News and publications
The below publications include a funding acknowledgement to the project. PREMSTEM researchers are highlighted as bold. Check out our research highlights page to find summaries of selected papers.
List of publications
Hypothermia combined with extracellular vesicles from clonally expanded immortalized mesenchymal stromal cells improves neurodevelopmental impairment in neonatal hypoxic-ischemic brain injury
Nicole Labusek, Parnian Ghari, Yanis Mouloud, Christian Köster, Eva Diesterbeck, Martin Hadamitzky, Ursula Felderhoff-Müser, Ivo Bendix, Bernd Giebel and Josephine Herz
J Neuroinflammation 20, 280 (2023); https://doi.org/10.1186/s12974-023-02961-0
Received: 8 September 2023 / Accepted: 16 November 2023 / Published: 27 November 2023
In this study the researchers hypothesised that intranasal administration of clonally expanded immortalised mesenchymal stromal cell-derived extracellular vesicles can overcome limitations of hypothermia as a therapy for hypoxic–ischemic encephalopathy. Therapeutic hypothermia is used to treat neonatal brain injury following hypoxia–ischemia (decreased oxygen or blood flow to the brain) but has limitations due to its short therapeutic window of six hours and limited efficacy.
Key roles of glial cells in the encephalopathy of prematurity
Juliette Van Steenwinckel, Cindy Bokobza, Mireille Laforge, Isabelle K. Shearer, Veronique E. Miron, Rejane Rua, Samantha M. Matta, Elisa L. Hill-Yardin, Bobbi Fleiss and Pierre Gressens
Glia. 2023; 2023;1–29; https://doi.org/10.1002/glia.24474
Received: 19 July 2023 / Revised: 17 September 2023 / Accepted: 19 September 2023 / Published: 1 November 2023
This review summarises the current state of knowledge for the roles of glia in infants with encephalopathy of prematurity (EoP) and its animal models, and a description of known glial-cell interactions in the context of EoP, such as the roles for border-associated macrophages. No longer just the ‘support cells’, we now clearly understand that during development glia are key for building a healthy brain. Glial dysfunction is a hallmark of EoP, notably, microgliosis, astrogliosis, and oligodendrocyte injury.
High sensitivity mapping of brain-wide functional networks in awake mice using simultaneous multi-slice fUS imaging
Adrien Bertolo, Jeremy Ferrier, Silvia Cazzanelli, Samuel Diebolt, Mickael Tanter, Sophie Pezet, Mathieu Pernot, Bruno-Félix Osmanski and Thomas Deffieux
Imaging Neuroscience 2023; https://doi.org/10.1162/imag_a_00030
Received: 12 July 2023 / Revised: 12 October 2023 / Accepted: 13 October 2023 / Published: 23 October 2023
In this study the researchers propose a new hybrid solution optimised and dedicated to brain-wide transcranial functional connectivity studies in mice, based on a newly developed multi-array transducer allowing simultaneous multi-slicing of the entire mouse cerebrum. They demonstrate that their approach provides a better imaging quality compared to other existing methods. They also show the ability to image the whole mouse brain non-invasively through the intact skin and skull during visual stimulation under light anaesthesia to validate this new approach.
Preterm Birth by Cesarean Section: The Gut-Brain Axis, a Key Regulator of Brain Development
Cécile Morin, Cindy Bokobza, Bobbi Fleiss, Elisa L. Hill-Yardin, Juliette Van Steenwinckel and Pierre Gressens
Dev Neurosci 2023; https://doi.org/10.1159/000534124
Received: 13 July 2022 / Accepted: 11 September 2023 / Published: 15 September 2023
In this review, the researchers explore links between preterm birth by caesarean sections (C-sections), gut microbiota alteration and neuroinflammation, highlighting C-sections (global rates of which are on the rise) as a risk factor for developmental disorders due to alterations in the microbiome. The mode of delivery or preterm birth are both factors which could lead to disturbance in the assembly and maturation of gut microbiota, with recent research highlighting how gut microbiota could affect brain development and behaviour.
Advances in neonatal cell therapies: Proceedings of the First Neonatal Cell Therapies Symposium (2022)
Atul Malhotra, Bernard Thebaud, Madison C. B. Paton, Bobbi Fleiss, Paris Papagianis, Elizabeth Baker, Laura Bennet, Tamara Yawno, Ngaire Elwood, Belinda Campbell, Kirat Chand, Lindsay Zhou, Tayla Penny, Timothy Nguyen, Salvatore Pepe, Alistair J. Gunn and Courtney A. McDonald
Pediatr Res 2023; https://doi.org/10.1038/s41390-023-02707-x
Received: 16 February 2023 / Revised: 8 May 2023 / Accepted: 8 June 2023 / Published: 28 June 2023
With advances in neonatal medicine, the survival of preterm and sick term newborn infants has improved substantially. Rates of preterm complications like chronic lung disease, brain injury and pulmonary hypertension remain high, as do the risks of long-term neurodevelopmental, pulmonary, cardiac and metabolic complications. This article summarises highlights from the 2022 Neonatal Cell Therapies Symposium where researchers presented the latest on cell therapies in the neonate and their potential to repair, protect, and in some cases regenerate vital body tissues.
Umbilical cord-mesenchymal stem cells induce a memory phenotype in CD4+ T cells
Ezgi Sengun, Tim G. A. M. Wolfs, Valéry L. E. van Bruggen, Bram van Cranenbroek, Elles R. Simonetti, Daan Ophelders, Marien I. de Jonge, Irma Joosten and Renate G. van der Molen
Front. Immunol. 2023; 14:1128359; https://doi.org/10.3389/fimmu.2023.1128359
Received: 20 December 2022 / Accepted: 1 June 2023 / Published: 20 June 2023
This study assessed the immunomodulatory effect of umbilical cord derived mesenchymal stem cells (UC-MSCs) on T cell phenotype and function, with a focus on activation, proliferation and maturation of CD4+ T cells with the aim of better understanding the UC-MSC mode of action. The data show that UC-MSCs clearly affect T cell activation, proliferation and maturation, depending on co-culture conditions for which both cell-cell contact and paracrine factors are needed.
Targeting the brain 5-HT7 receptor to prevent hypomyelination in a rodent model of perinatal white matter injuries
Cindy Bokobza, Alice Jacquens, David Guenoun, Blandine Bianco, Anne Galland, Maxime Pispisa, Alexandra Cruz, Manuela Zinni, Valérie Faivre, Anne Roumier, Sophie Lebon, Tania Vitalis, Zsolt Csaba, Tifenn Le Charpentier, Leslie Schwendimann, Pierrette Young-Ten, Vincent Degos, Patricia Monteiro, Pascal Dournaud, Pierre Gressens and Juliette Van Steenwinckel
J Neural Transm. 2022; https://doi.org/10.1007/s00702-022-02556-8
Received: 8 July 2022 / Accepted: 19 October 2022 / Published: 6 November 2022
In this article the research team highlights the concept of the HTR7 (5-HT receptor subtype 7) regulating brain inflammation in a context of white matter injury induced by perinatal exposure that models neurodevelopmental disorders associated with prematurity, including memory deficits, anxiety-like-behaviour, and deficits in social interactions. These data open new perspectives for therapy to protect the developing brain from the adverse effects of early immune activation.
The multiple faces of extracellular vesicles released by microglia: Where are we 10 years after?
Martina Gabrielli, Stefano Raffaele, Marta Fumagalli and Claudia Verderio
Front. Cell. Neurosci. 2022; 16:984690; https;//10.3389/fncel.2022.984690
Received: 2 July 2022 / Accepted: 23 August 2022 / Published: 13 September 2022
The review summarises the current knowledge on extracellular vesicles released by microglia, highlighting
their heterogeneous properties and multifaceted effects.
Magnetic Isolation of Microglial Cells from Neonate Mouse for Primary Cell Cultures
Cindy Bokobza, Alice Jacquens, Manuela Zinni, Valérie Faivre, Jennifer Hua, David Guenoun, Caroline
Userovici, Shyamala Mani, Vincent Degos, Pierre Gressens and Juliette Van Steenwinckel
J. Vis. Exp. 2022 (185), e62964; https://doi.org/10.3791/62964
Published: 25 July 2022
The paper describes a protocol which aims to get as close as possible to the physiological environment of microglia. Besides requiring no serum, the protocol exposes microglia as early as 48 hours after culture to prevent them from losing their physiological faculties.
A unique cerebellar pattern of microglia activation in a mouse model of encephalopathy of prematurity
Luisa Klein, Juliette Van Steenwinckel, Bobbi Fleiss, Till Scheuer, Christoph Bührer, Valerie Faivre, Sophie Lemoine, Corinne Blugeon, Leslie Schwendimann, Zsolt Csaba, Cindy Bokobza, Dulcie A. Vousden, Jason P. Lerch, Anthony C. Vernon, Pierre Gressens and Thomas Schmitz
Glia. 2022; 70:1699–1719; https://doi.org/10.1002/glia.24190
Received: 16 October 2021 / Revised: 26 April 2022 / Accepted: 29 April 2022 / Published: 27 April 2022
This study used a mouse model of inflammation-induced encephalopathy of prematurity driven by systemic administration of pro-inflammatory IL-1β to look to uncover causes of cerebellar damage, which is associated with impaired motor performance, lower IQ and poor language skills at school ages.
The Impact of Mouse Preterm Birth Induction by RU-486 on Microglial Activation and Subsequent Hypomyelination
Cécile Morin, David Guenoun, Irvin Sautet, Valérie Faivre, Zsolt Csaba, Leslie Schwendimann, Pierrette Young-Ten, Juliette Van Steenwinckel, Pierre Gressens and Cindy Bokobza
Int. J. Mol. Sci. 2022, 23(9), 4867; https://doi.org/10.3390/ijms23094867
Received: 7 March 2022 / Revised: 21 April 2022 / Accepted: 21 April 2022 / Published: 27 April 2022
This study aimed to elaborate and characterise a new model of induced-PTB and PWMIs by the gestational injection of RU-486 and the perinatal injection of pups with IL-1beta. A RU-486 single subcutaneous (s.c.) injection at embryonic day (E)18.5 induced PTB at E19.5 in pregnant OF1 mice.
Induction of Mitochondrial Fragmentation and Mitophagy after Neonatal Hypoxia–Ischemia
Syam Nair, Anna-Lena Leverin, Eridan Rocha-Ferreira, Kristina S. Sobotka, Claire Thornton, Carina Mallard and Henrik Hagberg
Cells 2022, 11, 1193; https://doi.org/10.3390/cells11071193
Received: 20 December 2021 / Accepted: 30 March 2022 / Published: 1 April 2022
This study investigated mitochondrial dynamics (fission, fusion, and mitochondrial autophagy (mitophagy) after HI in vivo in mice and oxygen/glucose deprivation (OGD) in vitro in primary neurons. It also analysed genes/proteins related to mitophagy after HI including PINK1/Parkin, BNIP3/NIX and FUNDC1. The data suggest
that OGD triggers mitochondrial fragmentation and an early increase in mitophagy.
Targeting microbial metabolites to treat autism
Rochellys Diaz Heijtz, Pierre Gressens and Jonathan R. Swann
Nat Med 28, 448–450 (2022). https://doi.org/10.1038/s41591-022-01711-8
Published: 14 February 2022
This article discusses data presented by Campbell et al. and Needham et al. in the study of the microbiota–gut–brain axis as researchers continue to find treatments to improve core symptoms of autism spectrum disorder, such as irritability and anxiety.
Peripheral immune cells and perinatal brain injury: a double-edged sword?
Josephine Herz, Ivo Bendix and Ursula Felderhoff-Müser
Pediatr Res 91, 392–403 (2022); https://doi.org/10.1038/s41390-021-01818-7
Received: 15 June 2021 / Revised: 24 August 2021 / Accepted: 14 September 2021 / Published: 8 November 2021
This review focuses on the role of peripheral immune cells and discusses processes involved in neuroinflammation under two frequent perinatal conditions, systemic infection/inflammation associated with encephalopathy of prematurity (EoP) and hypoxia/ischaemia in the context of neonatal encephalopathy and stroke at term. Different immune cell subsets in perinatal brain injury including their infiltration routes were reviewed and critical aspects such as sex differences and maturational stage discussed. Interactions with existing regenerative therapies such as stem cells and also potentials to develop novel immunomodulatory targets were considered.
miR-146b Protects the Perinatal Brain against Microglia-Induced Hypomyelination
Cindy Bokobza, Pooja Joshi, Anne-Laure Schang, Zsolt Csaba, Valérie Faivre, Amélie Montané, Anne Galland, Anouk Benmamar-Badel, Emmanuelle Bosher, Sophie Lebon, Leslie Schwendimann, Shyamala Mani, Pascal Dournaud, Valerie Besson, Bobbi Fleiss, Pierre Gressens and Juliette Van Steenwinckel
Ann Neurol. (2021); https://doi.org/10.1002/ana.26263
Received: 7 May 2020 / Accepted: 3 November 2021 / Available online: 5 November 2021
In the preterm newborn, perinatal inflammation mediated by microglia contributes significantly to neurodevelopmental injuries including white matter injury (WMI). This study demonstrates that miR-146b acts as a negative feedback mechanism against inflammatory activation specifically in microglia in a model of WMI, demonstrating that miR mediated therapies may have a future as efficient strategies to protect the developing brain against WMI.
The immune-inflammatory response of oligodendrocytes in a murine model of preterm white matter injury: the role of TLR3 activation
Marta Boccazzi, Juliette Van Steenwinckel, Anne-Laure Schang, Valérie Faivre, Tifenn Le Charpentier, Cindy Bokobza, Zsolt Csaba, Claudia Verderio, Marta Fumagalli, Shyamala Mani and Pierre Gressens
Cell Death Dis 12, 166 (2021); https://doi.org/10.1038/s41419-021-03446-9
Received: 2 June 2020 / Revised: 13 December 2020 / Accepted: 3 January 2021 / Available online: 8 February 2021
This study focused on toll-like receptor-3, a protein activated by double-strand RNA, which promotes neuroinflammation. The aim was to better understand its expression and role in oligodendrocytes (one of the last types of cell to form in the brain). The in vivo mouse model mimicked white matter injury occurring in preterm babies.
Therapeutic potential of stem cells for preterm infant brain damage: can we move from the heterogeneity of preclinical and clinical studies to established therapeutics?
Sofia Passera, Marta Boccazzi, Cindy Bokobza, Valerie Faivre, Fabio Mosca, Juliette Van Steenwinckel, Monica Fumagalli, Pierre Gressens and Bobbi Fleiss
Biochemical Pharmacology 2021, 114461; https://doi.org/10.3390/biom11010099
Received: 10 December 2020 / Revised: 27 January 2021 / Accepted: 2 February 2021 / Available online: 8 February 2021
In this review, the researchers summarise and discuss preclinical and clinical investigations which have studied stem cells as an effective neuroprotectant for perinatal brain injury.
Microglia-Mediated Neurodegeneration in Perinatal Brain Injuries
Bobbi Fleiss, Juliette Van Steenwinckel, Cindy Bokobza, Isabelle K. Shearer, Emily Ross-Munro and Pierre Gressens
Biomolecules 2021, 11(1), 99; https://doi.org/10.3390/biom11010099
Received: 29 November 2020 / Revised: 8 January 2021 / Accepted: 11 January 2021 / Published: 13 January 2021
This review looks at strategies developed experimentally to modulate microglia and reduce brain injury in babies. It focusses on four causes of perinatal brain injury which occur frequently in both westernised and emerging countries, including EoP and neonatal stroke, and reviews pharmacological approaches as well as novel nanoparticle mediated therapies.
Neuroprotection offered by mesenchymal stem cells in perinatal brain injury: Role of mitochondria, inflammation, and reactive oxygen species
Syam Nair, Eridan Rocha-Ferreira, Bobbi Fleiss, Cora H Nijboer, Pierre Gressens, Carina Mallard and Henrik Hagberg
Journal of Neurochemistry 2021, 2021;158:59–73; https://doi.org/10.1111/jnc.15267
Received: 15 July 2020 / Revised: 3 December 2020 / Accepted: 3 December 2020 / Published: 12 December 2020
This review summarises the present state, the underlying causes, challenges and possibilities for effective clinical translation of mesenchymal stem cell therapy.
Mesenchymal Stromal Cell-Derived Extracellular Vesicles Reduce Neuroinflammation, Promote Neural Cell Proliferation and Improve Oligodendrocyte Maturation in Neonatal Hypoxic-Ischemic Brain Injury
Nicole Kaminski, Christian Köster, Yanis Mouloud, Verena Börger, Ursula Felderhoff-Müser, Ivo Bendix, Bernd Giebel and Josephine Herz
A Model of Germinal Matrix Hemorrhage in Preterm Rat Pups
Masako Jinnai, Gabriella Koning, Gagandeep Singh-Mallah, Andrea Jonsdotter, Anna-Lena Leverin, Pernilla Svedin, Syam Nair, Satoru Takeda, Xiaoyang Wang, Carina Mallard, Carl Joakim Ek, Eridan Rocha-Ferreira and Henrik Hagberg
Preterm Brain Injury, Antenatal Triggers, and Therapeutics: Timing Is Key
Daan R.M.G. Ophelders, Ruth Gussenhoven, Luise Klein, Reint K. Jellema, Rob J.J. Westerlaken, Matthias C. Hütten, Jeroen Vermeulen, Guido Wassink, Alistair J. Gunn and Tim G.A.M. Wolfs
Cortical Gray Matter Injury in Encephalopathy of Prematurity: Link to Neurodevelopmental Disorders
Bobbi Fleiss, Pierre Gressens and Helen B. Stolp