Biology subjects

Faiz, M.

Publications and source records attributed to Faiz, M..

6 recordsLinked to original sources

bioRxiv2025

Spatially resolved transcriptomics identifies intercellular signaling post-ischemic stroke that controls neural stem cell proliferation

Stroke is the second leading cause of death and disability worldwide. Ischemic stroke mobilizes adult neural stem cells (NSCs) out of the quiescent state. The multifaceted responses of endogenous NSCs to ischemic stroke involve proliferation, migration, and differentiation. Hence one strategy which could be leveraged for recovery after ischemic stroke is the intrinsic mechanism of endogenous NSC mobilization. However, the survival rate of recruited endogenous NSCs is low. Moreover, the intercellular signals that activate NSCs after ischemic stroke are poorly understood. We hypothesized that after stroke, cells located in the cerebral lesion send signals to the NSC niche to initiate the regenerative response. To test this hypothesis, we used CellChat to computationally infer the cell-cell communication between the ischemic infarct region and ventricular-subventricular zone (V-SVZ) NSC niche from spatial gene expression profiles. We identified ligand-receptor pairs and signaling pathways involved in the signal transduction events at 2, 10, and 21 days after stroke. Out of several candidate genes of interest we identified, here we reported the regulatory function of galectin-9 on the proliferation of NSCs. Our present work portrays galectin-9 as a checkpoint signaling molecule that guards the responses of NSCs under physiological conditions and potentially during the recovery phase post-ischemic stroke. We suggest that TIM-3 mediates the inhibitory effect of galectin-9 on NSC proliferation and propose a working hypothesis that the stroke-induced proinflammatory factors stimulate the Toll-like receptor 4 (TLR4) on ependymal cells and result in the increased secretion of galectin-9, which in turn modulates neighboring NSCs. Our study paves the way for potential therapeutic approaches which leverage the TLR4 and galectin-9/TIM3 signaling pathways.

neuroscience↗

bioRxiv2025

Optogenetic stimulation of nigral astrocytes is neuroprotective in a 6-OHDA model of neurodegeneration.

HighlightsO_LIOptogenetic stimulation of nigral astrocytes attenuates motor deficits & Th+ cell loss in a 6-OHDA model of neurodegeneration C_LIO_LIBulk RNA-seq analysis reveals optogenetic stimulation of nigral astrocytes induces early changes in microglia C_LIO_LIsnRNA-seq shows 6-OHDA alone induces extensive gene expression changes across all cell populations within the SN C_LIO_LIOligodendrocytes within the SNc express Th, which is upregulated with DA neuron loss C_LI Parkinsons disease is characterized by the loss of dopaminergic neurons in the substantia nigra. Glial-glial crosstalk is essential for maintaining the regional milieu, and appears to be particularly important in modulating neuroinflammation and many aspects of neurodegeneration. In particular, astrocytes are critical for maintaining dopamine neuronal integrity and survival, and astroglial dysfunction is prominent in Parkinsons disease. As such, astrocytes represent a potentially critical therapeutic target in neurodegeneration. In this study, in vivo optogenetics were used to selectively stimulate astrocytes in the substantia nigra following a striatal 6-OHDA lesion. Remarkably, a single bout of optogenetic stimulation was sufficient to attenuate motor deficits and dopamine neuron loss induced by the neurotoxin. Furthermore, bulk RNA-seq and snRNA-seq analysis of the substantia nigra revealed extensive changes in both microglia and oligodendrocytes, suggesting that the neuroprotective effects of stimulating astrocytes may be mediated through alterations in glia-glia crosstalk. Altogether, this work demonstrates the importance of understanding glia-glia interactions in neurodegeneration.

neuroscience↗

bioRxiv2024

Direct lineage conversion of postnatal mouse cortical astrocytes to oligodendrocyte lineage cells

Oligodendrocyte lineage cells (OLCs) are lost in many CNS diseases. Here, we investigate the generation of new OLCs via ectopic expression of Sox10, Olig2 or Nkx6.2 in mouse postnatal astrocytes. Using stringent analyses including, Aldh1l1-astrocyte fate mapping and live cell imaging we confirm that Sox10 and Olig2, but not Nkx6.2, convert Aldh1l1pos astrocytes to induced OLCs (iOLCs). With single cell RNA sequencing (scRNA-seq) we uncover the molecular signatures of iOLCs. Transcriptomic analysis of Sox10- and control cultures over time reveals a clear trajectory from astrocytes to iOLCs. Finally, perturbation models CellOracle and Fatecode support the idea that Sox10 drives cells towards a terminal iOLC fate. Altogether, this multidimensional analysis shows bonafide conversion of astrocytes to iOLCs using Sox10 or Olig2 and provides a foundation for astrocyte DLR strategies to promote OLC repair.

developmental biology↗

bioRxiv2023

Megakaryocyte maturation involves activation of the IRE1α-dependent adaptive unfolded protein response

Endoplasmic reticulum stress triggers the unfolded protein response (UPR) to promote cell survival or apoptosis. Transient endoplasmic reticulum stress activation has been reported to trigger megakaryocyte production, and UPR activation has been reported as a feature of megakaryocytic cancers. However, the role of UPR signaling in megakaryocyte biology is not fully understood. We studied the involvement of UPR in human megakaryocytic differentiation using PMA (phorbol 12-myristate 13-acetate)-induced maturation of megakaryoblastic cell lines and thrombopoietin-induced differentiation of human peripheral blood-derived progenitors. Our results demonstrate that an adaptive UPR is a feature of megakaryocytic differentiation, and that this response is not associated with ER stress-induced apoptosis. Differentiation did not alter the response to the canonical endoplasmic reticulum stressors DTT or thapsigargin. However, thapsigargin, but not DTT, inhibited differentiation, consistent with the involvement of Ca2+ signaling in megakaryocyte differentiation.

cell biology↗

bioRxiv2021

Signal requirement for cortical potential of transplantable human neuroepithelial stem cells

The cerebral cortex develops from dorsal forebrain neuroepithelial progenitor cells. Initial expansion of the progenitor cell pool is followed by the generation of neurons of all the cortical layers and later, astrocytes and oligodendrocytes. However, the regulatory pathways that control the expansion and maintenance of the neuroepithelial progenitor cell pool are currently unknown. Here we define six basic pathway components that regulate proliferation of cortically specified human neuroepithelial stem cells (cNESCs) in vitro without the loss of developmental potential. We show that activation of FGF and inhibition of BMP and ACTIVIN A signalling are required for long-term cNESC proliferation. We also demonstrate that cNESCs preserve dorsal telencephalon-specific potential when GSK3, AKT and nuclear CATENIN-{beta}1 activity are low. Remarkably, regulation of these six pathway components supports the clonal expansion of cNESCs. Moreover, cNESCs differentiate to lower and upper layer cortical neurons both in vitro and in vivo. Identifying the mechanisms that drive the self-renewal and fate of cNESCs decision of neuroepithelial stem cells is key to developing new stem cell-based therapeutic approaches to treat neurological conditions.

developmental biology↗

bioRxiv2020

Direct reprogramming of astrocytes to neurons leads to functional recovery after stroke

Stroke is the leading cause of adult disability with few treatment options for stroke survivors. Astrocyte reprogramming to neurons enables the targeted in vivo generation of new cells at the site of injury and represents a novel approach for brain repair. A number of studies have demonstrated successful conversion of astrocytes to neurons in various models of brain injury and disease; however, the impact of this strategy on tissue and functional outcome following stroke is not well established. Using AAV delivery of the transcription factor NeuroD1, we reprogrammed astrocytes 7 days after endothelin-1 induced cortical stroke, and studied the long-term cellular and functional outcomes. We found that by 63 days post-stroke, 20% of neurons in the perilesional cortex were reprogrammed. Furthermore, reprogrammed neurons had matured into regionally appropriate neuronal subtypes. Importantly, this treatment was associated with improved functional outcome using the foot fault test and gait analysis. Together, our findings indicate that in vivo reprogramming is a promising regenerative approach for stroke repair.

neuroscience↗