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The postnatal rodent subventricular zone generates tens of thousands of neurons every day.
Human neurogenesis is a vibrant field of research with deep therapeutic potential.
We study postnatal and adult mammalian brain stem cells to uncover fundamental developmental mechanisms and disease pathogenesis.
The Szele group is working on fundamental developmental neurobiological questions in health and disease.
Our main discovery platform are the two stem cell niches of the brain - the subventricular zone (SVZ) and the dentate gyrus (DG). The SVZ and DG neurogenic niches contain stem cells, transit amplifying progenitors and neuroblasts. They are convenient biological systems to study fundamental developmental questions since one can easily modulate gene expression in them. We investigate the role of the SVZ in models of neurodegeneration and neuropsychiatric disorders. We also study human neurogenesis in postmortem sections and with induced pluripotential stem cells. We are interdisciplinary and have many excellent collaborators.
Many of our studies seek to understand how the SVZ and DG respond to disease with the ultimate goal of using molecular insights to augment neurogenesis and enhance progenitor migration towards brain injury. We have focused on Galectin-3 (Gal-3) a pro-inflammatory protein we showed is necessary for SVZ neuroblast migration. We also found Gal-3 is necessary for angiogenesis after stroke and that it is upregulated in multiple sclerosis (MS). The Szele group are pursuing novel mechanistic insight into epigenetic and lncRNA regulation of neurogenesis. Using floxed Eed and Ezh2 mice, we found that different components of the Polycomb repressive complex 2 regulate distinct neurogenic events. We showed with Keith Vance that lncRNA Paupar is necessary for SVZ/OB neurogenesis. We are also working with Eric O'Neill on tumorigenic signalling pathways in the SVZ. With Hiroko Isoda we are testing the neurogenic properties of phytochemicals and nutraceuticals.
We also have a longstanding interest in the role of abnormal neurodevelopment in neuropsychiatric disorders. We use an integrated suite of animal models, human post-mortem sections and human induced pluripotential stem cells (iPSC) to study Autism and Schizophrenia. In particular we showed how studying how dysbindin loss of function interacts with inflammation to regulate neurogenesis in a murine gene x environment interaction model. Istvan Adorjan, a former postdoc in the lab and now running an independent group at the Semmelweis University (Budapest), demonstrated that the striatum contains fewer calretinin+ interneuron in patients with autism. We are now working with Dr. Adorjan on studies of postmortem human sections in other neuropsychiatric disorders. In collaboration with Yichen Li and Justin Ichida we are growing iPSC and olfactory stem cells from subjects with adolescent onset schizophrenia. Together with Hagan Bayley's group in chemistry we are 3D printing hiPSC derived cortical cells.
The Szele lab uses a wide range of in vivo and in vitro techniques including stem cell cultures, migration assays, in vivo electroporation, over expression and knockdown, Cre-lox conditional knockouts, etc. We have used 2-photon time-lapse microscopy in slices to record and quantitatively analyse cell behaviours in the SVZ and are developing in vivo approaches of imaging neurogenesis.
We have bi-weekly lab meetings Tuesdays from 9-10.30 AM. Please email Francis Szele if you would like to join us for one or more of these.
We welcome enquiries for collaboration, postdoctoral fellowships or studentships.
15 April, 2020
Szele Lab News
14 July, 2020 Martin's PAPER ACCEPTED in Stem Cell Reports!
Way to go Martin!! Dr. Martin Ducker did his DPhil in our group and developed a robust assay of neuroblast migration.
A Semi-automated and Scalable 3D Spheroid Assay to Study Neuroblast Migration
The subventricular zone of the mammalian brain is the major source of adult born neurons. These neuroblasts normally migrate long distances to the olfactory bulbs but can be re-routed to locations of injury and promote neuroregeneration. Mechanistic understanding and pharmacological targets regulating neuroblast migration is sparse. The lack of migration assays limits development of pharmaceutical interventions targeting neuroblast recruitment. We therefore developed a physiologically relevant 3D neuroblast spheroid migration assay that permits the investigation of large numbers of interventions. To verify the assay, 1,012 kinase inhibitors were screened for their effects on migration. Several induced significant increases or decreases in migration. MuSK and PIK3CB were selected as putative targets and their knockdown validated increased neuroblast migration. Thus, compounds identified through this assay system could be explored for their potential in augmenting neuroblast recruitment to sites of injury for neuroregeneration, or for decreasing malignant invasion.
28 MAY, 2020 Fang's paper Accepted!
Well done Dr. Li!! This work was done in collaboration with Prof. Jan Czeruszka, (Oxford Materials Department).
Fangxin Li, Martin Ducker, Bin Sun, Francis G. Szele* and Jan T. Czernuszka* Interpenetrating polymer networks of collagen, hyaluronic acids, and chondroitin sulfate as scaffolds for brain tissue engineering. Acta Biomateriala, In Press, 2020.
Stem cells can provide neuro-protection and potentially neuro- replacement to patients suffering from traumatic brain injuries (TBI), with a practical option being delivery via engineered scaffolds. Collagen (Coll) and glycosaminoglycan (GAG) have been used as scaffolds for brain tissue engineering yet they often do not support cell differentiation and survival. In this study, we developed interpenetrating polymer network scaffolds comprising Coll, and incorporating two commonly found GAGs in the brain, chondroitin sulfate (CS) and/or hyaluronic acid (HA). We seeded these scaffolds with mouse neural stem cells from the subventricular zone (SVZ) niche. Compared to Coll-alone, all other substrates decreased the percent of nestin+ stem cells. Coll-CS-HA was more efficient at suppressing nestin expression than the other scaffolds; all SVZ cells lost nestin expression within 7 days of culture. In contrast to nestin, the percentage of microtubule associated protein 2 (MAP2+) neurons was greater in scaffolds containing, CS, HA or CS-HA, compared to Coll alone. Finally, Coll-CS increased the percentage of glial fibrillary acidic protein (GFAP+) astrocytes compared to Coll scaffolds. Overall, this work shows that Coll-HA and Coll-CS-HA scaffolds selectively enhance neurogenesis and may be advantageous in tissue engineering therapy for TBI.
12 May, 2020 OMS GRANT FUNDED
More great news! Our grant has been awarded by the Oxford Martin School. "Low-cost printed tissues that address the global catastrophe of brain disease" Francis Szele Co-PI, Zoltan Molnar (DPAG) Co-PI, Hagan Bayley (Cemistry) PI. 4 years, starting fall 2020, £934,907.
Summmary. Brain damage through injury or disease has devastating social and economic consequences that are expanding exponentially in impact. We will initiate a radical approach in which the brain is repaired with 3D-printed neural tissue derived from stem cells. Ultimately, we aim to produce a low-cost, "democratized" technology that addresses an indisputable global catastrophe.
5 May, 2020
Great News! Manuscript accepted in Advanced Materials (IF 26). This work was a collaboration with Hagan Bayley's group in Chemistry.
"Lipid bilayer supported 3D printing of human cerebral cortex cells reveals developmental interactions" Linna Zhou, Anne C. Wolfes, Yichen Li, Danny C. W. Chan, Ho Ko, Francis G. Szele* and Hagan Bayley* *co-communicating
Abstract: Current understanding of human brain development is rudimentary due to suboptimal in vitro and animal models. In particular, how initial cell positions impact subsequent human cortical development is unclear because experimental spatial control of cortical cell arrangement has been technically challenging. 3D cell printing provides a rapid customised approach for patterning. However, it has relied on materials do not represent the extracellular matrix of brain tissue. We therefore developed a lipid bilayer supported printing technique to 3D print human cortical cells in the soft, biocompatible extracellular matrix, Matrigel. Printed human neural stem cells (hNSCs) showed high viability, neural differentiation and the formation of functional, stimulus-responsive neural networks. By using pre-patterned arrangements of neurons and astrocytes, we found that hNSC process outgrowth and migration into cell-free matrix and into astrocyte-containing matrix were similar in extent. However, astrocytes enhanced the later developmental event of axon bundling. Both young and mature neurons migrated into compartments containing astrocytes, in contrast, astrocytes did not migrate into neuronal domains signifying non-reciprocal chemorepulsion. Therefore, precise pre-patterning by 3D printing allows the construction of natural and unnatural patterns that yield important insights into human cerebral cortex development.
24 April, 2020
"Galectin-3 diminishes Wnt signaling in the postnatal subventricular zone" Osama Al-Dalahmah, James Nicholson, Swip Draijer, Luana Campos Soares and Francis G. Szele
Manuscript accepted in Stem Cells. Congratulations to Osamah Al-Dalahmah and to Luana, James and Swip.
Significance Statement. Galectin-3 (Gal-3) is frequently increased in cancer and injury. It regulates inflammation and subventricular zone (SVZ) neurogenesis, yet the signaling pathways whereby it does so are poorly understood. Gal-3 increases Wnt signaling in cancer cells but here we show that it binds to b-catenin in SVZ cells and negatively regulates Wnt signaling. Gal-3 also decreased proliferation and increased cell cycle exit. Gal-3 decreased Wnt signaling in the same cells with increased BMP signaling. Since Gal-3 is drugable, these studies suggest Gal-3 modulators could be used to manipulate Wnt signaling in the clinical setting.
31 MARCH, 2020
FARAH ALAMMARI successfully defends her DPhil.
Congratulations to Dr. Alammari! Farah who did an outstanding job in her viva, the first in the lab to be held by Skype. Farah was in London, Prof Zoltan Molnar in Oxford and Professor Carmen Castro in Cadiz. Thanks to Zoltan and Carmen as well. Farah showed that the lncRNA Paupar and its binding partner Kap1 regulate neurogenesis int he SVZ.
18 March, 2020
LAB CLOSURE DUE TO CORONAVIRUS PANDEMIC
Sadly we had to finish all experiments, freeze down cells and maintain reduced animal colonies. We are working from home with several papers being resubmitted and commenced. We thank members of the lab and members of the department for their productive contributions during this period.
20 September, 2019
Congratulations to Osama Al-Dalahmah whose paper has been accepted in Glia.
"Galectin-3 modulates postnatal subventricular zone gliogenesis"
Osama Al-Dalahmah, Luana Campos Soares, James Nicholson, Swip Draijer, Mayara Mundim, Victor M. Lu, Bin Sun, Teadora Tyler, István Adorján, Eric O'Neill and Francis G. Szele
Thanks to all the contributors, especially Luana Campos Soares.
Postnatal subventricular zone (SVZ) neural stem cells generate forebrain glia, namely astrocytes and oligodendrocytes. The cues necessary for this process are unclear, despite this phase of brain development being pivotal in forebrain gliogenesis. Galectin-3 (Gal-3) is increased in multiple brain pathologies and thereby regulates astrocyte proliferation and inflammation in injury. To study the function of Gal-3 in inflammation and gliogenesis, we carried out functional studies in mouse. We overexpressed Gal-3 with electroporation and using immunohistochemistry surprisingly found no inflammation in the healthy postnatal SVZ. This allowed investigation of inflammation-independent effects of Gal-3 on gliogenesis. Loss of Gal-3 function via knockdown or conditional knockout reduced gliogenesis, whereas Gal-3 overexpression increased it. Gal-3 overexpression also increased the percentage of striatal astrocytes generated by the SVZ but decreased the percentage of oligodendrocytes. These novel findings were further elaborated with multiple analyses demonstrating that Gal-3 binds to the bone morphogenetic protein receptor one alpha (BMPR1a) and increases bone morphogenetic protein (BMP) signaling. Conditional knockout of BMPR1a abolished the effect of Gal-3 overexpression on gliogenesis. Gain-of-function of Gal-3 is relevant in pathological conditions involving the human forebrain, which is particularly vulnerable to hypoxia/ischemia during perinatal gliogenesis. Hypoxic/ischemic injury induces astrogliosis, inflammation and cell death. We show that Gal-3 immunoreactivity was increased in the perinatal human SVZ and striatum after hypoxia/ischemia. Our findings thus show a novel inflammation-independent function for Gal-3; it is necessary for gliogenesis and when increased in expression can induce astrogenesis via BMP signaling.
Osama is now carrying out a residency in Neuropathology at Columbia University.
01 July, 2019
Welcome to Professor Carmen Castro Gonzales. Carmen has joined the lab for 3 months as a visiting professor from University of Cadiz. Carmen is also a Plumer Fellow at St. Anne's College during this period.
23 March, 2019
A30P PD model paper published in Human Molecular Genetics! Well done Xueming!
The A30P α-synuclein mutation decreases subventricular zone proliferation
Xue-Ming Zhang, Sabina Anwar, Yongsoo Kim, Jennifer Brown, Isabelle Comte, Huan Cai, Ning-Ning Cai, Richard Wade-Martins and Francis G. Szele
Parkinson’s disease (PD) is associated with olfactory defects in addition to dopaminergic degeneration. Dopaminergic signalling is necessary for subventricular zone (SVZ) proliferation and olfactory bulb (OB) neurogenesis. Alpha-synuclein (α-syn or Snca) modulates dopaminergic neurotransmission, and SNCA mutations cause familial PD, but how α-syn and its mutations affect adult neurogenesis is unclear. To address this, we studied a bacterial artificial chromosome transgenic mouse expressing the A30P SNCA familial PD point mutation on an Snca−/− background. We confirmed that SNCA-A30P transgene recapitulates endogenous α-syn expression patterns and levels by immunohistochemical detection of endogenous α-syn in a wild-type mouse and transgenic SNCA-A30P α-syn protein in the forebrain. The number of SVZ stem cells (BrdU+GFAP+) was decreased in SNCA-A30P mice, whereas proliferating (phospho-histone 3+) cells were decreased in Snca−/− and even more so in SNCA-A30P mice. Similarly, SNCA-A30P mice had fewer Mash1+ transit-amplifying SVZ progenitor cells but Snca−/− mice did not. These data suggest the A30P mutation aggravates the effect of Snca loss in the SVZ. Interestingly, calbindin+ and calretinin (CalR)+ periglomerular neurons were decreased in both Snca−/−, and SNCA-A30P mice but tyrosine hydroxylase+ periglomerular OB neurons were only decreased in Snca−/− mice. Cell death decreased in the OB granule layer of Snca−/− and SNCA-A30P mice. In the same region, CalR+ numbers increased in Snca−/− and SNCA-A30P mice. Thus, α-syn loss and human A30P SNCA decrease SVZ proliferation, cell death in the OB and differentially alter interneuron numbers. Similar disruptions in human neurogenesis may contribute to the olfactory deficits, which are observed in PD.
22 January, 2019
Congratulations to Yichen LI who successfully defended her DPhiL viva examination.
"DISSECTING THE MECHANISMS UNDERLYING ADOLESCENT-ONSET SCHIZOPHRENIA USING PATIENT-DERIVED CELLS" Was a collaborative project with Dr. Sally Cowley and Dr.Anthony James and Dr. Jenny Taylor. Yichen is going on to do a postdoctoral fellowship in the lab of Justin Ichida in Los Angeles.
15 January, 2019
WelcomE TO VIVIANA MACARELLI AND EVI KAKOURI TO THE LAB!
Viviana is a visiting Master's student from Positano Italy and will be working with Luana Soares on Hippo signalling for nine months. Evi is an undergraduate Erasmus Scholarship student from Athens Greece and will be working with Julie Davies on the OxStem Neuro Project for six months.
22 DEcember, 2018
Our Collaborative paper with Hiroko Isoda's lab has been accepted in the journal Aging. Thanks to Julie Davies and Noelia Doldan in the lab for their excellent contributions.
"3,4,5-Tricaffeoylquinic acid induces adult neurogenesis and improves deficit of learning and memory in aging model senescence-accelerated prone 8 mice"
03 October, 2018
Jerry Qu has passed his transfer of status viva with flying colours. Jerry is continuing the tradition and working on a collaborative DPhil between Jan Czernuszka's group and ours. Well done Jerry.
01 OCTOBER, 2018
Welcome to Mega Suresh who has joined the lab as a postdoc to provide maternity cover for Penny Fouka on the OxStem Neuro project.
27 September, 2018
Fang Li successfully defended his DPhil! "Tissue Engineering for the Nervous System" Congratulations to Fang who carried out a collaborative DPhil between Jan Czernuszka's group (Dept. of Materials Sciences) and our group.
26 SEPTEMBER, 2018
Jie Yin passed his transfer of status viva! Jie is an "alumnus" of the lab and is carrying out his DPhil at the Ludwig Institute in Xin Lu's lab in a collaboration with our group.
10 September, 2018
"Rapid and efficient differentiation of functional motor neurons from human iPSC for neural injury modelling" a collaborative paper with Cathy Ye's group (Engineering) has been accepted in Stem Cell Research. Yichen Li in our group contributed to this paper and Fabio Bianchi in the Ye lab was the first author. Great work guys!
12 JUne, 2018
Abeer Al-Shammari's paper accepted by npj Schizophrenia.
Schizophrenia-related dysbindin-1 gene is required for innate immune response and homeostasis in the developing subventricular zone
Abeer R. Al-Shammari, Sanjeev K. Bhardwaj, Ksenia Musaelyan, Lalit K. Srivastava and Francis G. Szele
31 MAY, 2018
CONGRATULATIONS TO MARTIN DUCKER FOR SUCCESSFULLY DEFENDING HIS DPhil!! Martin was examined by Prof Clive Wilson (Internal) and Prof Pat Doherty (King's College, External). Well done Martin and thanks to both examiners.
24 May, 2018
CONGRATULATIONS to Farah Alammari who passed her Confirmation to DPhil status with flying colours.
8 April, 2018
Our Progress in Neurobiology Review Article accepted! Abeer Al-Shammari (Szele lab alumna), Chiara Bardella (Tomlinson Lab) and Luana Soares (Joint DPhil Student with Eric O'Neill) were co-first authors on: The Role of Inflammation in Subventricular Zone Cancer.
1 April, 2018
Welcome to two new Rotation Students. Crystal Leung is doing her asters In Neuroscience in Oxford is working on the spheroid migration assay with Martin Ducker. Victor Chan is visiting medical student from the Chinese University of Hong Kong.
08 February, 2018
Congratulations to Farah Allamari for her paper accepted in the EMBO J. Farah is co-first author of: Paupar LncRNA Promotes KAP1 Dependent Chromatin Changes And Regulates Olfactory Bulb Neurogenesis. This work was spearheaded by our collaborator Keith Vance at the University of Bath.
01 FEBRUARY, 2018
Good luck to Bin Sun in his new Postdoctoral Fellowship. Bin has joined Jesus Gil's lab at Imperial in London to study senescence. We wish him all the best and thank him for his excellent contributions to the lab. We'll miss you Bin!
07 January, 2018
Luana Campos Soares successfully passed her transfer of status to DPhil viva. Well done Luana! Luana is a graduate student in Oncology working on a collaboration with Prof. Eric O'Neill and is determining mechanistic interactions of Gal-3 and Hippo signalling in inflammation and cancer in the SVZ.
24 October, 2017
Congratulations to fiishing DPhil student Martin Ducker who has pitched his cell assay to block infiltration of highly aggressive glioblastoma brain tumour and triumphed in first place with unanimous praise from the panel of expert judges in the "IMAGINE IF! Oxford Accelerator competition.
07 October, 2017
Congratulations to Bin Sun whose paper is accepted by Cerebral Cortex. "Polycomb protein Eed is required for neurogenesis and cortical injury activation in the subventricular zone"
28 August, 2017
We welcome our new Postdoc Dr. Noelia Geribaldi Doldan. Noelia joins us from University of Cadiz and will lead our collaboration with Prof. Hiroko Isoda at University of Tsukuba.
28 August, 2017
Scientific Reports publishes 3D cell printing paper - collaboration with Bayley group, "High-Resolution Patterned Cellular Constructs by Droplet-Based 3D Printing"
27 June, 2017
Brain publishes Istvan Adorjan's paper, "Calretinin interneuron density in the caudate nucleus is lower in autism spectrum disorder"
1 April, 2017
We welcome 4 new rotation students! Abishek Arora, Master's in Neuroscience rotation student (April - August 2017), Victor Lu, Master's in Neuroscience rotation student (April - August 2017), Ben Cheung, undergraduate medical student from Chinese University of Hong Kong (April/May 2017), Thomson Loong, , undergraduate medical student from Chinese University of Hong Kong (April/May 2017)