Wernig Laboratory

"Only those who attempt the absurd can achieve the impossible."
– Albert Einstein
Our lab is generally interested in the molecular mechanisms that determine cell fates

Recently, we have identified a pool of transcription factors that are sufficient to convert skin fibroblasts directly into functional neuronal cells that we termed induced neuronal (iN) cells. This was a surprising finding and indicated that direct lineage reprogramming may be applicable to many somatic cell types and many different directions. Indeed, following our work others have identified transcription factors that could induce cardiomyocytes, blood progenitors, and hepatocytes from fibroblasts.

We are now focussing on two major aspects of iN and iPS cell reprogramming:

(i) we are fascinated by the puzzle how a hand full of transcription factors can so efficiently reprogram the entire epigenome of a cell so that it changes identity. To that end we are applying genome-wide expression analysis, chromatin immunoprecipitation, protein biochemistry, proteomics and functional screens.

(ii) it is equally exciting to now use reprogramming methods as tools to study or treat certain diseases. iPS cells have the great advantage that they can easily be genetically manipulated rendering them ideal for treating monogenetic disorders when combined with cell transplantation-based therapies. In particular we are working on Dystrophic Epidermolysis Bullosa in collaboration with Stanford's Dermatology Department. An exciting application of iN cell technology will be to try modeling neurological diseases in vitro. We perform both mouse and human experiments hoping to identify quantifiable phenotypes correlated with genotype and in a second step evaluate whether this assay could be used to discover novel drugs improve the disease progression.

Wernig Lab Research

Overview

Our lab is interested in the molecular mechanisms that define neural lineage identity focusing on transcription factors and chromatin biology. We use cellular reprogramming to understand how neurons are induced, how they mature and maintain their identity. Reprogramming also allows us to generate a novel tool box to study human neuronal and glial cell biology which become powerful human disease models in combination with genetic engineering. We further seek to develop reprogramming & genetic engineering approaches towards stem cell-based therapies. Finally, we study microglia-neuron interactions with the ultimate goal to understand the brain's immune system in health and disease and to exploit microglia for therapeutic and regenerative purposes.

induced neuronal cell from fibroblast

Human neuronal cell disease modeling

Neurosychiatric diseases like autism and schizophrenia are highly complex brain disorders difficult to model in mice in part due to complex genetic etiology and sometimes affecting human-specific genes. We develop novel human cell models to investigate disease-relevant cell biological phenomena.

Generation of defined human neuronal cell types to study neuronal cell biology

We have and continue to develop protocols to generate specific types of neurons such as pure glutamatergic and pure GABAergic neurons from human pluripotent stem cells using transcription factors. In combination with genetic engineering or deriving iPS cells from patients, we then interrogate the cell biology of human neurons that carry disease-causing mutations. A particular focus is on synaptic function as shown in the figure on the right on Fragile X Syndrome neurons in collaboration with Lu Chen and Tom Südhof's laboratories.

Making neurons from blood

The ability to generate functional induced neuronal cells from distantly related somatic cell types is fascinating but also offers the opportunity to obtain neurons from a larger cohort of human subjects. In particular blood is readily available and we showed can be efficiently converted into functional neurons from young and aged donors.

Cell scan

Developing next generation cell therapies

The combination of reprogramming and gene editing is truly powerful as it provides exciting new possibilities to generate cells that can be transplanted and have disease modifying activity. We currently apply this approach to restore monogenetic diseases, but our vision goes beyond simple regenerative medicine. We will be able to genetically engineer designer cells that functionally integrate into diseased tissue equipped with sensing and intelligent disease-response mechanisms.

Towards a Phase 1 clinical trial for the fatal skin disease Epidermolysis Bullosa

A rich text element can be used with static or dynamic content. For static content, just drop it into any page and begin editing. For dynamic content, add a rich text field to any collection and then connect a rich text element to that field in the settings panel. Voila!

Exploiting glia cell transplantation to treat neurodegenerative disease

Headings, paragraphs, blockquotes, figures, images, and figure captions can all be styled after a class is added to the rich text element using the "When inside of" nested selector system.

cell scan

Mechanisms of neural cell lineage identity

We are interested in the molecular mechanisms that define neuronal and glial cell identity. We found sets of transcription factors that can convert fibroblasts or lymphocytes into neurons and oligodendrocytes. These factors are also operational during normal development and are largely responsible to induce terminal lineages from progenitor cells.

"On target" pioneer factors and chromatin remodeling during neuronal induction

We found that Ascl1, one of our reprogramming factors, has a unique ability to access its physiological targets even in fibroblasts where these sites are in a closed chromatin configuration. We are fascinated by this "on target" pioneering property and are investigating how Ascl1 can access its target sites in an unfavorable chromatin environment and how it then remodels the chromatin at these sites to activate the neuronal transcriptional program.

Maintenance of neuronal identity

Once neurons are made, there ought to be also mechanisms that maintain neuronal identity. We stumbled upon a novel repressive mechanism: The neuronal-specific transcription factor Myt1l continuosly represses many non-neuronal programs in neurons leaving the neuronal program open to activate by other factors and thereby ensuring stable neuronal gene expression. Myt1l was also recently found to be mutated in autism and schizophrenia.

Mechanisms of neural cell lineage diagram

Microglia-neuron interactions in the healthy and diseased brain

Microglia, the brain's resident immune cells, are fascinating cells. They are derived from yolk sac progenitor cells early during development, are long-lived, and are not exchanged from bone marrow progenitor cells under physiological conditions. Microglia have been implicated in synaptic pruning, adult neurogenesis, and various brain diseases including Alzheimer's disease and Schizophrenia.

Developing an efficient microglia replacement system

We have developed a method to efficiently replace endogenous microglia from circulating cells without genetic manipulation. This does not happen physiologically but under certain conditions peripheral blood cells cross the blood-brain-barrier, migrate into the brain parenchyma and replace endogenous cells. We are investigating the cellular and molecular signals that enable circulating cells to invade the brain in order to further improve microglia replacement strategies.

The role of microglia in the normal and the diseased brain

Our ability to replace microglia provides us with a powerful tool to functionally perturb microglia function in normal and disease states. E.g. the microglial gene TREM2 is a strong Alzheimer's disease risk gene, but major questions about the neuro-immune interplay in the context of neurodegeneration and aging remain unsolved. Microglia replacement also provides an exciting prospect to develop novel cell therapies for a variety of brain diseases including enzyme deficiency syndromes, neurodegeneration, and brain tumors.

Wernig Lab Publications

Heterogeneity in old fibroblasts is linked to variability in reprogramming and wound healing.

Mahmoudi S, Mancini E, Xu L, Moore A, Jahanbani F, Hebestreit K, Srinivasan R, Li X, Devarajan K, Prélot L, Ang CE, Shibuya Y, Benayoun BA, Chang ALS, Wernig M, Wysocka J, Longaker MT, Snyder MP, Brunet A.

Age-associated chronic inflammation (inflammageing) is a central hallmark of ageing1, but its influence on specific cells remains largely unknown. Fibroblasts are present in most tissues and contribute to wound healing2,3. They are also the most widely used cell type for reprogramming to induced pluripotent stem (iPS) cells, a process that has implications for regenerative medicine and rejuvenation strategies4. Here we show that fibroblast cultures from old mice secrete inflammatory cytokines and exhibit increased variability in the efficiency of iPS cell reprogramming between mice. Variability between individuals is emerging as a feature of old age5-8, but the underlying mechanisms remain unknown. To identify drivers of this variability, we performed multi-omics profiling of fibroblast cultures from young and old mice that have different reprogramming efficiencies. This approach revealed that fibroblast cultures from old mice contain 'activated fibroblasts' that secrete inflammatory cytokines, and that the proportion of activated fibroblasts in a culture correlates with the reprogramming efficiency of that culture. Experiments in which conditioned medium was swapped between cultures showed that extrinsic factors secreted by activated fibroblasts underlie part of the variability between mice in reprogramming efficiency, and we have identified inflammatory cytokines, including TNF, as key contributors. Notably, old mice also exhibited variability in wound healing rate in vivo. Single-cell RNA-sequencing analysis identified distinct subpopulations of fibroblasts with different cytokine expression and signalling in the wounds of old mice with slow versus fast healing rates. Hence, a shift in fibroblast composition, and the ratio of inflammatory cytokines that they secrete, may drive the variability between mice in reprogramming in vitro and influence wound healing rate in vivo. This variability may reflect distinct stochastic ageing trajectories between individuals, and could help in developing personalized strategies to improve iPS cell generation and wound healing in elderly individuals.

Pubmed Link
2019
Heterogeneity in old fibroblasts is linked to variability in reprogramming and wound healing.
Nature

Mahmoudi S, Mancini E, Xu L, Moore A, Jahanbani F, Hebestreit K, Srinivasan R, Li X, Devarajan K, Prélot L, Ang CE, Shibuya Y, Benayoun BA, Chang ALS, Wernig M, Wysocka J, Longaker MT, Snyder MP, Brunet A.

View abstract
Hide abstracts
Pubmed listing
There is no abstract listed on Pubmed for this publication

Age-associated chronic inflammation (inflammageing) is a central hallmark of ageing1, but its influence on specific cells remains largely unknown. Fibroblasts are present in most tissues and contribute to wound healing2,3. They are also the most widely used cell type for reprogramming to induced pluripotent stem (iPS) cells, a process that has implications for regenerative medicine and rejuvenation strategies4. Here we show that fibroblast cultures from old mice secrete inflammatory cytokines and exhibit increased variability in the efficiency of iPS cell reprogramming between mice. Variability between individuals is emerging as a feature of old age5-8, but the underlying mechanisms remain unknown. To identify drivers of this variability, we performed multi-omics profiling of fibroblast cultures from young and old mice that have different reprogramming efficiencies. This approach revealed that fibroblast cultures from old mice contain 'activated fibroblasts' that secrete inflammatory cytokines, and that the proportion of activated fibroblasts in a culture correlates with the reprogramming efficiency of that culture. Experiments in which conditioned medium was swapped between cultures showed that extrinsic factors secreted by activated fibroblasts underlie part of the variability between mice in reprogramming efficiency, and we have identified inflammatory cytokines, including TNF, as key contributors. Notably, old mice also exhibited variability in wound healing rate in vivo. Single-cell RNA-sequencing analysis identified distinct subpopulations of fibroblasts with different cytokine expression and signalling in the wounds of old mice with slow versus fast healing rates. Hence, a shift in fibroblast composition, and the ratio of inflammatory cytokines that they secrete, may drive the variability between mice in reprogramming in vitro and influence wound healing rate in vivo. This variability may reflect distinct stochastic ageing trajectories between individuals, and could help in developing personalized strategies to improve iPS cell generation and wound healing in elderly individuals.

Oligodendrocyte Death in Pelizaeus-Merzbacher Disease Is Rescued by Iron Chelation.

Nobuta H, Yang N, Ng YH, Marro SG, Sabeur K, Chavali M, Stockley JH, Killilea DW, Walter PB, Zhao C, Huie P Jr, Goldman SA, Kriegstein AR, Franklin RJM, Rowitch DH, Wernig M.

Pelizaeus-Merzbacher disease (PMD) is an X-linked leukodystrophy caused by mutations in Proteolipid Protein 1 (PLP1), encoding a major myelin protein, resulting in profound developmental delay and early lethality. Previous work showed involvement of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress pathways, but poor PLP1 genotype-phenotype associations suggest additional pathogenetic mechanisms. Using induced pluripotent stem cell (iPSC) and gene-correction, we show that patient-derived oligodendrocytes can develop to the pre-myelinating stage, but subsequently undergo cell death. Mutant oligodendrocytes demonstrated key hallmarks of ferroptosis including lipid peroxidation, abnormal iron metabolism, and hypersensitivity to free iron. Iron chelation rescued mutant oligodendrocyte apoptosis, survival, and differentiationin vitro, and post-transplantation in vivo. Finally, systemic treatment of Plp1 mutant Jimpy mice with deferiprone, a small molecule iron chelator, reduced oligodendrocyte apoptosis and enabled myelin formation. Thus, oligodendrocyte iron-induced cell death and myelination is rescued by iron chelation in PMD pre-clinical models.

Pubmed Link
2019
Oligodendrocyte Death in Pelizaeus-Merzbacher Disease Is Rescued by Iron Chelation.
Cell Stem Cell

Nobuta H, Yang N, Ng YH, Marro SG, Sabeur K, Chavali M, Stockley JH, Killilea DW, Walter PB, Zhao C, Huie P Jr, Goldman SA, Kriegstein AR, Franklin RJM, Rowitch DH, Wernig M.

View abstract
Hide abstracts
Pubmed listing
There is no abstract listed on Pubmed for this publication

Pelizaeus-Merzbacher disease (PMD) is an X-linked leukodystrophy caused by mutations in Proteolipid Protein 1 (PLP1), encoding a major myelin protein, resulting in profound developmental delay and early lethality. Previous work showed involvement of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress pathways, but poor PLP1 genotype-phenotype associations suggest additional pathogenetic mechanisms. Using induced pluripotent stem cell (iPSC) and gene-correction, we show that patient-derived oligodendrocytes can develop to the pre-myelinating stage, but subsequently undergo cell death. Mutant oligodendrocytes demonstrated key hallmarks of ferroptosis including lipid peroxidation, abnormal iron metabolism, and hypersensitivity to free iron. Iron chelation rescued mutant oligodendrocyte apoptosis, survival, and differentiationin vitro, and post-transplantation in vivo. Finally, systemic treatment of Plp1 mutant Jimpy mice with deferiprone, a small molecule iron chelator, reduced oligodendrocyte apoptosis and enabled myelin formation. Thus, oligodendrocyte iron-induced cell death and myelination is rescued by iron chelation in PMD pre-clinical models.

In Vitro Modeling of the Bipolar Disorder and Schizophrenia Using Patient-Derived Induced Pluripotent Stem Cells with Copy Number Variations of PCDH15 and RELN.

Ishii T, Ishikawa M, Fujimori K, Maeda T, Kushima I, Arioka Y, Mori D, Nakatake Y, Yamagata B, Nio S, Kato TA, Yang N, Wernig M, Kanba S, Mimura M, Ozaki N, Okano H.

Bipolar disorder (BP) and schizophrenia (SCZ) are major psychiatric disorders, but the molecular mechanisms underlying the complicated pathologies of these disorders remain unclear. It is difficult to establish adequate in vitro models for pathological analysis because of the heterogeneity of these disorders. In the present study, to recapitulate the pathologies of these disorders in vitro, we established in vitro models by differentiating mature neurons from human induced pluripotent stem cells (hiPSCs) derived from BP and SCZ patient with contributive copy number variations, as follows: two BP patients with PCDH15 deletion and one SCZ patient with RELN deletion. Glutamatergic neurons and GABAergic neurons were induced from hiPSCs under optimized conditions. Both types of induced neurons from both hiPSCs exhibited similar phenotypes of MAP2 (microtubule-associated protein 2)-positive dendrite shortening and decreasing synapse numbers. Additionally, we analyzed isogenic PCDH15- or RELN-deleted cells. The dendrite and synapse phenotypes of isogenic neurons were partially similar to those of patient-derived neurons. These results suggest that the observed phenotypes are general phenotypes of psychiatric disorders, and our in vitro models using hiPSC-based technology may be suitable for analysis of the pathologies of psychiatric disorders.

Pubmed Link
2019
In Vitro Modeling of the Bipolar Disorder and Schizophrenia Using Patient-Derived Induced Pluripotent Stem Cells with Copy Number Variations of PCDH15 and RELN.
eNeuro

Ishii T, Ishikawa M, Fujimori K, Maeda T, Kushima I, Arioka Y, Mori D, Nakatake Y, Yamagata B, Nio S, Kato TA, Yang N, Wernig M, Kanba S, Mimura M, Ozaki N, Okano H.

View abstract
Hide abstracts
Pubmed listing
There is no abstract listed on Pubmed for this publication

Bipolar disorder (BP) and schizophrenia (SCZ) are major psychiatric disorders, but the molecular mechanisms underlying the complicated pathologies of these disorders remain unclear. It is difficult to establish adequate in vitro models for pathological analysis because of the heterogeneity of these disorders. In the present study, to recapitulate the pathologies of these disorders in vitro, we established in vitro models by differentiating mature neurons from human induced pluripotent stem cells (hiPSCs) derived from BP and SCZ patient with contributive copy number variations, as follows: two BP patients with PCDH15 deletion and one SCZ patient with RELN deletion. Glutamatergic neurons and GABAergic neurons were induced from hiPSCs under optimized conditions. Both types of induced neurons from both hiPSCs exhibited similar phenotypes of MAP2 (microtubule-associated protein 2)-positive dendrite shortening and decreasing synapse numbers. Additionally, we analyzed isogenic PCDH15- or RELN-deleted cells. The dendrite and synapse phenotypes of isogenic neurons were partially similar to those of patient-derived neurons. These results suggest that the observed phenotypes are general phenotypes of psychiatric disorders, and our in vitro models using hiPSC-based technology may be suitable for analysis of the pathologies of psychiatric disorders.

Differential Signaling Mediated by ApoE2, ApoE3, and ApoE4 in Human Neurons Parallels Alzheimer's Disease Risk.

Huang YA, Zhou B, Nabet AM, Wernig M, Südhof TC.


In blood, apolipoprotein E (ApoE) is a component of circulating lipoproteins and mediates the clearance of these lipoproteins from blood by binding to ApoE receptors. Humans express three genetic ApoE variants, ApoE2, ApoE3, and ApoE4, which exhibit distinct ApoE receptor-binding properties and differentially affect Alzheimer's disease (AD), such that ApoE2 protects against, and ApoE4 predisposes to AD. In brain, ApoE-containing lipoproteins are secreted by activated astrocytes and microglia, but their functions and role in AD pathogenesis are largely unknown. Ample evidence suggests that ApoE4 induces microglial dysregulation and impedes Aβ clearance in AD, but the direct neuronal effects of ApoE variants are poorly studied. Extending previous studies, we here demonstrate that the three ApoE variants differentially activate multiple neuronal signaling pathways and regulate synaptogenesis. Specifically, using human neurons (male embryonic stem cell-derived) cultured in the absence of glia to exclude indirect glial mechanisms, we show that ApoE broadly stimulates signal transduction cascades. Among others, such stimulation enhances APP synthesis and synapse formation with an ApoE4>ApoE3>ApoE2 potency rank order, paralleling the relative risk for AD conferred by these ApoE variants. Unlike the previously described induction of APP transcription, however, ApoE-induced synaptogenesis involves CREB activation rather than cFos activation. We thus propose that in brain, ApoE acts as a glia-secreted signal that activates neuronal signaling pathways. The parallel potency rank order of ApoE4>ApoE3>ApoE2 in AD risk and neuronal signaling suggests that ApoE4 may in an apparent paradox promote AD pathogenesis by causing a chronic increase in signaling, possibly via enhancing APP expression.SIGNIFICANCE STATEMENT Humans express three genetic variants of apolipoprotein E (ApoE), ApoE2, ApoE3, and ApoE4. ApoE4 constitutes the most important genetic risk factor for Alzheimer's disease (AD), whereas ApoE2 protects against AD. Significant evidence suggests that ApoE4 impairs microglial function and impedes astrocytic Aβ clearance in brain, but the direct neuronal effects of ApoE are poorly understood, and the differences between ApoE variants in these effects are unclear. Here, we report that ApoE acts on neurons as a glia-secreted signaling molecule that, among others, enhances synapse formation. In activating neuronal signaling, the three ApoE variants exhibit a differential potency of ApoE4>ApoE3>ApoE2, which mirrors their relative effects on AD risk, suggesting that differential signaling by ApoE variants may contribute to AD pathogenesis.

Pubmed Link
2019
Differential Signaling Mediated by ApoE2, ApoE3, and ApoE4 in Human Neurons Parallels Alzheimer's Disease Risk.
J Neurosci.

Huang YA, Zhou B, Nabet AM, Wernig M, Südhof TC.


View abstract
Hide abstracts
Pubmed listing
There is no abstract listed on Pubmed for this publication

In blood, apolipoprotein E (ApoE) is a component of circulating lipoproteins and mediates the clearance of these lipoproteins from blood by binding to ApoE receptors. Humans express three genetic ApoE variants, ApoE2, ApoE3, and ApoE4, which exhibit distinct ApoE receptor-binding properties and differentially affect Alzheimer's disease (AD), such that ApoE2 protects against, and ApoE4 predisposes to AD. In brain, ApoE-containing lipoproteins are secreted by activated astrocytes and microglia, but their functions and role in AD pathogenesis are largely unknown. Ample evidence suggests that ApoE4 induces microglial dysregulation and impedes Aβ clearance in AD, but the direct neuronal effects of ApoE variants are poorly studied. Extending previous studies, we here demonstrate that the three ApoE variants differentially activate multiple neuronal signaling pathways and regulate synaptogenesis. Specifically, using human neurons (male embryonic stem cell-derived) cultured in the absence of glia to exclude indirect glial mechanisms, we show that ApoE broadly stimulates signal transduction cascades. Among others, such stimulation enhances APP synthesis and synapse formation with an ApoE4>ApoE3>ApoE2 potency rank order, paralleling the relative risk for AD conferred by these ApoE variants. Unlike the previously described induction of APP transcription, however, ApoE-induced synaptogenesis involves CREB activation rather than cFos activation. We thus propose that in brain, ApoE acts as a glia-secreted signal that activates neuronal signaling pathways. The parallel potency rank order of ApoE4>ApoE3>ApoE2 in AD risk and neuronal signaling suggests that ApoE4 may in an apparent paradox promote AD pathogenesis by causing a chronic increase in signaling, possibly via enhancing APP expression.SIGNIFICANCE STATEMENT Humans express three genetic variants of apolipoprotein E (ApoE), ApoE2, ApoE3, and ApoE4. ApoE4 constitutes the most important genetic risk factor for Alzheimer's disease (AD), whereas ApoE2 protects against AD. Significant evidence suggests that ApoE4 impairs microglial function and impedes astrocytic Aβ clearance in brain, but the direct neuronal effects of ApoE are poorly understood, and the differences between ApoE variants in these effects are unclear. Here, we report that ApoE acts on neurons as a glia-secreted signaling molecule that, among others, enhances synapse formation. In activating neuronal signaling, the three ApoE variants exhibit a differential potency of ApoE4>ApoE3>ApoE2, which mirrors their relative effects on AD risk, suggesting that differential signaling by ApoE variants may contribute to AD pathogenesis.

Neuroligin-4 Regulates Excitatory Synaptic Transmission in Human Neurons.

Marro SG, Chanda S, Yang N, Janas JA, Valperga G, Trotter J, Zhou B, Merrill S, Yousif I, Shelby H, Vogel H, Kalani MYS, Südhof TC, Wernig M.

The autism-associated synaptic-adhesion gene Neuroligin-4 (NLGN4) is poorly conserved evolutionarily, limiting conclusions from Nlgn4 mouse models for human cells. Here, we show that the cellular and subcellular expression of human and murine Neuroligin-4 differ, with human Neuroligin-4 primarily expressed in cerebral cortex and localized to excitatory synapses. Overexpression of NLGN4 in human embryonic stem cell-derived neurons resulted in an increase in excitatory synapse numbers but a remarkable decrease in synaptic strength. Human neurons carrying the syndromic autism mutation NLGN4-R704C also formed more excitatory synapses but with increased functional synaptic transmission due to a postsynaptic mechanism, while genetic loss of NLGN4 did not significantly affect synapses in the human neurons analyzed. Thus, the NLGN4-R704C mutation represents a change-of-function mutation. Our work reveals contrasting roles of NLGN4 in human and mouse neurons, suggesting that human evolution has impacted even fundamental cell biological processes generally assumed to be highly conserved.

Pubmed Link
2019
Neuroligin-4 Regulates Excitatory Synaptic Transmission in Human Neurons.
Neuron

Marro SG, Chanda S, Yang N, Janas JA, Valperga G, Trotter J, Zhou B, Merrill S, Yousif I, Shelby H, Vogel H, Kalani MYS, Südhof TC, Wernig M.

View abstract
Hide abstracts
Pubmed listing
There is no abstract listed on Pubmed for this publication

The autism-associated synaptic-adhesion gene Neuroligin-4 (NLGN4) is poorly conserved evolutionarily, limiting conclusions from Nlgn4 mouse models for human cells. Here, we show that the cellular and subcellular expression of human and murine Neuroligin-4 differ, with human Neuroligin-4 primarily expressed in cerebral cortex and localized to excitatory synapses. Overexpression of NLGN4 in human embryonic stem cell-derived neurons resulted in an increase in excitatory synapse numbers but a remarkable decrease in synaptic strength. Human neurons carrying the syndromic autism mutation NLGN4-R704C also formed more excitatory synapses but with increased functional synaptic transmission due to a postsynaptic mechanism, while genetic loss of NLGN4 did not significantly affect synapses in the human neurons analyzed. Thus, the NLGN4-R704C mutation represents a change-of-function mutation. Our work reveals contrasting roles of NLGN4 in human and mouse neurons, suggesting that human evolution has impacted even fundamental cell biological processes generally assumed to be highly conserved.

Modeling Alzheimer's disease with human iPS cells: advancements, lessons, and applications.

Essayan-Perez S, Zhou B, Nabet AM, Wernig M, Huang YA.


One in three people will develop Alzheimer's disease (AD) or another dementia and, despite intense research efforts, treatment options remain inadequate. Understanding the mechanisms of AD pathogenesis remains our principal hurdle to developing effective therapeutics to tackle this looming medical crisis. In light of recent discoveries from whole-genome sequencing and technical advances in humanized models, studying disease risk genes with induced human neural cells presents unprecedented advantages. Here, we first review the current knowledge of the proposed mechanisms underlying AD and focus on modern genetic insights to inform future studies. To highlight the utility of human pluripotent stem cell-based innovations, we then present an update on efforts in recapitulating the pathophysiology by induced neuronal, non-neuronal and a collection of brain cell types, departing from the neuron-centric convention. Lastly, we examine the translational potentials of such approaches, and provide our perspectives on the promise they offer to deepen our understanding of AD pathogenesis and to accelerate the development of intervention strategies for patients and risk carriers.

Pubmed Link
2019
Modeling Alzheimer's disease with human iPS cells: advancements, lessons, and applications.
Neurobiol Dis.

Essayan-Perez S, Zhou B, Nabet AM, Wernig M, Huang YA.


View abstract
Hide abstracts
Pubmed listing
There is no abstract listed on Pubmed for this publication

One in three people will develop Alzheimer's disease (AD) or another dementia and, despite intense research efforts, treatment options remain inadequate. Understanding the mechanisms of AD pathogenesis remains our principal hurdle to developing effective therapeutics to tackle this looming medical crisis. In light of recent discoveries from whole-genome sequencing and technical advances in humanized models, studying disease risk genes with induced human neural cells presents unprecedented advantages. Here, we first review the current knowledge of the proposed mechanisms underlying AD and focus on modern genetic insights to inform future studies. To highlight the utility of human pluripotent stem cell-based innovations, we then present an update on efforts in recapitulating the pathophysiology by induced neuronal, non-neuronal and a collection of brain cell types, departing from the neuron-centric convention. Lastly, we examine the translational potentials of such approaches, and provide our perspectives on the promise they offer to deepen our understanding of AD pathogenesis and to accelerate the development of intervention strategies for patients and risk carriers.

Direct Reprogramming of Human Neurons Identifies MARCKSL1 as a Pathogenic Mediator of Valproic Acid-Induced Teratogenicity.

Chanda S, Ang CE, Lee QY, Ghebrial M, Haag D, Shibuya Y, Wernig M, Südhof TC.

Human pluripotent stem cells can be rapidly converted into functional neurons by ectopic expression of proneural transcription factors. Here we show that directly reprogrammed neurons, despite their rapid maturation kinetics, can model teratogenic mechanisms that specifically affect early neurodevelopment. We delineated distinct phases of in vitro maturation during reprogramming of human neurons and assessed the cellular phenotypes of valproic acid (VPA), a teratogenic drug. VPA exposure caused chronic impairment of dendritic morphology and functional properties of developing neurons, but not those of mature neurons. These pathogenic effects were associated with VPA-mediated inhibition of the histone deacetylase (HDAC) and glycogen synthase kinase-3 (GSK-3) pathways, which caused transcriptional downregulation of many genes, including MARCKSL1, an actin-stabilizing protein essential for dendritic morphogenesis and synapse maturation during early neurodevelopment. Our findings identify a developmentally restricted pathogenic mechanism of VPA and establish the use of reprogrammed neurons as an effective platform for modeling teratogenic pathways.

Pubmed Link
2019
Direct Reprogramming of Human Neurons Identifies MARCKSL1 as a Pathogenic Mediator of Valproic Acid-Induced Teratogenicity.
Cell Stem Cell

Chanda S, Ang CE, Lee QY, Ghebrial M, Haag D, Shibuya Y, Wernig M, Südhof TC.

View abstract
Hide abstracts
Pubmed listing
There is no abstract listed on Pubmed for this publication

Human pluripotent stem cells can be rapidly converted into functional neurons by ectopic expression of proneural transcription factors. Here we show that directly reprogrammed neurons, despite their rapid maturation kinetics, can model teratogenic mechanisms that specifically affect early neurodevelopment. We delineated distinct phases of in vitro maturation during reprogramming of human neurons and assessed the cellular phenotypes of valproic acid (VPA), a teratogenic drug. VPA exposure caused chronic impairment of dendritic morphology and functional properties of developing neurons, but not those of mature neurons. These pathogenic effects were associated with VPA-mediated inhibition of the histone deacetylase (HDAC) and glycogen synthase kinase-3 (GSK-3) pathways, which caused transcriptional downregulation of many genes, including MARCKSL1, an actin-stabilizing protein essential for dendritic morphogenesis and synapse maturation during early neurodevelopment. Our findings identify a developmentally restricted pathogenic mechanism of VPA and establish the use of reprogrammed neurons as an effective platform for modeling teratogenic pathways.

Reversible Disruption of Specific Transcription Factor-DNA Interactions Using CRISPR/Cas9.

Shariati SA, Dominguez A, Xie S, Wernig M, Qi LS, Skotheim JM.

The control of gene expression by transcription factor binding sites frequently determines phenotype. However, it is difficult to determine the function of single transcription factor binding sites within larger transcription networks. Here, we use deactivated Cas9 (dCas9) to disrupt binding to specific sites, a method we term CRISPRd. Since CRISPR guide RNAs are longer than transcription factor binding sites, flanking sequence can be used to target specific sites. Targeting dCas9 to an Oct4 site in the Nanog promoter displaced Oct4 from this site, reduced Nanog expression, and slowed division. In contrast, disrupting the Oct4 binding site adjacent to Pax6 upregulated Pax6 transcription and disrupting Nanog binding its own promoter upregulated its transcription. Thus, we can easily distinguish between activating and repressing binding sites and examine autoregulation. Finally, multiple guide RNA expression allows simultaneous inhibition of multiple binding sites, and conditionally destabilized dCas9 allows rapid reversibility.

Pubmed Link
2019
Reversible Disruption of Specific Transcription Factor-DNA Interactions Using CRISPR/Cas9.
Mol Cell.

Shariati SA, Dominguez A, Xie S, Wernig M, Qi LS, Skotheim JM.

View abstract
Hide abstracts
Pubmed listing
There is no abstract listed on Pubmed for this publication

The control of gene expression by transcription factor binding sites frequently determines phenotype. However, it is difficult to determine the function of single transcription factor binding sites within larger transcription networks. Here, we use deactivated Cas9 (dCas9) to disrupt binding to specific sites, a method we term CRISPRd. Since CRISPR guide RNAs are longer than transcription factor binding sites, flanking sequence can be used to target specific sites. Targeting dCas9 to an Oct4 site in the Nanog promoter displaced Oct4 from this site, reduced Nanog expression, and slowed division. In contrast, disrupting the Oct4 binding site adjacent to Pax6 upregulated Pax6 transcription and disrupting Nanog binding its own promoter upregulated its transcription. Thus, we can easily distinguish between activating and repressing binding sites and examine autoregulation. Finally, multiple guide RNA expression allows simultaneous inhibition of multiple binding sites, and conditionally destabilized dCas9 allows rapid reversibility.

TFAP2C- and p63-Dependent Networks Sequentially Rearrange Chromatin Landscapes to Drive Human Epidermal Lineage Commitment.
Li L, Wang Y, Torkelson JL, Shankar G, Pattison JM, Zhen HH, Fang F, Duren Z, Xin J, Gaddam S, Melo SP, Piekos SN, Li J, Liaw EJ, Chen L, Li R, Wernig M, Wong WH, Chang HY, Oro AE
Tissue development results from lineage-specific transcription factors (TFs) programming a dynamic chromatin landscape through progressive cell fate transitions. Here, we define epigenomic landscape during epidermal differentiation of human pluripotent stem cells (PSCs) and create inference networks that integrate gene expression, chromatin accessibility, and TF binding to define regulatory mechanisms during keratinocyte specification. We found two critical chromatin networks during surface ectoderm initiation and keratinocyte maturation, which are driven by TFAP2C and p63, respectively. Consistently, TFAP2C, but not p63, is sufficient to initiate surface ectoderm differentiation, and TFAP2C-initiated progenitor cells are capable of maturing into functional keratinocytes. Mechanistically, TFAP2C primes the surface ectoderm chromatin landscape and induces p63 expression and binding sites, thus allowing maturation factor p63 to positively autoregulate its own expression and close a subset of the TFAP2C-initiated surface ectoderm program. Our work provides a general framework to infer TF networks controlling chromatin transitions that will facilitate future regenerative medicine advances.
Pubmed Link
2019
TFAP2C- and p63-Dependent Networks Sequentially Rearrange Chromatin Landscapes to Drive Human Epidermal Lineage Commitment.
Cell Stem Cell
Li L, Wang Y, Torkelson JL, Shankar G, Pattison JM, Zhen HH, Fang F, Duren Z, Xin J, Gaddam S, Melo SP, Piekos SN, Li J, Liaw EJ, Chen L, Li R, Wernig M, Wong WH, Chang HY, Oro AE
View abstract
Hide abstracts
Pubmed listing
There is no abstract listed on Pubmed for this publication
Tissue development results from lineage-specific transcription factors (TFs) programming a dynamic chromatin landscape through progressive cell fate transitions. Here, we define epigenomic landscape during epidermal differentiation of human pluripotent stem cells (PSCs) and create inference networks that integrate gene expression, chromatin accessibility, and TF binding to define regulatory mechanisms during keratinocyte specification. We found two critical chromatin networks during surface ectoderm initiation and keratinocyte maturation, which are driven by TFAP2C and p63, respectively. Consistently, TFAP2C, but not p63, is sufficient to initiate surface ectoderm differentiation, and TFAP2C-initiated progenitor cells are capable of maturing into functional keratinocytes. Mechanistically, TFAP2C primes the surface ectoderm chromatin landscape and induces p63 expression and binding sites, thus allowing maturation factor p63 to positively autoregulate its own expression and close a subset of the TFAP2C-initiated surface ectoderm program. Our work provides a general framework to infer TF networks controlling chromatin transitions that will facilitate future regenerative medicine advances.
Global DNA methylation remodeling during direct reprogramming of fibroblasts to neurons.

Luo C, Lee QY, Wapinski O, Castanon R, Nery JR, Mall M, Kareta MS, Cullen SM, Goodell MA, Chang HY, Wernig M, Ecker JR.

Direct reprogramming of fibroblasts to neurons induces widespread cellular and transcriptional reconfiguration. Here, we characterized global epigenomic changes during the direct reprogramming of mouse fibroblasts to neurons using whole-genome base-resolution DNA methylation (mC) sequencing. We found that the pioneer transcription factor Ascl1 alone is sufficient for inducing the uniquely neuronal feature of non-CG methylation (mCH), but co-expression of Brn2 and Mytl1 was required to establish a global mCH pattern reminiscent of mature cortical neurons. Ascl1 alone induced promoter CG methylation (mCG) of fibroblast specific genes, while BAM overexpression additionally targets a competing myogenic program and directs a more faithful conversion to neuronal cells. Ascl1 induces local demethylation at its binding sites. Surprisingly, co-expression with Brn2 and Mytl1 inhibited the ability of Ascl1 to induce demethylation, suggesting a contextual regulation of transcription factor - epigenome interaction. Finally, we found that de novo methylation by DNMT3A is required for efficient neuronal reprogramming.

Pubmed Link
2019
Global DNA methylation remodeling during direct reprogramming of fibroblasts to neurons.
Elife

Luo C, Lee QY, Wapinski O, Castanon R, Nery JR, Mall M, Kareta MS, Cullen SM, Goodell MA, Chang HY, Wernig M, Ecker JR.

View abstract
Hide abstracts
Pubmed listing
There is no abstract listed on Pubmed for this publication

Direct reprogramming of fibroblasts to neurons induces widespread cellular and transcriptional reconfiguration. Here, we characterized global epigenomic changes during the direct reprogramming of mouse fibroblasts to neurons using whole-genome base-resolution DNA methylation (mC) sequencing. We found that the pioneer transcription factor Ascl1 alone is sufficient for inducing the uniquely neuronal feature of non-CG methylation (mCH), but co-expression of Brn2 and Mytl1 was required to establish a global mCH pattern reminiscent of mature cortical neurons. Ascl1 alone induced promoter CG methylation (mCG) of fibroblast specific genes, while BAM overexpression additionally targets a competing myogenic program and directs a more faithful conversion to neuronal cells. Ascl1 induces local demethylation at its binding sites. Surprisingly, co-expression with Brn2 and Mytl1 inhibited the ability of Ascl1 to induce demethylation, suggesting a contextual regulation of transcription factor - epigenome interaction. Finally, we found that de novo methylation by DNMT3A is required for efficient neuronal reprogramming.

The novel lncRNA lnc-NR2F1 is pro-neurogenic and mutated in human neurodevelopmental disorders.

Ang CE, Ma Q, Wapinski OL, Fan S, Flynn RA, Lee QY, Coe B, Onoguchi M, Olmos VH, Do BT, Dukes-Rimsky L, Xu J, Tanabe K, Wang L, Elling U, Penninger JM, Zhao Y, Qu K, Eichler EE, Srivastava A, Wernig M, Chang HY.

Long noncoding RNAs (lncRNAs) have been shown to act as important cell biological regulators including cell fate decisions but are often ignored in human genetics. Combining differential lncRNA expression during neuronal lineage induction with copy number variation morbidity maps of a cohort of children with autism spectrum disorder/intellectual disability versus healthy controls revealed focal genomic mutations affecting several lncRNA candidate loci. Here we find that a t(5:12) chromosomal translocation in a family manifesting neurodevelopmental symptoms disrupts specifically lnc-NR2F1. We further show that lnc-NR2F1 is an evolutionarily conserved lncRNA functionally enhances induced neuronal cell maturation and directly occupies and regulates transcription of neuronal genes including autism-associated genes. Thus, integrating human genetics and functional testing in neuronal lineage induction is a promising approach for discovering candidate lncRNAs involved in neurodevelopmental diseases.

Pubmed Link
2019
The novel lncRNA lnc-NR2F1 is pro-neurogenic and mutated in human neurodevelopmental disorders.
Elife

Ang CE, Ma Q, Wapinski OL, Fan S, Flynn RA, Lee QY, Coe B, Onoguchi M, Olmos VH, Do BT, Dukes-Rimsky L, Xu J, Tanabe K, Wang L, Elling U, Penninger JM, Zhao Y, Qu K, Eichler EE, Srivastava A, Wernig M, Chang HY.

View abstract
Hide abstracts
Pubmed listing
There is no abstract listed on Pubmed for this publication

Long noncoding RNAs (lncRNAs) have been shown to act as important cell biological regulators including cell fate decisions but are often ignored in human genetics. Combining differential lncRNA expression during neuronal lineage induction with copy number variation morbidity maps of a cohort of children with autism spectrum disorder/intellectual disability versus healthy controls revealed focal genomic mutations affecting several lncRNA candidate loci. Here we find that a t(5:12) chromosomal translocation in a family manifesting neurodevelopmental symptoms disrupts specifically lnc-NR2F1. We further show that lnc-NR2F1 is an evolutionarily conserved lncRNA functionally enhances induced neuronal cell maturation and directly occupies and regulates transcription of neuronal genes including autism-associated genes. Thus, integrating human genetics and functional testing in neuronal lineage induction is a promising approach for discovering candidate lncRNAs involved in neurodevelopmental diseases.

New Approaches, New Opportunities at the 2019 ISSCR Annual Meeting.
Melton D, Wernig M
Pubmed Link
2019
New Approaches, New Opportunities at the 2019 ISSCR Annual Meeting.
Stem Cell Reports
Melton D, Wernig M
View abstract
Hide abstracts
Pubmed listing
There is no abstract listed on Pubmed for this publication

Marius Wernig

M.D., Ph.D.

wernig@stanford.edu


Dr. Marius Wernig is an Associate Professor of Pathology at the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University. He graduated with an M.D. Ph.D. from the Technical University of Munich where he trained in developmental genetics in the lab of Rudi Balling. After completing his residency in Neuropathology and General Pathology at the University of Bonn, he then became a postdoctoral fellow in the lab of Dr. Rudolf Jaenisch at the Whitehead Institute for Biomedical Research/ MIT in Cambridge, MA. In 2008, Dr. Wernig joined the faculty of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University where he has been ever since.

He received an NIH Pathway to Independence Award, the Cozzarelli Prize for Outstanding Scientific Excellence from the National Academy of Sciences U.S.A., the Outstanding Investigator Award from the International Society for Stem Cell Research, the New York Stem Cell Foundation Robertson Stem Cell Prize, and more recently has been named a HHMI Faculty Scholar.

Dr. Wernig’s lab is interested in pluripotent stem cell biology and the molecular determinants of neural cell fate decisions. His laboratory was the first to generate functional neuronal cells reprogrammed directly from skin fibroblasts, which he termed induced neuronal (iN) cells. The lab is now working on identifying the molecular mechanisms underlying induced lineage fate changes, the phenotypic consequences of disease-causing mutations in human neurons and other neural lineages as well as the development of novel therapeutic gene targeting and cell transplantation-based strategies for a variety of monogenetic diseases.

Academic appointments

Associate Professor Institute for Stem Cell Biology and Regenerative Medicine


Member:
Bio-X
Cardiovascular Institute
Child Health Research Institute
Institute for Stem Cell Biology and Regenerative Medicine
Stanford Cancer Institute
Stanford Neurosciences Institute

Administrative appointments

Faculty Senate, Department of Pathology (2017 - Present)
Assistant Professor, Institute for Stem Cell Biology and Regenerative Medicine (2008 - 2014)

Honors & Awards

HHMI Faculty Scholar Award, Howard Hughes Medical Institute (2016)
New York Stem Cell Foundation Robertson Stem Cell Prize, New York Stem Cell Foundation (2014)
The Outstanding Young Investigator Award, International Society for Stem Cell Research (2013)
Ascina Award, Republic of Austria (2010)
Cozzarelli Prize for Outstanding Scientific Excellence, National Academy of Sciences USA (2009)
New Scholar in Aging, Ellison Medical Foundation (2010)
Robertson Investigator Award, New York Stem Cell Foundation (2010)
Donald E. and Delia B. Baxter Faculty Scholarship, Stanford University (2009)
Margaret and Herman Sokol Award, Biomedical Research (2007)
Longterm fellowship Human Frontiers Science Program Organisation, HFSP (2004-2006)

Boards, Advisory Committees

Professional Organizations Member, Society for Neuroscience (2003 - Present)
Member, International Society for Stem Cell Research (2004 - Present)
Editorial Board Member, Cell Stem Cell (2012 - Present)
Editorial Board Member, Stem Cell Reports (2013 - Present)
Member, Program Committee, Society for Neuroscience (2016 - Present)
Chair, Program Committee, International Society for Stem Cell Research (2017 - Present)

Professional Education

M.D., Technical University of Munich, Medicine (2000)

Wernig Lab Team

2019
2019
Angel Ayala
Master's Student
contactsee less
about me
see less

Angel earned his B.S. in Biology at California State Polytechnic University, Pomona. As an undergraduate he studied the effects of nicotine on diabetic individuals. As a CIRM fellow at Stanford University, he is interested in using microglia cell replacement and stem cell technology as a potential therapeutic for neurological disorders.

Bahareh Haddad Derafshi
PhD Student
contactsee less
about me
see less

My current research interests are focused on epigenetic regulation of cognition at the level of synapses, using iN system. In my free time I do sports and outdoor activities, cook healthy food, make mixed drinks, play music, and collect vinyl records.

Bo Zhou
Postdoc Fellow
contactsee less
about me
see less

I am studying synaptogenesis in Alzheimer’s Disease using human iNs as a model.

Gernot Neumayer
Postdoc Fellow
contactsee less
about me
see less

I am a passionate cellular and molecular biologistwith expertise in research related to cancer, genomic/chromosomal instability, DNA damage response, epigenetics,  proteomics and cellular identity. The latter topic attracted me to the Wernig lab where I aim to decipher the mechanisms that allow us to specifically switch the identity of a cell, converting differentiated somatic cells into induced neurons. I also work on a project that aims to integrate CRISPR/CAS9-mediated gene correction with iPS cell generation in order to establish a therapy for the devastating skin disease epidermolysis bullosa. In my free time I play underwater rugby, surf, spearfish and ski!

Ishan Kumar
PhD Student
contactsee less
about me
see less

I am a first-year PhD student interested in chromatin biology, cellular identity, and their practical applications. I am concurrently a third-year student at Stanford Law School, and previously attended Yale for my undergraduate studies.

Jacklyn Ha Luu
Undergrad
contactsee less
about me
see less

I am an undergraduate studying neurobiology and computer science. In the Wernig Lab, I am studying how the interactions between reprogramming factors and chromatin modifiers allow for fully developed fibrojacklynl@stanford.edublasts to reprogram into induced neuronal cells (iN).

Jinzhao Wang
Joint Postdoc Fellow
contactsee less
about me
see less

My research interests center around the application of patch clamp and calciumimaging methods on characterizing the phenotype of human-induced neuronal cells with neurological diseases-related mutations.

Justyna Janas
Postdoc Fellow
contactsee less
about me
see less

I studied small GTPase signaling and how its perturbation can contribute to cancer and neurological disorders during my PhD training at Cold Spring Harbor Laboratory. Since then, I have become increasingly fascinated by the epigenetic mechanisms of gene regulation, and how changes in epigenome influence cell function and fate decisions. In the Wernig lab, I am currently investigating the interactions between the reprogramming factors and chromatin modifiers. More specifically, I am interested in finding out how such interactions enable a terminally differentiated cell—for example, a fibroblast—to acquire new transcriptional program that allows its reprogramming into induced neuron (iN).

Katie Schaukowitch
Postdoc Fellow
contactsee less
about me
see less

My research interests include studying the molecular mechanisms underlying the establishment of neuronal identity and understanding how reprogramming factors can convert various cell types into neurons despite different epigenetic contexts.

Kevin Kumar
Resident fellow
contactsee less
about me
see less

I grew up in Long Island, NY. I attended college at Cornell University majoring in Biological Sciences with a concentration in Neurobiology and Behavior. After graduation in 2009, I moved to Nashville, TN to join the Medical Scientist Training Program at Vanderbilt University where I earned a combined MD/PhD. In 2016, I started my residency in Neurosurgery at Stanford. In the Wernig lab, I am interested in developing microglia-based regenerative therapies for neurodevelopmental and neurodegenerative disorders.

Lingjun Meng
Postdoc Fellow
contactsee less
about me
see less

I received my PhD from National Institute of Biological Sciences (NIBS) at Beijing, China. My PhD mentor is Dr. Xiaodong Wang, who is a chinese-born American biochemist best known for his work with cytochrome C on apoptosis. He is a member of United States National Academy of Sciences and Howard Hughes Medical Institute.

During my PhD stage, my major work is to try and find function of a protein named RIP3 in necrosis (other program cell death) pathway. I use human fetal neural stem cells to study mutation caused epigenetic rigidity in reprogramming process. A lot of patient diseases are caused by gene mutation, but we do not know which kind of cells and which site of mutate will cause disease. We try to work on neural stem cells to induce some point mutation to imitate brain cancer disease from reported mutation site in human patient. Then we will know which mutation site is the key and try to fix it by the biology method.

Madhuri Vangipuram
Life science research professional
contactsee less
about me
see less

The immense potential of genetic engineering technology as a tool to understand disease mechanisms and as a therapy motivates me to pursue research. I am studying CRISPR/Cas9 mediated gene correction of mutations in patients suffering from Epidermolysis bullosa. I am also studying iPSC-derived induced neurons to model neurological disorders.

Marius Mader
Postdoc Fellow
contactsee less
about me
see less

As a neurosurgical resident, my research interests include translational topics such as cell therapy and neuroregenerative mechanisms. In the Wernig lab, I study the cellular reprogramming potential of microglia. Moreover, I’m interested in the functional integration of induced neurons into neural systems.

Samuele Marro
Basic Life Res Scientist
contactsee less
about me
see less

With billions of neurons interconnected with many billions of synapses, our brain is the most complex object in the known universe. I like to think that I’m doing my part in understanding it. I use human neurons to study a synaptic protein called Neuroligin 4 that is not found in mice, therefore very complicated to study but at the same time extremely fascinating. When mutated Neuroligin 4 causes Autism and impairs the synaptic transmission of neurons.

Takeshi Uenaka
Postdoc Fellow
contactsee less
about me
see less

I worked as a neurologist for 10 years in Japan. During clinical practice, I saw a lot of patients who could not be treated by the current medicine. As a result, I became strongly attracted to basic research of neuroscience. I received my PhD in Dr. Tatsushi Toda’s lab at Kobe University, where I studied disease-modifying drug for Parkinson’s disease. As a post doc fellow in the Wernig lab, I’m interested in investigating the ubiquitylation enzymes that are associated with the pathophysiology of Alzheimer’s disease in order to cure patients with neurodegenerative diseases in the future. In my free time, I play with my children, go cycling, and read comics.

Tamas Danko
Basic Life Res Scientist
contactsee less
about me
see less

My research interest is to investigate how genetic background contributes to the pathomechanism of complex mental disorders such autism or schizophrenia. In order to achieve my goals I am using various experimental techniques including rodent and human neuronal cell culture  preparations, immunohistochemistry, gene and protein expression analysis and electrophysiology. As a scientist, my motto is: "We work in the dark to serve the light. "

Virginia Trakul
Administrative Associate
contactsee less
about me
see less

Virginia is a dentist that worked with underserved communities before taking time off to care for her family. She is happy to be the administrative associate for the Wernig lab. In her free time she enjoys reading, playing tennis, and spending time with her family.

Wendy Fong
Postdoc Fellow
contactsee less
about me
see less

Wendy received her Ph.D. from Columbia University, where she studied how cholesterol-rich membrane microdomains regulate a distinct function of a transmembrane protein, resulting in specific behavioral outcomes. In the Wernig lab, she aims to understand the molecular mechanisms by which neuronal identity is established and how its disruption leads to neurological diseases.

Yingfei Liu
PhD Visiting Student
contactsee less
about me
see less

Yingfei Liu is a Neurobiology PhD candidate from Xi`an Jiaotong University,China. She is studying here for two years as a Joint-Training Doctoral Program. Her previous research interest was the self-renewal and differentiation of theneural stem cells. Now She is studying the mechanisms of direct lineagereprogramming of fibroblasts into neurons.

Yohei Shibuya
Postdoc Fellow
contactsee less
about me
see less

I completed my PhD in Dr. TY Chang’s lab at Dartmouth College, where I studied cholesterol metabolism in health and disease. In the Wernig lab, my research focus is on studying neurological diseases in human neurons and other neural lineages. I am also interested in developing novel therapeutic approaches for treating incurable neurological disorders using reprogramming technology.

Yongjin Yoo
Postdoc Fellow
contactsee less
about me
see less

Yongjin received his Ph.D. in functional genomics in 2018 from the Seoul National University, South Korea. For his Ph.D., he focused on genetic mutations of human neurological patients and its functional impacts. Yongjin joined the Wernig lab in October 2018. In the Wernig lab, he is interested in developing therapeutic methods for neurological patients and understanding disease mechanisms using human stem cells and neurons.


Wernig Lab Alumni

2011
team-image
2008
team-image
2019
team-image
2017
team-image
2015
team-image
2010
team-image
2008
2008
2010
2010
2011
2011
2015
2015
2017
2017
Cheen Euong Ang
PhD student
see lesscontact
about me
see less

Cheen Euong Ang was a bioengineering PhD student in the Wernig lab. He spent his undergraduate career at McGill University, graduating with a B.Sc. in Chemistry with a focus in biological chemistry. Since coming to Stanford, Cheen Euong has been working on investigating the mechanisms of iN reprogramming and applying the iN platform in disease modeling and aging. Other than doing research in the lab, Cheen Euong has participated several scientific outreach programs such as the Stanford Biomedical Engineering Society undergraduate academic mentoring program and Stanford Institute of Medical Summer High School Student Research Program. Cheen moved on to do his postdoc in Xiaowei Zhuang at Harvard University in Cambridge, MA.

Daniel Haag
Postdoc Fellow
see lesscontact
about me
see less

I am a molecular biologist with a focus on neuro- and cancer biology. I am interested in using human iPSCs to develop new in vitro disease models, particularly for neuropsychiatric disorders and neurooncology. This led me to the Wernig lab where I started my postdoc to explore the advantages of direct neuronal reprogramming and the intricacies of step-wise differentiation of neural cell types. I am genetically engineering iPSC lines to generate complex genomic alterations and inducible mutations. Following differentiation into the corresponding disease-relevant tissue, I am puzzling together cellular phenotypes, transcriptional regulation, protein interactions, and epigenetic changes for a better understanding of the disease biology. In my spare time, I enjoy a new definition of chaos by my 2-year-old daughter.

Hiroko Nobuta
Postdoc Fellow
see lesscontact
about me
see less

Hiroko received Ph.D. from UCLA Neuroscience program in Jim Waschek's lab. She's currently a postdoc studying the disease mechanism of pediatric brain disorder Pelizaeus-Merzbacher Disorder, affecting oligodendrocyte development and myelination. She uses patient-derived iPS cells, gene targeting in iPS cells, and animal models.

Jackie Young
Administrative Associate
see lesscontact
about me
see less

I was an administrative associate for the Wernig Lab for a brief period in 2019.  I am a native San Franciscan and I love the bay area.  I received my undergrad from San Francisco State.  I am fluent inSpanish so if you ever need a Spanish lesson come by desk.  My husband and I have three beautiful childrenand during my time off I really enjoying spending time with my family.

Minjeong Lee
Lab Admin
see lesscontact
about me
see less

Minjeong was the administrative associate for the Wernig Lab. We all loved her positive spirit that made our lab a happy place. We were fortunate to have her for a full year! During her time off, she loved hanging out with my family and trying out different recipes. She moved on to a full time position in business.

Moritz Mall
Postdoc Fellow
see lesscontact
about me
see less

Dr. Moritz Mall is a postdoctoral fellow in the lab. After studying biochemistry and molecular biology at the LMU in Munich and the ETH in Zurich he received his Ph.D. from the EMBL in Heidelberg for his mechanistic studies on mitotic cell division. Besides surfing Moritz’s passion is to understand the molecular mechanisms of cell fate determination during reprogramming, development and disease.

Nan Yang
Postdoc Fellow
see lesscontact
about me
see less

A striking feature of the mammalian nervous system is its enormous cellular diversity. The biological question that drives my research in long-term is to understand how the nervous system develops and achieves its extraordinary complexity. I would also like to leverage my expertise in lineage reprogramming, stem cell biology, and neurobiology to develop reprogramming-based human cell culture models and study the fundamental processes underlying the development and function of human nervous system under normal and pathological conditions. Outside the lab, I like spending my time cycling, rock climbing and hiking.

Qian Yi Lee
Postdoc Fellow
see lesscontact
about me
see less

I am interested in studying the mechanisms of direct lineage reprogramming of fibroblasts into neurons.

Sarah Grieder
Research Assistant
see lesscontact
about me
see less

I am a Research Assistant in the Wernig Lab. My work mainly focuses on iPS-derived induced neurons to model human neuropsychiatric disorders. In my free time I love to read, sing and enjoy the California weather.

Soham Chanda
Postdoc Fellow
see lesscontact
about me
see less

Neuroligins are postsynaptic cell-adhesion molecules that play a major role in shaping synapse properties. My projects involve understanding the functional contributions of different Neuroligin isoforms, investigating the pathogenic mechanisms of autism-associated Neuroligin mutations, and applying this knowledge for neurological disease modeling in human neurons transdifferentiated from non-neuronal cells. My work combines fundamental biology with translational research using multidisciplinary approaches, e.g. cellular reprogramming, electrophysiology, imaging, gene-expression and biochemical analyses.

Wernig Lab Press

Wernig Lab Protocols & Recipes

Contact

We are always interested to hear from ambitious scientists and potential collaborators.

Marius Wernig
wernig@stanford.edu

Virginia Marie Trakul, Lab Admin
vtrakul@stanford.edu

Institute for Stem Cell Biology and Regenerative Medicine
Wernig Laboratory
265 Campus Drive G3141
Stanford, CA 94305
U.S.A.

Wernig Lab team graphic