Biology subjects

Noel, E. S.

Publications and source records attributed to Noel, E. S..

4 recordsLinked to original sources

bioRxiv2026

Histological assessment of integrated human cortical organoid grafts after controlled cortical impact

Rodent models are a mainstay of traumatic brain injury (TBI) research, including investigations into the pathophysiology and treatment of this condition. However, there are fundamental molecular and cellular differences between rodent and human neurons, as well as other cells of the brain. Brain organoids derived from human pluripotent stem cells recapitulate key features of the human brain and have been used to model a variety of neurological disorders. Here, we developed a novel in vivo model of human TBI based on controlled cortical impact (CCI) injuries of human organoid grafts transplanted into the brains of young adult rats. Cortical organoids derived from human induced pluripotent stem cells (iPSCs) were grown for 50-60 days in vitro before transplantation into rat visual cortex. Injures were performed 2 months later, and histological outcomes were examined at 7 or 30 days after injury. Injury cavities in the integrated grafts were identified at both endpoints with a progression toward larger cavities sizes with time. The injured human tissue exhibited evidence of neuroinflammation with elevated numbers of IBA1+ cells and axonal injury with APP+ cells. There was evidence of increased cell proliferation in the injured grafts acutely after injury that decreased with time. The injured grafts also showed evidence of phosphorylated tau aggregates and accumulation of PNAG, a polysaccharide associated with microbial pathogens. These results support the feasibility of using human organoid grafts in rats as a model of TBI, potentially including the study of long-term neurodegeneration and microbial penetration of the brain after injury.

neuroscience↗

bioRxiv2025

Mechanical fracturing of the extracellular matrix patterns the vertebrate heart

Pattern formation is fundamental to embryonic morphogenesis. In the zebrafish heart, spatially confined single-cell delamination in the ventricle outer curvature initiates trabeculation, a conserved morphogenetic process critical for heart function and embryonic life. Yet, what confines delamination in the ventricle outer curvature remains ill-understood. Contrary to the prevailing notion of patterning through biochemical signals, we now show that mechanical fracturing of the cardiac extracellular matrix (cECM) patterns delamination in the outer curvature. cECM fractures emerge preferentially in the outer curvature, cells delaminate into these fractures and experimental blocking of fractures blocks delamination. These fractures display characteristic signature of mechanical defects and myocardial tissue contractility is sufficient to fracture the cECM, independent of molecular signals, enzymatic activity, or delamination events. Notably, the anisotropic geometry of myocardial tissue generates higher mechanical strain in the outer curvature, thereby locally patterning cECM fractures and delamination. Consequently, cECM fractures evolve in response to dynamic changes in tissue geometry, and experimental manipulation of tissue geometry is sufficient to alter the fracture pattern. Together, our findings underscore mechanical fractures as a morphogenetic strategy, and more generally, corroborate the long-standing but understudied paradigm that tissue form-function can feed back to steer its own patterning.

developmental biology↗

bioRxiv2024

Early life adversity drives sex-dependent changes in 5-mC DNA methylation of parvalbumin cells in the prefrontal cortex in rats

Early life adversity (ELA) can result in increased risk for developing affective disorders, such as anxiety or depression, later in life, with women showing increased risk. Interactions between an individuals genes and their environment play key roles in producing, as well as mitigating, later life neuropathology. Our current understanding of the underlying epigenomic drivers of ELA associated anxiety and depression are limited, and this stems in part from the complexity of underlying biochemical processes associated with how early experiences shapes later life behavior. Epigenetic alterations, or experience-driven modifications to DNA, can be leveraged to understand the interplay between genes and the environment. The present study characterized DNA methylation patterning, assessed via evaluation of 5-methylcytosine (5-mC), following ELA in a Sprague Dawley rat model of ELA induced by early caregiver deprivation. This study utilized maternal separation to investigate sex- and age-specific outcomes of ELA on epigenetic patterning in parvalbumin (PV)-containing interneurons in the prefrontal cortex (PFC), a subpopulation of inhibitory neurons which are associated with ELA and affective dysfunction. While global analysis of 5-mC methylation and CpG site specific pyrosequencing of the PV promoter, Pvalb, showed no obvious effects of ELA, when analyses were restricted to assessing 5-mC intensity in colocalized PV cells, there were significant sex and age dependent effects. We found that ELA leads sex-specific changes in PV cell counts, and that cell counts can be predicted by 5-mC intensity, with males and females showing distinct patterns of methylation and PV outcomes. ELA also produced sex-specific effects in corticosterone reactivity, with juvenile females showing a blunted stress hormone response compared to controls. Overall, ELA led to a sex-specific developmental shift in PV profile, which is comparable to profiles that are seen at a later developmental timepoint, and this shift may be mediated in part by epigenomic alterations driven by altered DNA methylation.

neuroscience↗

bioRxiv2021

Lamb1a regulates atrial growth by limiting excessive, contractility-dependent second heart field addition during zebrafish heart development

During early vertebrate heart development, the heart transitions from a linear tube to a complex asymmetric structure. This process includes looping of the tube and ballooning of the emerging cardiac chambers, which occur simultaneously with growth of the heart. A key driver of cardiac growth is deployment of cells from the Second Heart Field (SHF) into both poles of the heart, with cardiac morphogenesis and growth intimately linked in heart development. Laminin is a core component of extracellular matrix (ECM) basement membranes, and although mutations in specific laminin subunits are linked with a variety of cardiac abnormalities, including congenital heart disease and dilated cardiomyopathy, no role for laminin has been identified in early vertebrate heart morphogenesis. We identified dynamic, tissue-specific expression of laminin subunit genes in the developing zebrafish heart, supporting a role for laminins in heart morphogenesis. lamb1a mutants exhibit cardiomegaly from 2dpf onwards, with subsequent progressive defects in cardiac morphogenesis characterised by a failure of the chambers to compact around the developing atrioventricular canal. We show that loss of lamb1a results in excess addition of SHF cells to the atrium, revealing that Lamb1a functions to limit heart size during cardiac development by restricting SHF addition to the venous pole. lamb1a mutants exhibit hallmarks of altered haemodynamics, and specifically blocking cardiac contractility in lamb1a mutants rescues heart size and atrial SHF addition. Furthermore, we identify that FGF and RA signalling, two conserved pathways promoting SHF addition, are regulated by heart contractility and are dysregulated in lamb1a mutants, suggesting that laminin mediates interactions between SHF deployment, heart biomechanics, and biochemical signalling during heart development. Together, this describes the first requirement for laminins in early vertebrate heart morphogenesis, reinforcing the importance of specialised ECM composition in cardiac development.

developmental biology↗