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 mono-genetic 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

Dystrophic Epidermolysis Bullosa is a severe, blistering monogenetic skin disease caused by mutations in the gene coding for type VII collagen. We have developed a 1-step gene editing/iPS cell reprogramming method to rapidly generate patient iPS cells corrected for their disease-causing mutations in the Collagen7a1 gene. In collaboration with dermatologist Tony Oro we are developing a cell manufacturing process compatible with Good Manufacturing Procedures (GMP) to obtain FDA-approval for a first in man Phase I clinical trial with with a genetically engineered iPS cell product.

Exploiting glia cell transplantation to treat neurodegenerative disease

Both oligodendrocyte precursor cells as well as microglia can efficiently repopulate the brain. We are interested in exploiting the properties of these cells to develop novel cell therapies for the brain either to use the transplanted cells to restore function such as myelination, to alter the function of transplanted cells for therepeutic benefit, to use the cells as vehicles for therapeutic molecules, or ultimately to develop designer cells that are engineered with genetic synthetic biology circuits to sense and interfere with disease processes of the brain.

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

Tip60-mediated H2A.Z acetylation promotes neuronal fate specification and bivalent gene activation
Justyna A Janas,Lichao Zhang,Jacklyn H Luu,Janos Demeter,Lingjun Meng,Samuele G Marro,Moritz Mall,Nancie A Mooney,Katie Schaukowitch,Yi Han Ng,Nan Yang,Yuhao Huang,Gernot Neumayer,Or Gozani,Joshua E Elias,Peter K Jackson,Marius Wernig
Cell lineage specification is accomplished by a concerted action of chromatin remodeling and tissue-specific transcription factors. However, the mechanisms that induce and maintain appropriate lineage-specific gene expression remain elusive. Here, we used an unbiased proteomics approach to characterize chromatin regulators that mediate the induction of neuronal cell fate. We found that Tip60 acetyltransferase is essential to establish neuronal cell identity partly via acetylation of the histone variant H2A.Z. Despite its tight correlation with gene expression and active chromatin, loss of H2A.Z acetylation had little effect on chromatin accessibility or transcription. Instead, loss of Tip60 and acetyl-H2A.Z interfered with H3K4me3 deposition and activation of a unique subset of silent, lineage-restricted genes characterized by a bivalent chromatin configuration at their promoters. Altogether, our results illuminate the mechanisms underlying bivalent chromatin activation and reveal that H2A.Z acetylation regulates neuronal fate specification by establishing epigenetic competence for bivalent gene activation and cell lineage transition.
Pubmed Link
2022
Tip60-mediated H2A.Z acetylation promotes neuronal fate specification and bivalent gene activation
Molecular cell
Justyna A Janas,Lichao Zhang,Jacklyn H Luu,Janos Demeter,Lingjun Meng,Samuele G Marro,Moritz Mall,Nancie A Mooney,Katie Schaukowitch,Yi Han Ng,Nan Yang,Yuhao Huang,Gernot Neumayer,Or Gozani,Joshua E Elias,Peter K Jackson,Marius Wernig
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Cell lineage specification is accomplished by a concerted action of chromatin remodeling and tissue-specific transcription factors. However, the mechanisms that induce and maintain appropriate lineage-specific gene expression remain elusive. Here, we used an unbiased proteomics approach to characterize chromatin regulators that mediate the induction of neuronal cell fate. We found that Tip60 acetyltransferase is essential to establish neuronal cell identity partly via acetylation of the histone variant H2A.Z. Despite its tight correlation with gene expression and active chromatin, loss of H2A.Z acetylation had little effect on chromatin accessibility or transcription. Instead, loss of Tip60 and acetyl-H2A.Z interfered with H3K4me3 deposition and activation of a unique subset of silent, lineage-restricted genes characterized by a bivalent chromatin configuration at their promoters. Altogether, our results illuminate the mechanisms underlying bivalent chromatin activation and reveal that H2A.Z acetylation regulates neuronal fate specification by establishing epigenetic competence for bivalent gene activation and cell lineage transition.
Directly induced human retinal ganglion cells mimic fetal RGCs and are neuroprotective after transplantation in vivo
Ziming Luo,Kun-Che Chang,Suqian Wu,Catalina Sun,Xin Xia,Michael Nahmou,Minjuan Bian,Rain R Wen,Ying Zhu,Sahil Shah,Bogdan Tanasa,Marius Wernig,Jeffrey L Goldberg
Retinal ganglion cell (RGC) replacement therapy could restore vision in glaucoma and other optic neuropathies. We developed a rapid protocol for directly induced RGC (iRGC) differentiation from human stem cells, leveraging overexpression of NGN2. Neuronal morphology and neurite growth were observed within 1 week of induction; characteristic RGC-specific gene expression confirmed identity. Calcium imaging demonstrated γ-aminobutyric acid (GABA)-induced excitation characteristic of immature RGCs. Single-cell RNA sequencing showed more similarities between iRGCs and early-stage fetal human RGCs than retinal organoid-derived RGCs. Intravitreally transplanted iRGCs survived and migrated into host retinas independent of prior optic nerve trauma, but iRGCs protected host RGCs from neurodegeneration. These data demonstrate rapid iRGC generation in vitro into an immature cell with high similarity to human fetal RGCs and capacity for retinal integration after transplantation and neuroprotective function after optic nerve injury. The simplicity of this system may benefit translational studies on human RGCs.
Pubmed Link
2022
Directly induced human retinal ganglion cells mimic fetal RGCs and are neuroprotective after transplantation in vivo
Stem cell reports
Ziming Luo,Kun-Che Chang,Suqian Wu,Catalina Sun,Xin Xia,Michael Nahmou,Minjuan Bian,Rain R Wen,Ying Zhu,Sahil Shah,Bogdan Tanasa,Marius Wernig,Jeffrey L Goldberg
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Retinal ganglion cell (RGC) replacement therapy could restore vision in glaucoma and other optic neuropathies. We developed a rapid protocol for directly induced RGC (iRGC) differentiation from human stem cells, leveraging overexpression of NGN2. Neuronal morphology and neurite growth were observed within 1 week of induction; characteristic RGC-specific gene expression confirmed identity. Calcium imaging demonstrated γ-aminobutyric acid (GABA)-induced excitation characteristic of immature RGCs. Single-cell RNA sequencing showed more similarities between iRGCs and early-stage fetal human RGCs than retinal organoid-derived RGCs. Intravitreally transplanted iRGCs survived and migrated into host retinas independent of prior optic nerve trauma, but iRGCs protected host RGCs from neurodegeneration. These data demonstrate rapid iRGC generation in vitro into an immature cell with high similarity to human fetal RGCs and capacity for retinal integration after transplantation and neuroprotective function after optic nerve injury. The simplicity of this system may benefit translational studies on human RGCs.
Synaptogenic effect of APP -Swedish mutation in familial Alzheimer's disease
Bo Zhou,Jacqueline G Lu,Alberto Siddu,Marius Wernig,Thomas C Südhof
Mutations in β-amyloid (Aβ) precursor protein (APP ) cause familial Alzheimer's disease (AD) probably by enhancing Aβ peptides production from APP. An antibody targeting Aβ (aducanumab) was approved as an AD treatment; however, some Aβ antibodies have been reported to accelerate, instead of ameliorating, cognitive decline in individuals with AD. Using conditional APP mutations in human neurons for perfect isogenic controls and translational relevance, we found that the APP -Swedish mutation in familial AD increased synapse numbers and synaptic transmission, whereas the APP deletion decreased synapse numbers and synaptic transmission. Inhibition of BACE1, the protease that initiates Aβ production from APP, lowered synapse numbers, suppressed synaptic transmission in wild-type neurons, and occluded the phenotype of APP -Swedish-mutant neurons. Modest elevations of Aβ, conversely, elevated synapse numbers and synaptic transmission. Thus, the familial AD-linked APP -Swedish mutation under physiologically relevant conditions increased synaptic connectivity in human neurons via a modestly enhanced production of Aβ. These data are consistent with the relative inefficacy of BACE1 and anti-Aβ treatments in AD and the chronic nature of AD pathogenesis, suggesting that AD pathogenesis is not simply caused by overproduction of toxic Aβ but rather by a long-term effect of elevated Aβ concentrations.
Pubmed Link
2022
Synaptogenic effect of APP -Swedish mutation in familial Alzheimer's disease
Science translational medicine
Bo Zhou,Jacqueline G Lu,Alberto Siddu,Marius Wernig,Thomas C Südhof
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Mutations in β-amyloid (Aβ) precursor protein (APP ) cause familial Alzheimer's disease (AD) probably by enhancing Aβ peptides production from APP. An antibody targeting Aβ (aducanumab) was approved as an AD treatment; however, some Aβ antibodies have been reported to accelerate, instead of ameliorating, cognitive decline in individuals with AD. Using conditional APP mutations in human neurons for perfect isogenic controls and translational relevance, we found that the APP -Swedish mutation in familial AD increased synapse numbers and synaptic transmission, whereas the APP deletion decreased synapse numbers and synaptic transmission. Inhibition of BACE1, the protease that initiates Aβ production from APP, lowered synapse numbers, suppressed synaptic transmission in wild-type neurons, and occluded the phenotype of APP -Swedish-mutant neurons. Modest elevations of Aβ, conversely, elevated synapse numbers and synaptic transmission. Thus, the familial AD-linked APP -Swedish mutation under physiologically relevant conditions increased synaptic connectivity in human neurons via a modestly enhanced production of Aβ. These data are consistent with the relative inefficacy of BACE1 and anti-Aβ treatments in AD and the chronic nature of AD pathogenesis, suggesting that AD pathogenesis is not simply caused by overproduction of toxic Aβ but rather by a long-term effect of elevated Aβ concentrations.
Endocytosis in the axon initial segment maintains neuronal polarity
Kelsie Eichel,Takeshi Uenaka,Vivek Belapurkar,Rui Lu,Shouqiang Cheng,Joseph S Pak,Caitlin A Taylor,Thomas C Südhof,Robert Malenka,Marius Wernig,Engin Özkan,David Perrais,Kang Shen
Neurons are highly polarized cells that face the fundamental challenge of compartmentalizing a vast and diverse repertoire of proteins in order to function properly1 . The axon initial segment (AIS) is a specialized domain that separates a neuron's morphologically, biochemically and functionally distinct axon and dendrite compartments2,3 . How the AIS maintains polarity between these compartments is not fully understood. Here we find that in Caenorhabditis elegans, mouse, rat and human neurons, dendritically and axonally polarized transmembrane proteins are recognized by endocytic machinery in the AIS, robustly endocytosed and targeted to late endosomes for degradation. Forcing receptor interaction with the AIS master organizer, ankyrinG, antagonizes receptor endocytosis in the AIS, causes receptor accumulation in the AIS, and leads to polarity deficits with subsequent morphological and behavioural defects. Therefore, endocytic removal of polarized receptors that diffuse into the AIS serves as a membrane-clearance mechanism that is likely to work in conjunction with the known AIS diffusion-barrier mechanism to maintain neuronal polarity on the plasma membrane. Our results reveal a conserved endocytic clearance mechanism in the AIS to maintain neuronal polarity by reinforcing axonal and dendritic compartment membrane boundaries.
Pubmed Link
2022
Endocytosis in the axon initial segment maintains neuronal polarity
Nature
Kelsie Eichel,Takeshi Uenaka,Vivek Belapurkar,Rui Lu,Shouqiang Cheng,Joseph S Pak,Caitlin A Taylor,Thomas C Südhof,Robert Malenka,Marius Wernig,Engin Özkan,David Perrais,Kang Shen
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Neurons are highly polarized cells that face the fundamental challenge of compartmentalizing a vast and diverse repertoire of proteins in order to function properly1 . The axon initial segment (AIS) is a specialized domain that separates a neuron's morphologically, biochemically and functionally distinct axon and dendrite compartments2,3 . How the AIS maintains polarity between these compartments is not fully understood. Here we find that in Caenorhabditis elegans, mouse, rat and human neurons, dendritically and axonally polarized transmembrane proteins are recognized by endocytic machinery in the AIS, robustly endocytosed and targeted to late endosomes for degradation. Forcing receptor interaction with the AIS master organizer, ankyrinG, antagonizes receptor endocytosis in the AIS, causes receptor accumulation in the AIS, and leads to polarity deficits with subsequent morphological and behavioural defects. Therefore, endocytic removal of polarized receptors that diffuse into the AIS serves as a membrane-clearance mechanism that is likely to work in conjunction with the known AIS diffusion-barrier mechanism to maintain neuronal polarity on the plasma membrane. Our results reveal a conserved endocytic clearance mechanism in the AIS to maintain neuronal polarity by reinforcing axonal and dendritic compartment membrane boundaries.
Transition to a mesenchymal state in neuroblastoma confers resistance to anti-GD2 antibody via reduced expression of ST8SIA1
Nathaniel W Mabe,Min Huang,Guillermo N Dalton,Gabriela Alexe,Daniel A Schaefer,Anna C Geraghty,Amanda L Robichaud,Amy S Conway,Delan Khalid,Marius M Mader,Julia A Belk,Kenneth N Ross,Michal Sheffer,Miles H Linde,Nghi Ly,Winnie Yao,Maria Caterina Rotiroti,Benjamin A H Smith,Marius Wernig,Carolyn R Bertozzi,Michelle Monje,Constantine S Mitsiades,Ravindra Majeti,Ansuman T Satpathy,Kimberly Stegmaier,Robbie G Majzner
Immunotherapy with anti-GD2 antibodies has advanced the treatment of children with high-risk neuroblastoma, but nearly half of patients relapse, and little is known about mechanisms of resistance to anti-GD2 therapy. Here, we show that reduced GD2 expression was significantly correlated with the mesenchymal cell state in neuroblastoma and that a forced adrenergic-to-mesenchymal transition (AMT) conferred downregulation of GD2 and resistance to anti-GD2 antibody. Mechanistically, low-GD2-expressing cell lines demonstrated significantly reduced expression of the ganglioside synthesis enzyme ST8SIA1 (GD3 synthase), resulting in a bottlenecking of GD2 synthesis. Pharmacologic inhibition of EZH2 resulted in epigenetic rewiring of mesenchymal neuroblastoma cells and re-expression of ST8SIA1, restoring surface expression of GD2 and sensitivity to anti-GD2 antibody. These data identify developmental lineage as a key determinant of sensitivity to anti-GD2 based immunotherapies and credential EZH2 inhibitors for clinical testing in combination with anti-GD2 antibody to enhance outcomes for children with neuroblastoma.
Pubmed Link
2022
Transition to a mesenchymal state in neuroblastoma confers resistance to anti-GD2 antibody via reduced expression of ST8SIA1
Nature cancer
Nathaniel W Mabe,Min Huang,Guillermo N Dalton,Gabriela Alexe,Daniel A Schaefer,Anna C Geraghty,Amanda L Robichaud,Amy S Conway,Delan Khalid,Marius M Mader,Julia A Belk,Kenneth N Ross,Michal Sheffer,Miles H Linde,Nghi Ly,Winnie Yao,Maria Caterina Rotiroti,Benjamin A H Smith,Marius Wernig,Carolyn R Bertozzi,Michelle Monje,Constantine S Mitsiades,Ravindra Majeti,Ansuman T Satpathy,Kimberly Stegmaier,Robbie G Majzner
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Immunotherapy with anti-GD2 antibodies has advanced the treatment of children with high-risk neuroblastoma, but nearly half of patients relapse, and little is known about mechanisms of resistance to anti-GD2 therapy. Here, we show that reduced GD2 expression was significantly correlated with the mesenchymal cell state in neuroblastoma and that a forced adrenergic-to-mesenchymal transition (AMT) conferred downregulation of GD2 and resistance to anti-GD2 antibody. Mechanistically, low-GD2-expressing cell lines demonstrated significantly reduced expression of the ganglioside synthesis enzyme ST8SIA1 (GD3 synthase), resulting in a bottlenecking of GD2 synthesis. Pharmacologic inhibition of EZH2 resulted in epigenetic rewiring of mesenchymal neuroblastoma cells and re-expression of ST8SIA1, restoring surface expression of GD2 and sensitivity to anti-GD2 antibody. These data identify developmental lineage as a key determinant of sensitivity to anti-GD2 based immunotherapies and credential EZH2 inhibitors for clinical testing in combination with anti-GD2 antibody to enhance outcomes for children with neuroblastoma.
Generation of functional human oligodendrocytes from dermal fibroblasts by direct lineage conversion
Koji Tanabe,Hiroko Nobuta,Nan Yang,Cheen Euong Ang,Philip Huie,Sacha Jordan,Michael C Oldham,David H Rowitch,Marius Wernig
Oligodendrocytes, the myelinating cells of the central nervous system, possess great potential for disease modeling and cell transplantation-based therapies for leukodystrophies. However, caveats to oligodendrocyte differentiation protocols ( Ehrlich et al., 2017; Wang et al., 2013; Douvaras and Fossati, 2015) from human embryonic stem and induced pluripotent stem cells (iPSCs), which include slow and inefficient differentiation, and tumorigenic potential of contaminating undifferentiated pluripotent cells, are major bottlenecks towards their translational utility. Here, we report the rapid generation of human oligodendrocytes by direct lineage conversion of human dermal fibroblasts (HDFs). We show that the combination of the four transcription factors OLIG2, SOX10, ASCL1 and NKX2.2 is sufficient to convert HDFs to induced oligodendrocyte precursor cells (iOPCs). iOPCs resemble human primary and iPSC-derived OPCs based on morphology and transcriptomic analysis. Importantly, iOPCs can differentiate into mature myelinating oligodendrocytes in vitro and in vivo. Finally, iOPCs derived from patients with Pelizaeus Merzbacher disease, a hypomyelinating leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene, showed increased cell death compared with iOPCs from healthy donors. Thus, human iOPCs generated by direct lineage conversion represent an attractive new source for human cell-based disease models and potentially myelinating cell grafts.
Pubmed Link
2022
Generation of functional human oligodendrocytes from dermal fibroblasts by direct lineage conversion
Development (Cambridge, England)
Koji Tanabe,Hiroko Nobuta,Nan Yang,Cheen Euong Ang,Philip Huie,Sacha Jordan,Michael C Oldham,David H Rowitch,Marius Wernig
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Oligodendrocytes, the myelinating cells of the central nervous system, possess great potential for disease modeling and cell transplantation-based therapies for leukodystrophies. However, caveats to oligodendrocyte differentiation protocols ( Ehrlich et al., 2017; Wang et al., 2013; Douvaras and Fossati, 2015) from human embryonic stem and induced pluripotent stem cells (iPSCs), which include slow and inefficient differentiation, and tumorigenic potential of contaminating undifferentiated pluripotent cells, are major bottlenecks towards their translational utility. Here, we report the rapid generation of human oligodendrocytes by direct lineage conversion of human dermal fibroblasts (HDFs). We show that the combination of the four transcription factors OLIG2, SOX10, ASCL1 and NKX2.2 is sufficient to convert HDFs to induced oligodendrocyte precursor cells (iOPCs). iOPCs resemble human primary and iPSC-derived OPCs based on morphology and transcriptomic analysis. Importantly, iOPCs can differentiate into mature myelinating oligodendrocytes in vitro and in vivo. Finally, iOPCs derived from patients with Pelizaeus Merzbacher disease, a hypomyelinating leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene, showed increased cell death compared with iOPCs from healthy donors. Thus, human iOPCs generated by direct lineage conversion represent an attractive new source for human cell-based disease models and potentially myelinating cell grafts.
Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice
Markus Wöhr,Wendy M Fong,Justyna A Janas,Moritz Mall,Christian Thome,Madhuri Vangipuram,Lingjun Meng,Thomas C Südhof,Marius Wernig
BACKGROUND: The zinc finger domain containing transcription factor Myt1l is tightly associated with neuronal identity and is the only transcription factor known that is both neuron-specific and expressed in all neuronal subtypes. We identified Myt1l as a powerful reprogramming factor that, in combination with the proneural bHLH factor Ascl1, could induce neuronal fate in fibroblasts. Molecularly, we found it to repress many non-neuronal gene programs, explaining its supportive role to induce and safeguard neuronal identity in combination with proneural bHLH transcriptional activators. Moreover, human genetics studies found MYT1L mutations to cause intellectual disability and autism spectrum disorder often coupled with obesity. METHODS: Here, we generated and characterized Myt1l-deficient mice. A comprehensive, longitudinal behavioral phenotyping approach was applied. RESULTS: Myt1l was necessary for survival beyond 24 h but not for overall histological brain organization. Myt1l heterozygous mice became increasingly overweight and exhibited multifaceted behavioral alterations. In mouse pups, Myt1l haploinsufficiency caused mild alterations in early socio-affective communication through ultrasonic vocalizations. In adulthood, Myt1l heterozygous mice displayed hyperactivity due to impaired habituation learning. Motor performance was reduced in Myt1l heterozygous mice despite intact motor learning, possibly due to muscular hypotonia. While anxiety-related behavior was reduced, acoustic startle reactivity was enhanced, in line with higher sensitivity to loud sound. Finally, Myt1l haploinsufficiency had a negative impact on contextual fear memory retrieval, while cued fear memory retrieval appeared to be intact. LIMITATIONS: In future studies, additional phenotypes might be identified and a detailed characterization of direct reciprocal social interaction behavior might help to reveal effects of Myt1l haploinsufficiency on social behavior in juvenile and adult mice. CONCLUSIONS: Behavioral alterations in Myt1l haploinsufficient mice recapitulate several clinical phenotypes observed in humans carrying heterozygous MYT1L mutations and thus serve as an informative model of the human MYT1L syndrome.
Pubmed Link
2022
Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice
Molecular autism
Markus Wöhr,Wendy M Fong,Justyna A Janas,Moritz Mall,Christian Thome,Madhuri Vangipuram,Lingjun Meng,Thomas C Südhof,Marius Wernig
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BACKGROUND: The zinc finger domain containing transcription factor Myt1l is tightly associated with neuronal identity and is the only transcription factor known that is both neuron-specific and expressed in all neuronal subtypes. We identified Myt1l as a powerful reprogramming factor that, in combination with the proneural bHLH factor Ascl1, could induce neuronal fate in fibroblasts. Molecularly, we found it to repress many non-neuronal gene programs, explaining its supportive role to induce and safeguard neuronal identity in combination with proneural bHLH transcriptional activators. Moreover, human genetics studies found MYT1L mutations to cause intellectual disability and autism spectrum disorder often coupled with obesity. METHODS: Here, we generated and characterized Myt1l-deficient mice. A comprehensive, longitudinal behavioral phenotyping approach was applied. RESULTS: Myt1l was necessary for survival beyond 24 h but not for overall histological brain organization. Myt1l heterozygous mice became increasingly overweight and exhibited multifaceted behavioral alterations. In mouse pups, Myt1l haploinsufficiency caused mild alterations in early socio-affective communication through ultrasonic vocalizations. In adulthood, Myt1l heterozygous mice displayed hyperactivity due to impaired habituation learning. Motor performance was reduced in Myt1l heterozygous mice despite intact motor learning, possibly due to muscular hypotonia. While anxiety-related behavior was reduced, acoustic startle reactivity was enhanced, in line with higher sensitivity to loud sound. Finally, Myt1l haploinsufficiency had a negative impact on contextual fear memory retrieval, while cued fear memory retrieval appeared to be intact. LIMITATIONS: In future studies, additional phenotypes might be identified and a detailed characterization of direct reciprocal social interaction behavior might help to reveal effects of Myt1l haploinsufficiency on social behavior in juvenile and adult mice. CONCLUSIONS: Behavioral alterations in Myt1l haploinsufficient mice recapitulate several clinical phenotypes observed in humans carrying heterozygous MYT1L mutations and thus serve as an informative model of the human MYT1L syndrome.
Is hypoimmunogenic stem cell therapy safe in times of pandemics?
Friederike Matheus,Tal Raveh,Anthony E Oro,Marius Wernig,Micha Drukker
The manipulation of human leukocyte antigens (HLAs) and immune modulatory factors in "universal" human pluripotent stem cells (PSCs) holds promise for immunological tolerance without HLA matching. This paradigm raises concerns should "universal" grafts become virally infected. Furthermore, immunological manipulation might functionally impair certain progeny, such as hematopoietic stem cells. We discuss the risks and benefits of hypoimmunogenic PSCs, and the need to further advance HLA matching and autologous strategies.
Pubmed Link
2022
Is hypoimmunogenic stem cell therapy safe in times of pandemics?
Stem cell reports
Friederike Matheus,Tal Raveh,Anthony E Oro,Marius Wernig,Micha Drukker
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The manipulation of human leukocyte antigens (HLAs) and immune modulatory factors in "universal" human pluripotent stem cells (PSCs) holds promise for immunological tolerance without HLA matching. This paradigm raises concerns should "universal" grafts become virally infected. Furthermore, immunological manipulation might functionally impair certain progeny, such as hematopoietic stem cells. We discuss the risks and benefits of hypoimmunogenic PSCs, and the need to further advance HLA matching and autologous strategies.
Treatment of a genetic brain disease by CNS-wide microglia replacement
Yohei Shibuya,Kevin K Kumar,Marius Marc-Daniel Mader,Yongjin Yoo,Luis Angel Ayala,Mu Zhou,Manuel Alexander Mohr,Gernot Neumayer,Ishan Kumar,Ryo Yamamoto,Paul Marcoux,Benjamin Liou,F Chris Bennett,Hiromitsu Nakauchi,Ying Sun,Xiaoke Chen,Frank L Heppner,Tony Wyss-Coray,Thomas C Südhof,Marius Wernig
Hematopoietic cell transplantation after myeloablative conditioning has been used to treat various genetic metabolic syndromes but is largely ineffective in diseases affecting the brain presumably due to poor and variable myeloid cell incorporation into the central nervous system. Here, we developed and characterized a near-complete and homogeneous replacement of microglia with bone marrow cells in mice without the need for genetic manipulation of donor or host. The high chimerism resulted from a competitive advantage of scarce donor cells during microglia repopulation rather than enhanced recruitment from the periphery. Hematopoietic stem cells, but not immediate myeloid or monocyte progenitor cells, contained full microglia replacement potency equivalent to whole bone marrow. To explore its therapeutic potential, we applied microglia replacement to a mouse model for Prosaposin deficiency, which is characterized by a progressive neurodegeneration phenotype. We found a reduction of cerebellar neurodegeneration and gliosis in treated brains, improvement of motor and balance impairment, and life span extension even with treatment started in young adulthood. This proof-of-concept study suggests that efficient microglia replacement may have therapeutic efficacy for a variety of neurological diseases.
Pubmed Link
2022
Treatment of a genetic brain disease by CNS-wide microglia replacement
Science translational medicine
Yohei Shibuya,Kevin K Kumar,Marius Marc-Daniel Mader,Yongjin Yoo,Luis Angel Ayala,Mu Zhou,Manuel Alexander Mohr,Gernot Neumayer,Ishan Kumar,Ryo Yamamoto,Paul Marcoux,Benjamin Liou,F Chris Bennett,Hiromitsu Nakauchi,Ying Sun,Xiaoke Chen,Frank L Heppner,Tony Wyss-Coray,Thomas C Südhof,Marius Wernig
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There is no abstract listed on Pubmed for this publication
Hematopoietic cell transplantation after myeloablative conditioning has been used to treat various genetic metabolic syndromes but is largely ineffective in diseases affecting the brain presumably due to poor and variable myeloid cell incorporation into the central nervous system. Here, we developed and characterized a near-complete and homogeneous replacement of microglia with bone marrow cells in mice without the need for genetic manipulation of donor or host. The high chimerism resulted from a competitive advantage of scarce donor cells during microglia repopulation rather than enhanced recruitment from the periphery. Hematopoietic stem cells, but not immediate myeloid or monocyte progenitor cells, contained full microglia replacement potency equivalent to whole bone marrow. To explore its therapeutic potential, we applied microglia replacement to a mouse model for Prosaposin deficiency, which is characterized by a progressive neurodegeneration phenotype. We found a reduction of cerebellar neurodegeneration and gliosis in treated brains, improvement of motor and balance impairment, and life span extension even with treatment started in young adulthood. This proof-of-concept study suggests that efficient microglia replacement may have therapeutic efficacy for a variety of neurological diseases.
RTN4/NoGo-receptor binding to BAI adhesion-GPCRs regulates neuronal development

Jie Wang, Yi Miao, Rebecca Wicklein, Zijun Sun, Jinzhao Wang, Kevin M Jude, Ricardo A Fernandes, Sean A Merrill, Marius Wernig, K Christopher Garcia, Thomas C Südhof

RTN4-binding proteins were widely studied as "NoGo" receptors, but their physiological interactors and roles remain elusive. Similarly, BAI adhesion-GPCRs were associated with numerous activities, but their ligands and functions remain unclear. Using unbiased approaches, we observed an unexpected convergence: RTN4 receptors are high-affinity ligands for BAI adhesion-GPCRs. A single thrombospondin type 1-repeat (TSR) domain of BAIs binds to the leucine-rich repeat domain of all three RTN4-receptor isoforms with nanomolar affinity. In the 1.65 Å crystal structure of the BAI1/RTN4-receptor complex, C-mannosylation of tryptophan and O-fucosylation of threonine in the BAI TSR-domains creates a RTN4-receptor/BAI interface shaped by unusual glycoconjugates that enables high-affinity interactions. In human neurons, RTN4 receptors regulate dendritic arborization, axonal elongation, and synapse formation by differential binding to glial versus neuronal BAIs, thereby controlling neural network activity. Thus, BAI binding to RTN4/NoGo receptors represents a receptor-ligand axis that, enabled by rare post-translational modifications, controls development of synaptic circuits.

Pubmed Link
2022
RTN4/NoGo-receptor binding to BAI adhesion-GPCRs regulates neuronal development
Cell

Jie Wang, Yi Miao, Rebecca Wicklein, Zijun Sun, Jinzhao Wang, Kevin M Jude, Ricardo A Fernandes, Sean A Merrill, Marius Wernig, K Christopher Garcia, Thomas C Südhof

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There is no abstract listed on Pubmed for this publication

RTN4-binding proteins were widely studied as "NoGo" receptors, but their physiological interactors and roles remain elusive. Similarly, BAI adhesion-GPCRs were associated with numerous activities, but their ligands and functions remain unclear. Using unbiased approaches, we observed an unexpected convergence: RTN4 receptors are high-affinity ligands for BAI adhesion-GPCRs. A single thrombospondin type 1-repeat (TSR) domain of BAIs binds to the leucine-rich repeat domain of all three RTN4-receptor isoforms with nanomolar affinity. In the 1.65 Å crystal structure of the BAI1/RTN4-receptor complex, C-mannosylation of tryptophan and O-fucosylation of threonine in the BAI TSR-domains creates a RTN4-receptor/BAI interface shaped by unusual glycoconjugates that enables high-affinity interactions. In human neurons, RTN4 receptors regulate dendritic arborization, axonal elongation, and synapse formation by differential binding to glial versus neuronal BAIs, thereby controlling neural network activity. Thus, BAI binding to RTN4/NoGo receptors represents a receptor-ligand axis that, enabled by rare post-translational modifications, controls development of synaptic circuits.

Marius Wernig

M.D., Ph.D.

wernig@stanford.edu


Dr. Marius Wernig is a Professor of Pathology and a Co-Director of 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, the Ogawa-Yamanaka Stem Cell Prize delivered by the Gladstone Institute and more recently has been named a Faculty Scholar by the Howard Hughes Medical Institute.

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

2022
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Alan Bortoncello Napole
Life Science Research Professional
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Alan Napole is an LSRP working on elucidating the mechanisms of transgene silencing following iN differentiation from pluripotent stem cells. Concurrently, Alan is also working on understanding the role of microglia in multiple sclerosis via EAE mice models. Previously, he was a CIRM scholar working closely with microglia replacement strategies to develop a human mouse microglia chimera for investigation of neuroimmunological diseases. Alan is currently applying to medical school with interests in neuroscience and surgery. Outside of the lab, he enjoys attending music festivals, playing soccer, and cooking.

Christian Thome
Postdoc Fellow
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My current project focuses on the function of synaptic proteins in the context of human neurons. Brain research has made tremendous advances in the last decades using animal models. However, most neuropathological conditions, such as autism or schizophrenia, are unique to human physiology. Thus, I study the effect of genetic alterations of synaptic proteins in induced human neurons using immunohistochemistry, analysis of gene and protein expression, as well as electrophysiology.

Danwei Wu
Neurology Resident Fellow
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Danwei Wu is a Stanford neurology resident in the Neuroscience Scholar Track and aspiring neuroimmunologist. Prior to starting residency, she completed an HHMI Medical Research Fellowship with Dr. Vann Bennett at Duke University studying neuron-specific membrane domains and their interaction with cytoskeletal structures. Her current research interest includes cell-based therapies for multiple sclerosis, molecular pathways of neuro-repair, and pathogenesis of autoimmunity. She is interested in developing new therapies for neurologic diseases.  Outside of the lab, she enjoys hiking and reading science fiction.

Emma O'Connell
PhD Student
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I am a PhD student in the Neurosciences Interdepartmental Program and joined the lab in summer 2022. I am interested in developing methods to reprogram stem cells directly into oligodendrocytes. I then hope to use these cells to study the role of oligodendrocytes in aging and neurodegeneration. In my free time I like to read, ski, and play tennis.

Gernot Neumayer
Postdoc Fellow
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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
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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 Researcher
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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
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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
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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 Han
Undergrad Researcher
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I am a Bachelor of Science candidate in Bioengineering at Stanford University. My research in the Wernig Lag involves investigating the relationship between microglia and the IKBKAP gene, specifically its role in mechanisms such as microglia regeneration and the transdifferentiation of hematopoietic stem and progenitor cells into microglia-like cells.

Katie Schaukowitch
Postdoc Fellow
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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.

Kayla Vodenahl
PhD Student
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Kayla is a PhD student in the Neurosciences Interdepartmental Program and joined the lab in summer 2022. She is interested in leveraging the lab's cell reprogramming techniques to study the roles of individual cell types in proteinopathies. She aims to faithfully recapitulate disease states and uncover the underlying molecular mechanisms that lead to neurodegeneration. In her free time, Kayla can be found birding, hiking, or performing with the Stanford Symphony Orchestra.

Marius Mader
Postdoc Fellow
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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.

Micah Williams
Undergrad Researcher
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I am an undergraduate student studying Human Biology. At Wernig Lab, I am helping to research how microglial cells organize and communicate with each other. I am interested in understanding the relationship between changes in the organization of microglia and other neural cells and the progression of neuronal diseases.

Takeshi Uenaka
Postdoc Fellow
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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.

Tamara Chan
PhD Student
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I am a PhD student in the Department of Neurosciences and I joined the Wernig lab in the summer of 2020. I hope to study the fundamental cell biology of microglia giving rise to stable tiling in the brain. Furthermore, I am interested in how these mechanisms contribute to brain homeostasis and change with neuronal disease.

Tamas Danko
Basic Life Res Scientist
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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. "

Yongjin Yoo
Postdoc Fellow
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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

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Angel Ayala
Master's Student
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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. Unfortunately, COVID19 cut some of the last of his time he was planning to stay with us. We are proud of Angel that he got into the PhD program at UC Irvine where he moved during these challenging times of natural disasters of the year 2020. Good luck Angel!

Bahareh Haddad Derafshi
PhD Student
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Bahareh's research interests were focused on epigenetic regulation of cognition at the level of synapses, using iN system. In my free time she likes to do sports and outdoor activities, cook healthy food, make mixed drinks, play music, and collect vinyl records. After graduating from our Stem Cell and Regenerative Medicine PhD program she moved on as postdoctoral fellow to Boston.

Bo Zhou
Postdoc Fellow
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Bo was studying synaptogenesis in Alzheimer’s Disease using human iNs as a model. She was lured away by industry and accepted an attractive offer from Genentech.

Cheen Euong Ang
PhD student
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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.

Christina Tan
Postdoc Fellow
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Graduating from UC Berkeley majoring in Biology with an honors in Neuroscience, and having worked as an MD at the Royal Melbourne Hospital, I have developed a particular interest in translational neuroscience. In the lab, I am investigating the efficacy of cell therapies for neurological disorders. I am currently working on microglia based therapies for major neurological diseases, including multiple sclerosis.

Daniel Haag
Postdoc Fellow
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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
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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
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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.

Kevin Kumar
Resident fellow
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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
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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
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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.

Minjeong Lee
Lab Admin
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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
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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
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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
PhD Student
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I am interested in studying the mechanisms of direct lineage reprogramming of fibroblasts into neurons.

Ron Danziger
Postdoc Fellow
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I grew up in Australia where I completed an undergraduate degree in neuroscience and an MD at the University of Melbourne, Australia. I then completed my intern year at the Royal Melbourne Hospital.  I have a keen interest in stem cell therapeutics and their potential application in treating debilitating neurological conditions. My current research focus is on novel microglia based therapies that can potentially ameliorate disease progression in multiple sclerosis.

Samuele Marro
Basic Life Res Scientist
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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. After leaving his prominent imprint on the lab he moved on to join the faculty at Mount Sanai School of Medicine in New York. Good luck Samuele, we will miss you!

Sarah Grieder
Research Assistant
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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
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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.

Virginia Trakul
Administrative Associate
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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. Unfortunately, due to COVID19 Virginia needed more time to care for her children and had to leave us. She was a delight to have around and we will dearly miss her!

Wendy Fong
Postdoc Fellow
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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 aimed to understand the molecular mechanisms by which neuronal identity is established and how its disruption leads to neurological diseases focusing on the gene Myt1l.

Yingfei Liu
PhD Visiting Student
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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 the neural stem cells. Now She is studying the mechanisms of direct lineage reprogramming of fibroblasts into neurons. Yingfei was great to have in the lab. COVID19 also affected Yingfei's carreer. In the midst of great progress COVID19 precluded much of her continuing to work. She went back to China to arrange for her PhD defense and we are hoping to be able to continue to work with her in the future. Good luck Yingfei!

Yohei Shibuya
Postdoc Fellow
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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.

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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

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Wernig Laboratory
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