Garcia Diaz, B. | Search bioRxiv

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↗

bioRxiv2026

Strategies for the modulation of mitochondrial metabolism and activity in the treatment of neurodegenerative diseases: A systematic review and meta-analysis.

Neurodegenerative diseases (NDDs) are currently raising their prevalences and new preclinical low-cost investigations of drug design are urging. NDDs encompass a wide range of disorders, including Alzheimers, Parkinsons, ALS and others, many of which share mitochondrial dysfunction as a common pathological feature. As such, targeting mitochondrial metabolism has emerged as a promising therapeutic strategy. However, while rodent models are widely used in NDD research, they are costly and time-consuming, raising the need to consider other alternatives to accelerate the search for novel therapies. In this line, zebrafish (Danio rerio) have gained outstanding popularity as a valuable option. This systematic review aims to provide an extensive overview about the current strategies that use zebrafish assays to investigate modulations of mitochondrial function as new therapies against NDDs. The review was performed following an electronic search of different databases (PubMed, Embase, Scopus and Web of Science) after the PRISMA procedure. Articles published in the English language were identified and screened based on the keywords used: mitochondrial metabolism, therapy, neurodegenerative diseases and zebrafish. Following 176 entries, exclusion criteria reduced the record to 34 final studies. Overall, we found that these studies investigate 37 compounds: 24 natural, 6 semisynthetic, 5 synthetic and 2 compounds of not-determined origin; to ameliorate 9 prevalent diseases: ARSACS, Alzheimers, Parkinsons, Huntingtons diseases, Leigh and Wolfram syndromes, Amyotrophic lateral sclerosis, Limb - girdle muscular dystrophy 2G and hyperglycemia-associated amnesia. Additionally, a meta-analysis of these compounds and their gene interactions provides insights into their mechanisms of action and advances our understanding of NDDs, and furnishes us with a powerful tool to predictive potential new drugs or to repurpose existing ones. To conclude, this systematic review suggests that zebrafish have become an effective model for screening potential drugs for NDDs with symptomatology difficult to replicate in rodent models. Moreover, the use of computational tools is also emphasized as a promising strategy to guide therapeutic discovery more efficiently, reducing both time and costs, in developing treatments for NDDs. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/710294v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@18893a1org.highwire.dtl.DTLVardef@1943a12org.highwire.dtl.DTLVardef@709146org.highwire.dtl.DTLVardef@51a488_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗