Biology subjects

Mozafari, S.

Publications and source records attributed to Mozafari, S..

4 recordsLinked to original sources

bioRxiv2026

Development of a Humanized Mouse Model for Studying adult Spinal Cord myelination, remyelination and Drug Efficacy

Oligodendrocytes are essential for central nervous system (CNS) function through their roles in myelination and neuronal support. Remyelination, the regeneration of myelin after damage, often fails in human demyelinating diseases, leading to progressive neurological dysfunction. While the biology of rodent oligodendroglia has been investigated in depth, species-specific differences have hindered the study of human oligodendrocyte progenitor cells maturation using current animal models. To address this gap, we developed a humanized oligodendroglia chimeric mouse model by transplanting human iPSC-derived O4+ oligodendroglial progenitors (hiOLs) into the developing spinal cord of myelin deficient-immunosuppressed mice followed by demyelination of the adult humanized spinal cord. This paradigm allows in vivo investigation of hiOL fate during their maturation and ageing, and the response of their settled progeny to demyelinating injury. Following transplantation during postnatal development, hiOLs proliferated, migrated, and differentiated into mature oligodendrocytes, initiating axonal myelination. A population of undifferentiated, proliferative adult human oligodendrocyte progenitors presisted, indicating a reservoir of these cells capable of responding to injury. Spinal cord focal demyelination via lysolecithin injection in the adult humanized spinal cord led to transient loss of human-derived mature oligodendrocytes and myelin, followed by myelin recovery together with endogenous cells. Treatment with the histamine receptor H3 antagonist, bavisant, a recently identified promyelinating compound, significantly enhanced hiOL maturation and myelin production, indicating promotion of their differentiation when administered post-demyelination. Electron microscopy showed an increased number of human-derived remyelinated axons together with decreased g-ratios in bavisant treated animals. This humanized spinal cord model of myelination/demyelination-remyelination faithfully recapitulates key aspects of human oligodendrocyte biology and CNS repair, providing a powerful tool to study human-specific myelination and remyelination mechanisms and screen for emerging remyelinating therapies. Its application in disease modeling and preclinical testing holds promise for advancing personalized treatments in demyelinating and neurodegenerative disorders.

neuroscience↗

bioRxiv2024

Therapeutic potential of human mesenchymal stromal cell-derived mitochondria in a rat model of post-surgical digestive fistula: towards an energetic nano-biotherapy

BackgroundTissue regeneration heavily relies on cellular energy production, with mitochondria playing a crucial role. Dysfunctional mitochondria are implicated in various degenerative diseases, driving interest in targeting mitochondrial transplantation for tissue repair. Wound healing is highly compromised in gastrointestinal conditions resulting in fistula development, particularly after sleeve gastrectomy. Human mesenchymal stem/stromal cells (hMSCs) and their cell-free products such as mitochondria offer potential benefits due to their therapeutic properties on cellular energy production. Here we investigated the therapeutic advantage of hMSCs-derived mitochondria nano-biotherapy in a rat model of post-surgical fistula healing. MethodsViable and structurally intact mitochondria were isolated from hMSCs before exposure to human colonic epithelial cells (HCEC-1CT) culture or transplantation into a rat model of post-operative fistula. ResultsOur findings reveal significant dose-dependent improvement on cellular metabolic activity and ATP content of the recipient cells. Assessment of the external fistula orifice developed following post sleeve gastrectomy fistula, revealed a substantial healing in all transplanted rats compared to control group. ConclusionOur findings highlight the therapeutic potential of hMSCs-derived mitochondria in post-surgical fistula healing. This research contributes to advancing cell-free regenerative strategies for gastrointestinal conditions, offering new insights into mitochondrial-based therapies for enhancing wound healing and tissue repair.

systems biology↗

bioRxiv2020

Beneficial contribution of iPSC-progeny to connexin 47 dynamics during demyelination-remyelination

Oligodendrocytes are extensively coupled to astrocytes, a phenomenon ensuring glial homeostasis and maintenance of CNS myelin. Molecular disruption of this communication occurs in demyelinating diseases such as multiple sclerosis. Less is known about the vulnerability and reconstruction of the panglial network during adult demyelination-remyelination. Here, we took advantage of LPC-induced demyelination to investigate the expression dynamics of the oligodendrocyte specific connexin 47 (Cx47) and whether this dynamic could be modulated by grafted iPSC-neural progeny. Our data show that deconstruction of the panglial network following demyelination is larger in size than demyelination. Loss of Cx47 expression is timely rescued during remyelination and accelerated by the grafted neural precursors. Moreover, mouse and human iPS-derived oligodendrocytes express Cx47, which co-labels with astrocyte Cx43, indicating their integration into the panglial network. These data suggest that full lesion repair following transplantation occurs by panglial reconstruction in addition to remyelination. Targeting panglial elements by cell therapy or pharmacological compounds may help accelerating or stabilizing re/myelination in myelin disorders.

neuroscience↗

bioRxiv2020

Multiple sclerosis iPSC-derived oligodendroglia conserve their intrinsic properties to functionally interact with axons and glia in vivo

The remyelination failure in multiple sclerosis (MS) is associated with a migration/differentiation block of oligodendroglia. The reason for this block is highly debated. It could result from disease-related extrinsic regulators of the oligodendroglial biology or reflect MS oligodendrocyte intrinsic properties. To avoid confounding immune-mediated extrinsic effect, we used an immune-deficient, dysmyelinating mouse model, to compare side-by-side induced pluripotent stem-cell-derived O4+ oligodendroglia from MS and healthy donors following their engraftment in the developing CNS. We show that the MS-progeny survives, proliferates and differentiates into oligodendrocytes to the same extent as controls. Quantitative multi-parametric imaging indicates that MS and control oligodendrocytes generate equal amounts of myelin, with bona-fide nodes of Ranvier and promote equal restoration of their host slow conduction. Moreover, the MS-derived progeny expressed oligodendrocyte- and astrocyte-specific connexins and established functional connections with donor and host glial cells. Thus, MS pluripotent stem cell-derived progeny fully integrates into functional axo-glial and glial-glial components, reinforcing the view that the MS oligodendrocyte differentiation block is not due to intrinsic oligodendroglial deficits. These biological findings as well as the fully integrated human-murine chimeric model should facilitate the development of pharmacological or cell-based therapies to promote CNS remyelination. One Sentence SummaryMultiple Sclerosis oligodendroglia, regardless of major immune manipulators, are intrinsically capable of myelination and making functional axo-glia and glia-glia connections after engraftment in the murine CNS, reinforcing the view that the MS oligodendrocyte differentiation block is not due to major intrinsic oligodendroglial deficits but most likely to environmental conditions.

neuroscience↗