clinical application of this exciting technology. We report a cancer-selective strategy to enhance the safety of stem cell therapies. Briefly, using a cell engineering approach, we show that aggressive cancers derived from human or murine induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) are strikingly sensitive to temporary MYC blockade. On the other hand, differentiated tissues derived from human or mouse iPSCs can readily tolerate temporary MYC inactivation. In cancer cells, endogenous MYC is required to maintain the metabolic and epigenetic functions of the embryonic and cancer-specific pyruvate kinase M2 isoform (PKM2). In summary, our results implicate PKM2 in cancer's increased MYC dependence and indicate dominant MYC inhibition as a cancer-selective fail-safe for stem cell therapies.
    Full-text · Article · Sep 2014 · Cell Reports
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    ABSTRACT: Human pluripotent stem cells (hPSCs) have great potential for studying human embryonic development, for modeling human diseases in the dish and as a source of transplantable cells for regenerative applications after disease or accidents. Neural crest (NC) cells are the precursors for a large variety of adult somatic cells, such as cells from the peripheral nervous system and glia, melanocytes and mesenchymal cells. They are a valuable source of cells to study aspects of human embryonic development, including cell fate specification and migration. Further differentiation of NC progenitor cells into terminally differentiated cell types offers the possibility to model human diseases in vitro, investigate disease mechanisms and generate cells for regenerative medicine. This article presents the adaptation of a currently available in vitro differentiation protocol for the derivation of NC cells from hPSCs. This new protocol requires 18 days of differentiation, is feeder-free, easily scalable and highly reproducible among human embryonic stem cell (hESC) lines as well as human induced pluripotent stem cell (hiPSC) lines. Both old and new protocols yield NC cells of equal identity.
    Preview · Article · May 2014 · Journal of Visualized Experiments

Publication Stats

11k Citations
1,687.27 Total Impact Points

Institutions

  • 2015
    • Cornell University
      Итак, New York, United States
  • 2000-2015
    • Memorial Sloan-Kettering Cancer Center
      • • Division of Developmental Biology
      • • Department of Radiology
      New York, New York, United States
    • National Institutes of Health
      • Laboratory of Molecular Biology
      Maryland, United States
  • 2013
    • The Rockefeller University
      • Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology
      New York, New York, United States
  • 2003-2010
    • Weill Cornell Medical College
      • Department of Neurology and Neuroscience
      New York, New York, United States
  • 2006
    • City of Hope National Medical Center
      • Department of Neurosciences
      Duarte, CA, United States
  • 2002
    • Wake Forest University
      • School of Medicine
      Winston-Salem, North Carolina, United States
  • 1996
    • Universität Bern
      Berna, Bern, Switzerland
    • Paul Scherrer Institut
      Aargau, Switzerland