Biology subjects

Assir, M. Z. K.

Publications and source records attributed to Assir, M. Z. K..

3 recordsLinked to original sources

bioRxiv2026

DNA damage-induced senescence reshapes transcriptomic and functional landscape of human neural progenitor cells

Ageing-related decline in hippocampal neurogenesis has been associated with cognitive impairment and neurodegenerative disease, yet experimentally tractable human models to study the underlying cellular and molecular mechanisms remain limited. Cellular senescence has emerged as a candidate driver of age-related tissue dysfunction, but its induction and consequences in human NPCs have not been well characterized. Here, we established a human in vitro model of NPC senescence using induced pluripotent stem cell-derived NPCs exposed to transient low-dose doxorubicin to activate the DNA damage response (DDR) while minimizing acute cytotoxicity. Doxorubicin-treated NPCs developed a stable senescent phenotype characterized by increased senescence-associated {beta}-galactosidase activity, reduced proliferation, persistent DNA damage, and sustained induction of p21 and p16. Transcriptomic profiling revealed widespread senescence-associated remodeling, including activation of p53 and inflammatory programs and repression of cell cycle and DNA repair pathways. Senescent NPCs exhibited apoptosis resistance despite transcriptional priming of apoptotic pathways and underwent mitochondrial remodeling with a shift towards oxidative metabolism. In parallel, they acquired a senescence-associated secretory phenotype enriched in inflammatory, TGF{beta}-related and pro-angiogenic factors, and conditioned media from these cells promoted angiogenesis in vascular organoids. Importantly, key senescence-associated features were recapitulated in human hippocampal organoids, confirming the robustness of this paradigm in a three-dimensional neural context. Together, these findings establish a tractable human model of DDR-driven NPC senescence and identify senescence as a mechanism linking genotoxic stress to impaired progenitor function, metabolic rewiring, and paracrine niche remodeling relevant to hippocampal ageing and neurodegeneration.

neuroscience↗

bioRxiv2025

A Human Hippocampal Organoid Model with Sustained Neural Stem Cells Reveals State Shifts Under Glucocorticoid Stress

The human hippocampus is a critical brain region for learning, memory, and stress regulation, distinguished by its ability to sustain neurogenesis after birth. This plasticity is driven by hippocampal neural stem cells (NSCs), which generate new neurons and maintain circuit integrity, but are highly sensitive to environmental and pathological influences. Mechanistic insight into human hippocampal development and neurogenesis remains limited by the absence of physiologically relevant models. Here, we establish an optimized protocol to generate human induced pluripotent stem cell-derived hippocampal organoids that recapitulate key features of hippocampal development. These organoids maintain organized NSC niches, support ongoing neurogenesis, and generate hippocampus-specific cell types. Cellular, transcriptomic, and electrophysiological analyses confirm progressive neuronal maturation, synapse formation, and functional activity, highlighting the physiological relevance of the system. Using this model, we modeled excess prenatal glucocorticoid exposure with dexamethasone, which perturbed NSC dynamics by reducing proliferation and inducing a precocious quiescent-like state. RNA sequencing revealed downregulation of NSC activation genes and upregulation of quiescence- and autophagy-associated programs, suggesting that glucocorticoid signaling enforces an early transition toward quiescence. These findings reveal a mechanism by which excessive glucocorticoid exposure may impair hippocampal growth. Together, this study introduces a robust human hippocampal organoid platform for dissecting the regulation of hippocampal development and for modeling the impact of environmental stressors on human neurogenesis.

neuroscience↗

bioRxiv2024

IL-17A Alters Human Cortical Development in a 3D Ex Vivo Model of Maternal Immune Activation

Human brain development depends on the coordinated interaction of diverse cell types and extracellular matrix (ECM) components, which are essential for proper neurogenesis and cortical organization. Epidemiological and animal studies have demonstrated that maternal immune activation (MIA) disrupts brain development, leading to impaired neurogenesis and increased risk of neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD) and schizophrenia. However, the cellular and molecular mechanisms by which MIA impacts human cortical development remain poorly understood. Here we introduce a 3D ex vivo culture system, termed cerebroids, derived from dorsolateral prefrontal cortex of human fetal brain tissue, which faithfully preserves key developmental processes, along with critical cellular diversity and structural integrity of the developing human cortex. Using this platform, we show that IL-17A, a cytokine strongly implicated in NDDs, induces premature cortical folding, increases cortical thickness, and accelerates neurogenesis and neuronal maturation. Transcriptomic and proteomic analyses reveal significant dysregulation of ECM-related pathways, including the upregulation of proteoglycans such as brevican and versican. Notably, treatment with the anti-inflammatory agent parthenolide, an inhibitor of NF-{kappa}B and HDAC1 pathways, reverses IL-17A-induced cortical abnormalities, restoring normal cortical thickness, folding, and neurogenesis. These findings provide valuable insights into how IL-17A disrupts human cortical development during MIA, advancing our understanding of NDD-associated structural cortical alterations.

neuroscience↗