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Cell Reports. Medicine Dec 2023Cutaneous neurofibromas (cNFs) are tumors that develop in more than 99% of individuals with neurofibromatosis type 1 (NF1). They develop in the dermis and can number in...
Cutaneous neurofibromas (cNFs) are tumors that develop in more than 99% of individuals with neurofibromatosis type 1 (NF1). They develop in the dermis and can number in the thousands. cNFs can be itchy and painful and negatively impact self-esteem. There is no US Food and Drug Administration (FDA)-approved drug for their treatment. Here, we screen a library of FDA-approved drugs using a cNF cell model derived from human induced pluripotent stem cells (hiPSCs) generated from an NF1 patient. We engineer an NF1 mutation in the second allele to mimic loss of heterozygosity, differentiate the NF1 and NF1 hiPSCs into Schwann cell precursors (SCPs), and use them to screen a drug library to assess for inhibition of NF1 but not NF1 cell proliferation. We identify econazole nitrate as being effective against NF1 hiPSC-SCPs. Econazole cream selectively induces apoptosis in Nf1 murine nerve root neurosphere cells and human cNF xenografts. This study supports further testing of econazole for cNF treatment.
Topics: United States; Humans; Animals; Mice; Neurofibromatosis 1; Econazole; Induced Pluripotent Stem Cells; Neurofibroma; Skin Neoplasms; Apoptosis
PubMed: 38086379
DOI: 10.1016/j.xcrm.2023.101309 -
Diabetologia Dec 2023Our aim was to investigate structural changes of cutaneous Schwann cells (SCs), including nociceptive Schwann cells (nSCs) and axons, in individuals with diabetic...
AIMS/HYPOTHESIS
Our aim was to investigate structural changes of cutaneous Schwann cells (SCs), including nociceptive Schwann cells (nSCs) and axons, in individuals with diabetic polyneuropathy. We also aimed to investigate the relationship between these changes and peripheral neuropathic symptoms in type 1 diabetes.
METHODS
Skin biopsies (3 mm) taken from carefully phenotyped participants with type 1 diabetes without polyneuropathy (T1D, n=25), type 1 diabetes with painless diabetic polyneuropathy (T1DPN, n=30) and type 1 diabetes with painful diabetic polyneuropathy (P-T1DPN, n=27), and from healthy control individuals (n=25) were immunostained with relevant antibodies to visualise SCs and nerve fibres. Stereological methods were used to quantify the expression of cutaneous SCs and nerve fibres.
RESULTS
There was a difference in the number density of nSCs not abutting to nerve fibres between the groups (p=0.004) but not in the number density of nSCs abutting to nerve fibres, nor in solitary or total subepidermal SC soma number density. The overall dermal SC expression (measured by dermal SC area fraction and subepidermal SC process density) and peripheral nerve fibre expression (measured by intraepidermal nerve fibre density, dermal nerve fibre area fraction and subepidermal nerve fibre density) differed between the groups (all p<0.05): significant differences were seen in participants with T1DPN and P-T1DPN compared with those without diabetic polyneuropathy (healthy control and T1D groups) (all p<0.05). No difference was found between participants in the T1DPN and P-T1DPN group, nor between participants in the T1D and healthy control group (all p>0.05). Correlational analysis showed that cutaneous SC processes and nerve fibres were highly associated, and they were weakly negatively correlated with different neuropathy measures.
CONCLUSIONS/INTERPRETATION
Cutaneous SC processes and nerves, but not SC soma, are degenerated and interdependent in individuals with diabetic polyneuropathy. However, an increase in structurally damaged nSCs was seen in individuals with diabetic polyneuropathy. Furthermore, dermal SC processes and nerve fibres correlate weakly with clinical measures of neuropathy and may play a partial role in the pathophysiology of diabetic polyneuropathy in type 1 diabetes.
Topics: Humans; Diabetic Neuropathies; Diabetes Mellitus, Type 1; Nerve Fibers; Peripheral Nerves; Schwann Cells
PubMed: 37728731
DOI: 10.1007/s00125-023-06009-z -
Cell Death & Disease Sep 2023Hearing loss (HL) is the most common and heterogeneous disorder of the sensory system, with a large morbidity in the worldwide population. Among cells of the acoustic... (Review)
Review
Hearing loss (HL) is the most common and heterogeneous disorder of the sensory system, with a large morbidity in the worldwide population. Among cells of the acoustic nerve (VIII cranial nerve), in the cochlea are present the hair cells, the spiral ganglion neurons, the glia-like supporting cells, and the Schwann cells (SCs), which alterations have been considered cause of HL. Notably, a benign SC-derived tumor of the acoustic nerve, named vestibular schwannoma (VS), has been indicated as cause of HL. Importantly, SCs are the main glial cells ensheathing axons and forming myelin in the peripheral nerves. Following an injury, the SCs reprogram, expressing some stemness features. Despite the mechanisms and factors controlling their biological processes (i.e., proliferation, migration, differentiation, and myelination) have been largely unveiled, their role in VS and HL was poorly investigated. In this review, we enlighten some of the mechanisms at the base of SCs transformation, VS development, and progression, likely leading to HL, and we pose great attention on the environmental factors that, in principle, could contribute to HL onset or progression. Combining the biomolecular bench-side approach to the clinical bedside practice may be helpful for the diagnosis, prediction, and therapeutic approach in otology.
Topics: Humans; Neuroma, Acoustic; Hearing Loss; Deafness; Schwann Cells; Neuroglia
PubMed: 37741837
DOI: 10.1038/s41419-023-06141-z -
Nature Communications Dec 2023The complex neuromuscular network that controls body movements is the target of severe diseases that result in paralysis and death. Here, we report the development of a...
The complex neuromuscular network that controls body movements is the target of severe diseases that result in paralysis and death. Here, we report the development of a robust and efficient self-organizing neuromuscular junction (soNMJ) model from human pluripotent stem cells that can be maintained long-term in simple adherent conditions. The timely application of specific patterning signals instructs the simultaneous development and differentiation of position-specific brachial spinal neurons, skeletal muscles, and terminal Schwann cells. High-content imaging reveals self-organized bundles of aligned muscle fibers surrounded by innervating motor neurons that form functional neuromuscular junctions. Optogenetic activation and pharmacological interventions show that the spinal neurons actively instruct the synchronous skeletal muscle contraction. The generation of a soNMJ model from spinal muscular atrophy patient-specific iPSCs reveals that the number of NMJs and muscle contraction is severely affected, resembling the patient's pathology. In the future, the soNMJ model could be used for high-throughput studies in disease modeling and drug development. Thus, this model will allow us to address unmet needs in the neuromuscular disease field.
Topics: Humans; Neuromuscular Junction; Motor Neurons; Muscle Fibers, Skeletal; Muscular Atrophy, Spinal; Muscle, Skeletal; Induced Pluripotent Stem Cells
PubMed: 38114482
DOI: 10.1038/s41467-023-43781-3 -
Biology Open Oct 2023The central and peripheral nervous systems (CNS and PNS, respectively) are two separate yet connected domains characterized by molecularly distinct cellular components... (Review)
Review
The central and peripheral nervous systems (CNS and PNS, respectively) are two separate yet connected domains characterized by molecularly distinct cellular components that communicate via specialized structures called transition zones to allow information to travel from the CNS to the periphery, and vice versa. Until recently, nervous system transition zones were thought to be selectively permeable only to axons, and the establishment of the territories occupied by glial cells at these complex regions remained poorly described and not well understood. Recent work now demonstrates that transition zones are occupied by dynamic glial cells and are precisely regulated over the course of nervous system development. This review highlights recent work on glial cell migration in and out of the spinal cord, at motor exit point (MEP) and dorsal root entry zone (DREZ) transition zones, in the physiological and diseased nervous systems. These cells include myelinating glia (oligodendrocyte lineage cells, Schwann cells and motor exit point glia), exit glia, perineurial cells that form the perineurium along spinal nerves, as well as professional and non-professional phagocytes (microglia and neural crest cells).
Topics: Neuroglia; Spinal Cord; Schwann Cells; Axons; Neurogenesis
PubMed: 37787575
DOI: 10.1242/bio.060037 -
Cell Reports Nov 2023Schwann cells respond to acute axon damage by transiently transdifferentiating into specialized repair cells that restore sensorimotor function. However, the molecular...
Schwann cells respond to acute axon damage by transiently transdifferentiating into specialized repair cells that restore sensorimotor function. However, the molecular systems controlling repair cell formation and function are not well defined, and consequently, it is unclear whether this form of cellular plasticity has a role in peripheral neuropathies. Here, we identify Mitf as a transcriptional sensor of axon damage under the control of Nrg-ErbB-PI3K-PI5K-mTorc2 signaling. Mitf regulates a core transcriptional program for generating functional repair Schwann cells following injury and during peripheral neuropathies caused by CMT4J and CMT4D. In the absence of Mitf, core genes for epithelial-to-mesenchymal transition, metabolism, and dedifferentiation are misexpressed, and nerve repair is disrupted. Our findings demonstrate that Schwann cells monitor axonal health using a phosphoinositide signaling system that controls Mitf nuclear localization, which is critical for activating cellular plasticity and counteracting neural disease.
Topics: Humans; Peripheral Nervous System Diseases; Schwann Cells; Axons; Signal Transduction; Cell Plasticity; Nerve Regeneration; Peripheral Nerve Injuries; Sciatic Nerve
PubMed: 38007688
DOI: 10.1016/j.celrep.2023.113282 -
Neural Regeneration Research Feb 2024Injuries caused by trauma and neurodegenerative diseases can damage the peripheral nervous system and cause functional deficits. Unlike in the central nervous system,... (Review)
Review
Injuries caused by trauma and neurodegenerative diseases can damage the peripheral nervous system and cause functional deficits. Unlike in the central nervous system, damaged axons in peripheral nerves can be induced to regenerate in response to intrinsic cues after reprogramming or in a growth-promoting microenvironment created by Schwann cells. However, axon regeneration and repair do not automatically result in the restoration of function, which is the ultimate therapeutic goal but also a major clinical challenge. Transforming growth factor (TGF) is a multifunctional cytokine that regulates various biological processes including tissue repair, embryo development, and cell growth and differentiation. There is accumulating evidence that TGF-β family proteins participate in peripheral nerve repair through various factors and signaling pathways by regulating the growth and transformation of Schwann cells; recruiting specific immune cells; controlling the permeability of the blood-nerve barrier, thereby stimulating axon growth; and inhibiting remyelination of regenerated axons. TGF-β has been applied to the treatment of peripheral nerve injury in animal models. In this context, we review the functions of TGF-β in peripheral nerve regeneration and potential clinical applications.
PubMed: 37488894
DOI: 10.4103/1673-5374.377588 -
Cells Apr 2024Neurofibromatosis 1 (NF1) is a multisymptomatic disorder with highly variable presentations, which include short stature, susceptibility to formation of the... (Review)
Review
Neurofibromatosis 1 (NF1) is a multisymptomatic disorder with highly variable presentations, which include short stature, susceptibility to formation of the characteristic benign tumors known as neurofibromas, intense freckling and skin discoloration, and cognitive deficits, which characterize most children with the condition. Attention deficits and Autism Spectrum manifestations augment the compromised learning presented by most patients, leading to behavioral problems and school failure, while fragmented sleep contributes to chronic fatigue and poor quality of life. Neurofibromin (Nf1) is present ubiquitously during human development and postnatally in most neuronal, oligodendrocyte, and Schwann cells. Evidence largely from animal models including suggests that the symptomatic variability may reflect distinct cell-type-specific functions of the protein, which emerge upon its loss, or mutations affecting the different functional domains of the protein. This review summarizes the contributions of in modeling multiple NF1 manifestations, addressing hypotheses regarding the cell-type-specific functions of the protein and exploring the molecular pathways affected upon loss of the highly conserved fly homolog dNf1. Collectively, work in this model not only has efficiently and expediently modelled multiple aspects of the condition and increased understanding of its behavioral manifestations, but also has led to pharmaceutical strategies towards their amelioration.
Topics: Animals; Neurofibromatosis 1; Disease Models, Animal; Humans; Drosophila melanogaster; Drosophila Proteins; Neurofibromin 1; Drosophila
PubMed: 38667335
DOI: 10.3390/cells13080721 -
Progress in Neurobiology Aug 2023Myelin improves axonal conduction velocity and is essential for nerve development and regeneration. In peripheral nerves, Schwann cells depend on bidirectional...
Myelin improves axonal conduction velocity and is essential for nerve development and regeneration. In peripheral nerves, Schwann cells depend on bidirectional mechanical and biochemical signaling to form the myelin sheath but the mechanism underlying this process is not understood. Rho GTPases are integrators of "outside-in" signaling that link cytoskeletal dynamics with cellular architecture to regulate morphology and adhesion. Using Schwann cell-specific gene inactivation in the mouse, we discovered that RhoA promotes the initiation of myelination, and is required to both drive and terminate myelin growth at different stages of peripheral myelination, suggesting developmentally-specific modes of action. In Schwann cells, RhoA targets actin filament turnover, via Cofilin 1, actomyosin contractility and cortical actin-membrane attachments. This mechanism couples actin cortex mechanics with the molecular organization of the cell boundary to target specific signaling networks that regulate axon-Schwann cell interaction/adhesion and myelin growth. This work shows that RhoA is a key component of a biomechanical response required to control Schwann cell state transitions for proper myelination of peripheral nerves.
Topics: Mice; Animals; Actins; Schwann Cells; Myelin Sheath; Peripheral Nerves; Axons
PubMed: 37315917
DOI: 10.1016/j.pneurobio.2023.102481 -
International Journal of Molecular... Nov 2023A diverse array of neurological and psychiatric disorders, including multiple sclerosis, Alzheimer's disease, and schizophrenia, exhibit distinct myelin abnormalities at... (Review)
Review
A diverse array of neurological and psychiatric disorders, including multiple sclerosis, Alzheimer's disease, and schizophrenia, exhibit distinct myelin abnormalities at both the molecular and histological levels. These aberrations are closely linked to dysfunction of oligodendrocytes and alterations in myelin structure, which may be pivotal factors contributing to the disconnection of brain regions and the resulting characteristic clinical impairments observed in these conditions. Astrocytes, which significantly outnumber neurons in the central nervous system by a five-to-one ratio, play indispensable roles in the development, maintenance, and overall well-being of neurons and oligodendrocytes. Consequently, they emerge as potential key players in the onset and progression of a myriad of neurological and psychiatric disorders. Furthermore, targeting astrocytes represents a promising avenue for therapeutic intervention in such disorders. To gain deeper insights into the functions of astrocytes in the context of myelin-related disorders, it is imperative to employ appropriate in vivo models that faithfully recapitulate specific aspects of complex human diseases in a reliable and reproducible manner. One such model is the cuprizone model, wherein metabolic dysfunction in oligodendrocytes initiates an early response involving microglia and astrocyte activation, culminating in multifocal demyelination. Remarkably, following the cessation of cuprizone intoxication, a spontaneous process of endogenous remyelination occurs. In this review article, we provide a historical overview of studies investigating the responses and putative functions of astrocytes in the cuprizone model. Following that, we list previously published works that illuminate various aspects of the biology and function of astrocytes in this multiple sclerosis model. Some of the studies are discussed in more detail in the context of astrocyte biology and pathology. Our objective is twofold: to provide an invaluable overview of this burgeoning field, and, more importantly, to inspire fellow researchers to embark on experimental investigations to elucidate the multifaceted functions of this pivotal glial cell subpopulation.
Topics: Humans; Animals; Mice; Cuprizone; Demyelinating Diseases; Astrocytes; Myelin Sheath; Oligodendroglia; Multiple Sclerosis; Microglia; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 38003609
DOI: 10.3390/ijms242216420