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Cells
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Perinatal Brain Injury—from Pathophysiology to Therapy
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Perinatal Brain Injury—from Pathophysiology to Therapy

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Neuroscience".

Deadline for manuscript submissions: 31 May 2026 | Viewed by 28036

Special Issue Editors

Dr. Cora H.A. Nijboer

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Guest Editor
Division Woman and Baby, Department for Developmental Origins of Disease, Wilhelmina Children's Hospital (Part of UMC Utrecht), Brain Center UMC Utrecht, P.O. Box 85090, 3508 AB Utrecht, The Netherlands
Interests: brain; child health; infection & immunity; regenerative medicine and stem cells
Dr. Bobbi Fleiss

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Guest Editor
School of Health and Biomedical Sciences, STEM College, RMIT University, Bundoora, VIC, Australia
Interests: the basic development of microglia; innovative approaches in delayed chronic pharmacologic interventions; investigating the utility of a biocompatible hydrogel to regenerate neonatal stroke injury
Dr. Ivo Bendix

E-Mail Website
Guest Editor
Department of Pediatrics I, Neonatology & Experimental Perinatal Neurosciences, University Hospital Essen, Centre for Translational Neuro- and Behavioural Sciences, C-TNBS, Faculty of Medicine, University Duisburg-Essen, 45147 Essen, Germany
Interests: perinatal neuroscience; oligodendrocytes; myelination deficits; neonatal hyperoxia; inflammation; hypoxia-Ischemia

Special Issue Information

Dear Colleagues,

A perinatal brain injury is a major risk factor for adverse neurodevelopmental outcomes and can trigger disturbed brain development with complex cellular and molecular alterations leading to long-term motor and cognitive deficits. The critical factors for adverse neurodevelopment include infection/inflammation, disturbed oxygenation (hyperoxia and hypoxia), blood flow (ischemia) hemorrhagic events and fetal malnutrition. Though our understanding of pathophysiological hallmarks has increased tremendously and standard care has improved markedly, interventions in the perinatal period to improve these neurological outcomes are still very limited. Therefore, there is still a need to improve our understanding of the underlying pathomechanisms in the developing brain, not only on a cellular level, but also in complex in vivo models. Basic scientific knowledge can be used to identify new therapeutic targets that will lead to treatments to improve the long-term outcomes and the quality of life of affected infants and their families.

This Special Issue aims to collect high-quality original manuscripts and reviews covering recent biomedical or clinical findings related to perinatal brain injuries, including new pharmacological or cell-based regenerative approaches to ameliorate the long-lasting deleterious consequences for brain development.

Dr. Cora H.A. Nijboer
Dr. Bobbi Fleiss
Dr. Ivo Bendix
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • preterm birth
  • perinatal brain injury
  • infection
  • inflammation
  • hypoxia
  • ischemia
  • hyperoxia
  • malnutrition
  • regenerative therapies
  • pharmacological intervention
  • stem cells

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Published Papers (11 papers)

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Research

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18 pages, 18000 KB  
Article
Does Antenatal Lactoferrin Protect Hippocampal Development in Ovine Fetuses with Growth Restriction?
by Dahyun Kang, Ingrid Dudink, Tegan A. White, Amy E. Sutherland, Tamara Yawno, Yen Pham, Petra S. Huppi, Stéphane V. Sizonenko, Suzanne L. Miller and Beth J. Allison
Cells 2025, 14(24), 1951; https://doi.org/10.3390/cells14241951 - 9 Dec 2025
Viewed by 745
Abstract
Early-onset fetal growth restriction (FGR) is associated with prolonged fetoplacental hypoxia and altered brain development, including deficits in hippocampal structure and function. Neuroprotective actions of lactoferrin have been described, mediated via anti-inflammatory and antioxidant properties. Here, we investigated whether the antenatal administration of [...] Read more.
Early-onset fetal growth restriction (FGR) is associated with prolonged fetoplacental hypoxia and altered brain development, including deficits in hippocampal structure and function. Neuroprotective actions of lactoferrin have been described, mediated via anti-inflammatory and antioxidant properties. Here, we investigated whether the antenatal administration of lactoferrin (1) improves hippocampal structure, (2) promotes neuronal growth, and (3) mitigates neuroinflammation in the hippocampus of fetal sheep with FGR. Early-onset FGR was induced by performing single umbilical artery ligation surgery on ovine fetuses at ~89 days gestational age (dGA; term ~148 dGA), compared with appropriate for gestational age (AGA) controls. Lactoferrin supplementation to the ewe commenced at 95 dGA (oral, 36 g/day) and continued until 127 dGA (fetal group) or birth (newborn group). Experimental fetal groups included control appropriate for gestational age (AGA; n = 8), FGR (n = 5), control + lactoferrin (AGA + Lacto; n = 6), and FGR + lactoferrin (FGR + Lacto; n = 6). In the fetal group, results showed that neither FGR nor lactoferrin altered hippocampal structure at 127 dGA. Lactoferrin exposure significantly increased neuronal abundance but also altered neuronal morphology. Lactoferrin increased the neurotrophic factor, brain-derived neurotrophic factor (BDNF) in the hippocampus. Lactoferrin exerted region-specific anti-inflammatory effects, with reduced total microglial cell count and resting microglia count in the Cornu Ammonis (CA)3 region only. In the newborn cohort, we observed increased circulating haematocrit concentration in early life. These findings support that antenatal lactoferrin has an anti-inflammatory effect in the fetal brain and increases fetal brain neurotrophic factor BDNF. Still, prolonged exposure during pregnancy may yield mixed effects on fetal brain development and haematological balance. Full article
(This article belongs to the Special Issue Perinatal Brain Injury—from Pathophysiology to Therapy)
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22 pages, 4199 KB  
Article
Neuroserpin: A Potential Neuroprotective Agent in Mild Neonatal Hypoxic–Ischaemic Encephalopathy
by Eri Kawashita, Yumi Fukuzaki, Jan Fischer, Lei Shi, Yumei Liao, Lancelot Jamie Millar, Peiyun Zhong, Anna Hoerder-Suabedissen, Luana Campos Soares and Zoltán Molnár
Cells 2025, 14(23), 1840; https://doi.org/10.3390/cells14231840 - 21 Nov 2025
Viewed by 1306
Abstract
Neonatal hypoxic–ischaemic encephalopathy (HIE) remains a leading cause of infant morbidity and mortality worldwide, with therapeutic hypothermia being the only clinically approved treatment. This study investigates the cortical expression pattern of neuroserpin during postnatal brain development and evaluates its neuroprotective potential in hypoxia–ischaemia [...] Read more.
Neonatal hypoxic–ischaemic encephalopathy (HIE) remains a leading cause of infant morbidity and mortality worldwide, with therapeutic hypothermia being the only clinically approved treatment. This study investigates the cortical expression pattern of neuroserpin during postnatal brain development and evaluates its neuroprotective potential in hypoxia–ischaemia (HI)-induced brain damage using a modified Rice–Vannucci model. Experiments were conducted in both male and female neuroserpin knockout (KO) mice and through administration of exogenous neuroserpin into the brain. Between postnatal day 4 to 14 (P4–P14), neuroserpin-immunoreactive cell density peaked at P8–P10 in cortical layers 5 and 6b, with a gradual increase in layers 2/3 and minimal changes in layers 4 and 6a. Despite comparable levels of ischaemic brain damage between the KO and wild-type (WT) mice, exogenous neuroserpin administration suppressed the HI-induced oxidative stress. Additionally, it reduced microglial activation and reactive astrogliosis in the cortex in mild HIE, mitigating cortical thinning and preserving neuronal distribution. These findings suggest that endogenous neuroserpin alone is insufficient for neuroprotection against HI-induced damage, but exogenous neuroserpin shows promise as a pharmacological intervention for mild neonatal HIE. Full article
(This article belongs to the Special Issue Perinatal Brain Injury—from Pathophysiology to Therapy)
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16 pages, 7850 KB  
Article
Foetal Growth Restriction Effects on Grey and White Matter in the Prefrontal Cortex and Basal Ganglia of Postnatal Day 10 Piglets
by Bhuvaneswari Harishankar, Kirat K. Chand, Paul B. Colditz and Julie A. Wixey
Cells 2025, 14(22), 1776; https://doi.org/10.3390/cells14221776 - 12 Nov 2025
Viewed by 727
Abstract
Foetal growth restriction (FGR) is commonly caused by placental insufficiency and increases the risk of perinatal morbidity and mortality. The developing brain is vulnerable to FGR, which can result in adverse long-term neurodevelopmental outcomes. Newborn pigs with spontaneous FGR (<10th centile body weight) [...] Read more.
Foetal growth restriction (FGR) is commonly caused by placental insufficiency and increases the risk of perinatal morbidity and mortality. The developing brain is vulnerable to FGR, which can result in adverse long-term neurodevelopmental outcomes. Newborn pigs with spontaneous FGR (<10th centile body weight) and normally grown (NG) littermates were reared to postnatal day 10 (P10; n = 8 FGR and n = 9 NG). Neuropathology was assessed in the prefrontal cortex (PFC) and basal ganglia (BG), which play a key role in cognitive and motor functions. FGR piglets show decreased neuronal count (NeuN) and structural integrity (MAP2) associated with increased apoptotic activity (Casp-3 and -9) in the PFC and BG. Hypomyelination was consistently observed in the white matter of the FGR brain. There was increased microglial activation (Iba-1) and GFAP-positive astrocytes in both the grey and white matter of the PFC and BG, along with increased apoptotic activity in the FGR brain. These findings suggest that the FGR piglet brain shows impaired grey and white matter associated with increased apoptosis in the PFC and BG that persists at P10. Increased glial activation and apoptotic astrocytes may impact neuronal survival and potentially contribute to adverse long-term neurodevelopmental outcomes, highlighting the need for targeted therapeutic interventions to promote effective brain repair in infants with FGR. Full article
(This article belongs to the Special Issue Perinatal Brain Injury—from Pathophysiology to Therapy)
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13 pages, 14281 KB  
Article
Exenatide Is Neuroprotective in a New Rabbit Model of Hypoxia-Ischemia
by Eridan Rocha-Ferreira, Malin Carlsson, Pernilla Svedin, Kerstin Ebefors, Owen Herrock, Anna-Lena Leverin and Henrik Hagberg
Cells 2025, 14(21), 1715; https://doi.org/10.3390/cells14211715 - 1 Nov 2025
Viewed by 833
Abstract
Hypoxia-ischemia is a serious perinatal complication affecting neonates globally. Animal models have increased the understanding of its pathophysiology and have been used to investigate potential therapies. Exenatide, clinically used for the treatment of type 2 diabetes mellitus, also protects the rodent brain from [...] Read more.
Hypoxia-ischemia is a serious perinatal complication affecting neonates globally. Animal models have increased the understanding of its pathophysiology and have been used to investigate potential therapies. Exenatide, clinically used for the treatment of type 2 diabetes mellitus, also protects the rodent brain from hypoxia-ischemia. The rabbit brain has an earlier neurodevelopmental maturation than rodents, as well as similar postnatal maturation to humans. We hereby introduce a new, reproducible hypoxia-ischemia model in rabbit kits at postnatal day (P) 3–4. Following hypoxia-ischemia, rabbit kits received different exenatide concentrations: 170 μg/g (2-dose) or 500 μg/g (1- or 2-dose), or vehicle. The brains were collected seven days later for histological assessment showing that 500 μg/g exenatide, either as a 1- or 2-dose regimen, reduced brain tissue loss by 90% in hypoxia-ischemia experiments both at P3 and P4. A second cohort received a 1-dose 500 μg/g of exenatide or vehicle, and were sacrificed at different early time-points for glucose, ketone bodies, body weight, and temperature measurements. Our results showed a transient 2-fold increase in ketone bodies (0.6 to 1.3 mmol/L) at 6 h. Exenatide did not affect glucose, body temperature or weight gain and appears to be safe and well tolerated in the rabbit model of hypoxia-ischemia. Full article
(This article belongs to the Special Issue Perinatal Brain Injury—from Pathophysiology to Therapy)
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43 pages, 5385 KB  
Article
Hypothermia Shifts Neurodegeneration Phenotype in Neonatal Human Hypoxic–Ischemic Encephalopathy but Not in Related Piglet Models: Possible Relationship to Toxic Conformer and Intrinsically Disordered Prion-like Protein Accumulation
by Lee J. Martin, Jennifer K. Lee, Mark V. Niedzwiecki, Adriana Amrein Almira, Cameron Javdan, May W. Chen, Valerie Olberding, Stephen M. Brown, Dongseok Park, Sophie Yohannan, Hasitha Putcha, Becky Zheng, Annalise Garrido, Jordan Benderoth, Chloe Kisner, Javid Ghaemmaghami, Frances J. Northington and Panagiotis Kratimenos
Cells 2025, 14(8), 586; https://doi.org/10.3390/cells14080586 - 12 Apr 2025
Cited by 4 | Viewed by 3660
Abstract
Hypothermia (HT) is used clinically for neonatal hypoxic–ischemic encephalopathy (HIE); however, the brain protection is incomplete and selective regional vulnerability and lifelong consequences remain. Refractory damage and impairment with HT cooling/rewarming could result from unchecked or altered persisting cell death and proteinopathy. We [...] Read more.
Hypothermia (HT) is used clinically for neonatal hypoxic–ischemic encephalopathy (HIE); however, the brain protection is incomplete and selective regional vulnerability and lifelong consequences remain. Refractory damage and impairment with HT cooling/rewarming could result from unchecked or altered persisting cell death and proteinopathy. We tested two hypotheses: (1) HT modifies neurodegeneration type, and (2) intrinsically disordered proteins (IDPs) and encephalopathy cause toxic conformer protein (TCP) proteinopathy neonatally. We studied postmortem human neonatal HIE cases with or without therapeutic HT, neonatal piglets subjected to global hypoxia-ischemia (HI) with and without HT or combinations of HI and quinolinic acid (QA) excitotoxicity surviving for 29–96 h to 14 days, and human oligodendrocytes and neurons exposed to QA for cell models. In human and piglet encephalopathies with normothermia, the neuropathology by hematoxylin and eosin staining was similar; necrotic cell degeneration predominated. With HT, neurodegeneration morphology shifted to apoptosis-necrosis hybrid and apoptotic forms in human HIE, while neurons in HI piglets were unshifting and protected robustly. Oligomers and putative TCPs of α-synuclein (αSyn), nitrated-Syn and aggregated αSyn, misfolded/oxidized superoxide dismutase-1 (SOD1), and prion protein (PrP) were detected with highly specific antibodies by immunohistochemistry, immunofluorescence, and immunoblotting. αSyn and SOD1 TCPs were seen in human HIE brains regardless of HT treatment. αSyn and SOD1 TCPs were detected as early as 29 h after injury in piglets and QA-injured human oligodendrocytes and neurons in culture. Cell immunophenotyping by immunofluorescence showed αSyn detected with antibodies to aggregated/oligomerized protein; nitrated-Syn accumulated in neurons, sometimes appearing as focal dendritic aggregations. Co-localization also showed aberrant αSyn accumulating in presynaptic terminals. Proteinase K-resistant PrP accumulated in ischemic Purkinje cells, and their target regions had PrP-positive neuritic plaque-like pathology. Immunofluorescence revealed misfolded/oxidized SOD1 in neurons, axons, astrocytes, and oligodendrocytes. HT attenuated TCP formation in piglets. We conclude that HT differentially affects brain damage in humans and piglets. HT shifts neuronal cell death to other forms in human while blocking ischemic necrosis in piglet for sustained protection. HI and excitotoxicity also acutely induce formation of TCPs and prion-like proteins from IDPs globally throughout the brain in gray matter and white matter. HT attenuates proteinopathy in piglets but seemingly not in humans. Shifting of cell death type and aberrant toxic protein formation could explain the selective system vulnerability, connectome spreading, and persistent damage seen in neonatal HIE leading to lifelong consequences even after HT treatment. Full article
(This article belongs to the Special Issue Perinatal Brain Injury—from Pathophysiology to Therapy)
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21 pages, 5521 KB  
Article
A Novel Model for Simultaneous Evaluation of Hyperoxia-Mediated Brain and Lung Injury in Neonatal Rats
by Stefanie Obst, Meray Serdar, Josephine Herz, Karina Kempe, Meriem Assili, Mandana Rizazad, Dharmesh Hirani, Miguel A. Alejandre Alcazar, Stefanie Endesfelder, Marius A. Möbius, Mario Rüdiger, Ursula Felderhoff-Müser and Ivo Bendix
Cells 2025, 14(6), 443; https://doi.org/10.3390/cells14060443 - 16 Mar 2025
Cited by 3 | Viewed by 2779
Abstract
Despite improved neonatal intensive care, the risk of premature-born infants developing bronchopulmonary dysplasia (BPD) and encephalopathy of prematurity (EoP) remains high. With hyperoxia being a major underlying factor, both preterm-birth-related complications are suggested to be closely interrelated. However, experimental models are lacking for [...] Read more.
Despite improved neonatal intensive care, the risk of premature-born infants developing bronchopulmonary dysplasia (BPD) and encephalopathy of prematurity (EoP) remains high. With hyperoxia being a major underlying factor, both preterm-birth-related complications are suggested to be closely interrelated. However, experimental models are lacking for the assessment of the potentially close interplay between both organs. To establish a model, suitable for the assessment of both affected organs, Wistar rats were exposed to 80% oxygen from postnatal day 2 (P2) for seven days. Brain and lung tissues were analysed via histomorphometry, immunohistochemistry, real-time PCR, and western blot at term P11. In the brain, hyperoxia induced significant hypomyelination accompanied by a reduction in oligodendrocytes and CD68 expression on microglia cells. These changes correlate with arrested alveolarisation and an increased number of macrophages in the lung. Interestingly, in contrast to the reduced formation of pulmonary microvessels, an increased vascular density was detected in the brain. Seven days of hyperoxia induces typical characteristics of BPD and EoP in neonatal rats, thereby linking impaired alveolarisation with disturbed myelination in the brain and providing an experimental model for understanding pathophysiological mechanisms and identifying organ-spanning novel therapeutic interventions targeting both diseases. Full article
(This article belongs to the Special Issue Perinatal Brain Injury—from Pathophysiology to Therapy)
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20 pages, 4667 KB  
Article
Human Umbilical Cord-Mesenchymal Stem Cells Promote Extracellular Matrix Remodeling in Microglia
by Marta Tiffany Lombardo, Martina Gabrielli, Florence Julien-Marsollier, Valérie Faivre, Tifenn Le Charpentier, Cindy Bokobza, Deborah D’Aliberti, Nicola Pelizzi, Camilla Halimi, Silvia Spinelli, Juliette Van Steenwinckel, Elisabetta A. M. Verderio, Pierre Gressens, Rocco Piazza and Claudia Verderio
Cells 2024, 13(19), 1665; https://doi.org/10.3390/cells13191665 - 9 Oct 2024
Cited by 4 | Viewed by 3494
Abstract
Human mesenchymal stem cells modulate the immune response and are good candidates for cell therapy in neuroinflammatory brain disorders affecting both adult and premature infants. Recent evidence indicates that through their secretome, mesenchymal stem cells direct microglia, brain-resident immune cells, toward pro-regenerative functions, [...] Read more.
Human mesenchymal stem cells modulate the immune response and are good candidates for cell therapy in neuroinflammatory brain disorders affecting both adult and premature infants. Recent evidence indicates that through their secretome, mesenchymal stem cells direct microglia, brain-resident immune cells, toward pro-regenerative functions, but the mechanisms underlying microglial phenotypic transition are still under investigation. Using an in vitro coculture approach combined with transcriptomic analysis, we identified the extracellular matrix as the most relevant pathway altered by the human mesenchymal stem cell secretome in the response of microglia to inflammatory cytokines. We confirmed extracellular matrix remodeling in microglia exposed to the mesenchymal stem cell secretome via immunofluorescence analysis of the matrix component fibronectin and the extracellular crosslinking enzyme transglutaminase-2. Furthermore, an analysis of hallmark microglial functions revealed that changes in the extracellular matrix enhance ruffle formation by microglia and cell motility. These findings point to extracellular matrix changes, associated plasma membrane remodeling, and enhanced microglial migration as novel mechanisms by which mesenchymal stem cells contribute to the pro-regenerative microglial transition. Full article
(This article belongs to the Special Issue Perinatal Brain Injury—from Pathophysiology to Therapy)
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23 pages, 9821 KB  
Article
The Temporal Relationship between Blood–Brain Barrier Integrity and Microglial Response following Neonatal Hypoxia Ischemia
by Arya Jithoo, Tayla R. Penny, Yen Pham, Amy E. Sutherland, Madeleine J. Smith, Maria Petraki, Michael C. Fahey, Graham Jenkin, Atul Malhotra, Suzanne L. Miller and Courtney A. McDonald
Cells 2024, 13(8), 660; https://doi.org/10.3390/cells13080660 - 9 Apr 2024
Cited by 18 | Viewed by 3591
Abstract
Blood–brain barrier (BBB) dysfunction and neuroinflammation are key mechanisms of brain injury. We performed a time-course study following neonatal hypoxia–ischemia (HI) to characterize these events. HI brain injury was induced in postnatal day 10 rats by single carotid artery ligation followed by hypoxia [...] Read more.
Blood–brain barrier (BBB) dysfunction and neuroinflammation are key mechanisms of brain injury. We performed a time-course study following neonatal hypoxia–ischemia (HI) to characterize these events. HI brain injury was induced in postnatal day 10 rats by single carotid artery ligation followed by hypoxia (8% oxygen, 90 min). At 6, 12, 24, and 72 h (h) post-HI, brains were collected to assess neuropathology and BBB dysfunction. A significant breakdown of the BBB was observed in the HI injury group compared to the sham group from 6 h in the cortex and hippocampus (p < 0.001), including a significant increase in albumin extravasation (p < 0.0033) and decrease in basal lamina integrity and tight-junction proteins. There was a decrease in resting microglia (p < 0.0001) transitioning to an intermediate state from as early as 6 h post-HI, with the intermediate microglia peaking at 12 h (p < 0.0001), which significantly correlated to the peak of microbleeds. Neonatal HI insult leads to significant brain injury over the first 72 h that is mediated by BBB disruption within 6 h and a transitioning state of the resident microglia. Key BBB events coincide with the appearance of the intermediate microglial state and this relationship warrants further research and may be a key target for therapeutic intervention. Full article
(This article belongs to the Special Issue Perinatal Brain Injury—from Pathophysiology to Therapy)
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Review

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19 pages, 1543 KB  
Review
The Potential Clinical Relevance of Necrosis–Necroptosis Pathways for Hypoxic–Ischaemic Encephalopathy
by Benjamin A. Lear, Alice J. McDouall, Olivia J. Lear, Simerdeep K. Dhillon, Christopher A. Lear, Frances J. Northington, Laura Bennet and Alistair J. Gunn
Cells 2025, 14(24), 1984; https://doi.org/10.3390/cells14241984 - 14 Dec 2025
Viewed by 765
Abstract
Hypoxic–ischaemic encephalopathy (HIE) is a major cause of neonatal brain injury and is associated with a high rate of death and lifelong disability. Its pathogenesis is still poorly understood, and there is no proven treatment for preterm infants. Therapeutic hypothermia for term and [...] Read more.
Hypoxic–ischaemic encephalopathy (HIE) is a major cause of neonatal brain injury and is associated with a high rate of death and lifelong disability. Its pathogenesis is still poorly understood, and there is no proven treatment for preterm infants. Therapeutic hypothermia for term and near-term infants partially improves outcomes, highlighting the need to target additional mechanisms. This review evaluates evidence that necrosis and necroptosis contribute materially to evolving brain injury in both term and preterm brains. Serial imaging studies suggest that lesions typically develop over many days after birth for term infants and over many weeks after birth for preterm infants. Growing evidence from animal studies shows that severe white matter injury can be mediated by programmed necroptosis. In particular, lesions that evolve late after acute HI are characterised by necrosis in association with agglomerations of microglia, with little apoptotic cell death. Critically, preclinical studies in large and small animals show that outcomes can be dramatically improved by very delayed intervention after HI including with cell therapy, anti-inflammatory agents, and endogenous neurotrophins. These findings strongly support the hypothesis that there may be a window of therapeutic opportunity for days or even weeks after birth to prevent delayed necrotic lesions. Full article
(This article belongs to the Special Issue Perinatal Brain Injury—from Pathophysiology to Therapy)
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16 pages, 3352 KB  
Review
Clinical Evidence of Mesenchymal Stromal Cells for Cerebral Palsy: Scoping Review with Meta-Analysis of Efficacy in Gross Motor Outcomes
by Madison C. B. Paton, Alexandra R. Griffin, Remy Blatch-Williams, Annabel Webb, Frances Verter, Pedro S. Couto, Alexey Bersenev, Russell C. Dale, Himanshu Popat, Iona Novak and Megan Finch-Edmondson
Cells 2025, 14(10), 700; https://doi.org/10.3390/cells14100700 - 12 May 2025
Cited by 3 | Viewed by 4415
Abstract
Mesenchymal stromal cells (MSCs) have been under clinical investigation for the treatment of cerebral palsy (CP) for over a decade. However, the field has been limited by study heterogeneity and variable reports of efficacy. We conducted a scoping review of published and registered [...] Read more.
Mesenchymal stromal cells (MSCs) have been under clinical investigation for the treatment of cerebral palsy (CP) for over a decade. However, the field has been limited by study heterogeneity and variable reports of efficacy. We conducted a scoping review of published and registered reports of MSC treatment for CP, with meta-analysis of Gross Motor Function Measure (GMFM) outcomes to summarize research and provide future recommendations. Thirty published reports and 10 registered trials were identified, including 1292 people with CP receiving MSCs. Most received ≥2 doses (72%) of umbilical cord tissue MSCs (75%), intrathecally (40%) or intravenously (38%), and 31% were treated via compassionate/Expanded access. MSC treatment was safe and meta-analyses demonstrated that MSCs conferred significant improvements in GMFM at 3 − (1.05 (0.19–1.92), p = 0.02), 6 − (0.97 (0.30–1.64), p = 0.005) and 12 months (0.99 (0.30–1.67), p = 0.005) post-treatment. Whilst MSCs are safe and improve GMFM outcomes in CP with large effect sizes, study and participant variability continues to confound data interpretation and limits subgroup analyses. With no published Phase 3 trials and high rates of compassionate access, the field would benefit from well-designed trials with unified outcomes. Additionally, data sharing to enable Individual Participant Data Meta-Analysis would support the determination of optimal source, route and dose to progress towards regulatory approval. Full article
(This article belongs to the Special Issue Perinatal Brain Injury—from Pathophysiology to Therapy)
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28 pages, 3756 KB  
Review
Unveiling the Emerging Role of Extracellular Vesicle–Inflammasomes in Hyperoxia-Induced Neonatal Lung and Brain Injury
by Karen Young, Merline Benny, Augusto Schmidt and Shu Wu
Cells 2024, 13(24), 2094; https://doi.org/10.3390/cells13242094 - 18 Dec 2024
Cited by 5 | Viewed by 3730
Abstract
Extremely premature infants are at significant risk for developing bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI). Although BPD is a predictor of poor neurodevelopmental outcomes, it is currently unknown how BPD contributes to brain injury and long-term NDI in pre-term infants. Extracellular vesicles [...] Read more.
Extremely premature infants are at significant risk for developing bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI). Although BPD is a predictor of poor neurodevelopmental outcomes, it is currently unknown how BPD contributes to brain injury and long-term NDI in pre-term infants. Extracellular vesicles (EVs) are small, membrane-bound structures released from cells into the surrounding environment. EVs are involved in inter-organ communication in diverse pathological processes. Inflammasomes are large, multiprotein complexes that are part of the innate immune system and are responsible for triggering inflammatory responses and cell death. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is pivotal in inflammasome assembly and activating inflammatory caspase-1. Activated caspase-1 cleaves gasdermin D (GSDMD) to release a 30 kD N-terminal domain that can form membrane pores, leading to lytic cell death, also known as pyroptosis. Activated caspase-1 can also cleave pro-IL-1β and pro-IL-18 to their active forms, which can be rapidly released through the GSDMD pores to induce inflammation. Recent evidence has emerged that activation of inflammasomes is associated with neonatal lung and brain injury, and inhibition of inflammasomes reduces hyperoxia-induced neonatal lung and brain injury. Additionally, multiple studies have demonstrated that hyperoxia stimulates the release of lung-derived EVs that contain inflammasome cargos. Adoptive transfer of these EVs into the circulation of normal neonatal mice and rats induces brain inflammatory injury. This review focuses on EV–inflammasomes’ roles in mediating lung-to-brain crosstalk via EV-dependent and EV-independent mechanisms critical in BPD, brain injury, and NDI pathogenesis. EV–inflammasomes will be discussed as potential therapeutic targets for neonatal lung and brain injury. Full article
(This article belongs to the Special Issue Perinatal Brain Injury—from Pathophysiology to Therapy)
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