Aug 2026· Stem Cell Research & Therapy· 0 citations
TL;DR
This model provides opportunities to investigate the mechanisms underlying perinatal insults and serves as a promising tool for novel treatments such as stem cell-based therapy, drug discovery and screening, helping to bridge the translational gap between preclinical studies in animal models and clinical applications.
Abstract
Perinatal brain injury (PBI) is a leading cause of childhood morbidity and mortality, often resulting in long-term neurological deficits. Despite its relatively high prevalence, PBI lacks reliable biomarkers for early detection and effective therapeutic approaches. The etiology of PBI is multifactorial and includes not only preterm birth but also hypoxia-ischemia, infection, and inflammation. While animal models and two-dimensional cell cultures have contributed to our understanding of PBI pathophysiology as well as to the development of novel treatment strategies, they fail to fully capture the complexity of injury in the developing human brain. Human brain organoids have recently emerged as transformative platforms recapitulating key features of fetal-neonatal brain development, including relevant cell types, gene expression patterns, cytoarchitecture, and functional electrophysiological properties. This model therefore provides opportunities to investigate the mechanisms underlying perinatal insults and serves as a promising tool for novel treatments such as stem cell-based therapy, drug discovery and screening, helping to bridge the translational gap between preclinical studies in animal models and clinical applications. Recent innovations, including the development of vascularization strategies, the incorporation of glial cells, brain organoid-on-chip technologies, and assembloids, have further increased the physiological relevance of these methods. This review highlights recent advances in organoid-based models of PBI and highlights their potential and challenges as next-generation tools for mechanistic studies and therapeutic innovations.
Recent advances and ongoing challenges of human cortical organoid models of genetic and acquired epilepsies hold promise for advancing mechanistic understanding of epilepsy and enabling the development of more precise therapeutic strategies.
Miranda Walker, Jack M. Parent· Epilepsy Currents· 0 citations
Traumatic brain injury (TBI) is a major global health issue, with approximately 27 million new cases annually. TBI significantly increases the risk of developing post-traumatic epilepsy (PTE), which may emerge weeks to years after the initial injury. Currently, effective therapies for both TBI and PTE remain limited. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have demonstrated anti-inflammatory and neuroprotective effects in preclinical TBI models. VivaZome’s proprietary cells (VZT-PCs) share characteristics with MSCs, including similar surface markers and immunomodulatory properties. Native EVs from VZT-PCs are enriched in microRNAs with known anti-inflammatory properties. This study assessed the therapeutic effect of VZT-PC-derived EVs in a murine model of TBI. Adult C57BL/6 mice underwent controlled cortical impact (CCI) and received either vehicle control or VZT-PC-EVs. Functional recovery was assessed using the Rotarod test and the Elevated Plus maze (EPM) test. After 4 weeks post TBI induction, PTE was evaluated using pentylenetetrazol challenge and video-electroencephalography. Native EV-treated TBI mice showed improved performance in Rotarod trials, where latency to fall was significantly increased at 24 h post injury, indicating enhanced motor coordination. Exploratory behavior in the EPM was also improved following EV administration, indicating mice exhibited reduced anxiety-like behavior. EV-treated mice exhibited a trend toward reduced seizure frequency and increased latency to generalized seizures, though not statistically significant. Collectively, these findings support the therapeutic potential of VZT-PC-derived native EVs in enhancing motor function and possibly reducing epileptogenicity following moderate TBI, highlighting VZT-PCs as a promising source of EVs for brain injury therapy.
Smriti Murali Krishna, Min Chen, Baani Bagga et al.· Neurotrauma Reports· 0 citations
Key findings demonstrate that organoids effectively capture genotype–phenotype relationships for major AD genes, enable the dissection of signaling pathway dysregulation (Wnt/β-catenin), and when combined with CRISPR editing and single-cell multi-omics, reveal cell-type-specific disease mechanisms.
Qing Zhao, Songtao Li, Yanxiu Ju et al.· Frontiers in Cell and Develo...· 0 citations
Microglia play dynamic roles in the developing brain and are central mediators of injury responses in perinatal brain injury. In mice, microglial gene regulatory and transcriptional programes reveal progression through early, pre-mature and mature stages. In contrast, microglial maturation has not been systematically characterised in the large-brained species most widely used to model human perinatal brain injury, particularly sheep and pigs. These large-animal models are indispensable as they share gyrencephaly, an expanded subplate, and clinically relevant physiology with the human infant brain. Here, we integrate established mouse and human frameworks of microglial maturation with a critical re-analysis of available sheep and pig datasets to assess whether rodent-derived insights into microglial development extend to large-animal models. Current sheep datasets lack sufficient resolution to infer maturation states, whereas pig data, although limited, reveal stage-dependent patterns consistent with late-gestation human development. This review also briefly considers emerging data on microglial development in non-human primates and the extent to which microglial gene expression programes appear conserved across species. Overall, microglial transitions are most dynamic during fetal and early postnatal life, underscoring the importance of developmentally aligned benchmarks for interpreting injury responses and informing microglia-targeted neuroprotective strategies. IMPACT: This article provides the first structured comparison of microglial maturation across human and mouse and uses these frameworks to benchmark large-brain animal models of perinatal brain injury, addressing a key translational gap. It shows that while existing sheep datasets lack sufficient resolution to define microglial maturation states, available pig data align closely with human late-gestation microglial development, supporting their use for developmental benchmarking. The work highlights that failure to account for microglial developmental stage risks misinterpretation of injury responses and underscores the need for developmentally aligned microglial markers in large-animal and non-human primate models to guide microglia-targeted neuroprotective strategies.
Isabelle K Shearer, Adrienne M. Antonson, Juliette van Steenwinckel et al.· Pediatric Research· 0 citations
Ischemic stroke remains a leading contributor to mortality and long-term neurological disability worldwide. While improvements in emergency care have increased survival rates, most effective clinical interventions are largely restricted to the acute phase of injury. As a result, increasing attention has shifted toward understanding cellular processes that influence tissue remodelling and recovery during the chronic stage. Microglia, the resident immune cells of the central nervous system, play a critical role in shaping recovery outcomes, yet their behaviour during the chronic stage of stroke remains poorly defined. An increasingly compelling area of research has investigated regenerative gene therapies. One such therapy involves adeno-associated virus (AAV) mediated delivery of the transcription factor NeuroD1, which has demonstrated robust neuroregenerative effects in both rodent and non-human primate models of ischemic stroke, including increased neuronal density and reduced gliosis. Despite these promising outcomes, the impact of NeuroD1 treatment on microglial populations during the chronic stage of stroke is not well understood. The present study investigates microglial distribution and phenotype in chronic-stage ischemic stroke tissue following AAV-NeuroD1 gene therapy in non-human primates. Brain tissue collected nine months after transient middle cerebral artery occlusion was immunolabeled for Iba1 to identify microglia and counterstained with DAPI to label nuclei. Quantitative image analysis was performed to assess microglial density and spatial distribution in ipsilateral, stroke-affected regions compared to contralateral control regions, as well as across control, low-titer, and high-titer NeuroD1 treatment groups. By examining microglial patterns in chronically injured tissue, this study provides foundational insight into how regenerative gene therapy may influence the long-term neuroimmune environment after stroke.