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Genes & Diseases Jan 2024Adhesion G protein-coupled receptors (aGPCRs) are the second largest diverse group within the GPCR superfamily, which play critical roles in many physiological and... (Review)
Review
Adhesion G protein-coupled receptors (aGPCRs) are the second largest diverse group within the GPCR superfamily, which play critical roles in many physiological and pathological processes through cell-cell and cell-extracellular matrix interactions. The adhesion GPCR Adgrg6, also known as GPR126, is one of the better-characterized aGPCRs. GPR126 was previously found to have critical developmental roles in Schwann cell maturation and its mediated myelination in the peripheral nervous system in both zebrafish and mammals. Current studies have extended our understanding of GPR126-mediated roles during development and in human diseases. In this review, we highlighted these recent advances in GPR126 in expression profile, molecular structure, ligand-receptor interactions, and associated physiological and pathological functions in development and diseases.
PubMed: 37588228
DOI: 10.1016/j.gendis.2023.02.016 -
Stem Cell Research & Therapy Sep 2023Peripheral nerve injury (PNI) is one of the public health concerns that can result in a loss of sensory or motor function in the areas in which injured and non-injured... (Review)
Review
Peripheral nerve injury (PNI) is one of the public health concerns that can result in a loss of sensory or motor function in the areas in which injured and non-injured nerves come together. Up until now, there has been no optimized therapy for complete nerve regeneration after PNI. Exosome-based therapies are an emerging and effective therapeutic strategy for promoting nerve regeneration and functional recovery. Exosomes, as natural extracellular vesicles, contain bioactive molecules for intracellular communications and nervous tissue function, which could overcome the challenges of cell-based therapies. Furthermore, the bioactivity and ability of exosomes to deliver various types of agents, such as proteins and microRNA, have made exosomes a potential approach for neurotherapeutics. However, the type of cell origin, dosage, and targeted delivery of exosomes still pose challenges for the clinical translation of exosome therapeutics. In this review, we have focused on Schwann cell and mesenchymal stem cell (MSC)-derived exosomes in nerve tissue regeneration. Also, we expressed the current understanding of MSC-derived exosomes related to nerve regeneration and provided insights for developing a cell-free MSC therapeutic strategy for nerve injury.
Topics: Humans; Peripheral Nerve Injuries; Extracellular Vesicles; Exosomes; Cell- and Tissue-Based Therapy; Mesenchymal Stem Cells
PubMed: 37726794
DOI: 10.1186/s13287-023-03467-5 -
Neural Regeneration Research Jul 2024Runx2 is a major regulator of osteoblast differentiation and function; however, the role of Runx2 in peripheral nerve repair is unclear. Here, we analyzed Runx2...
Runx2 is a major regulator of osteoblast differentiation and function; however, the role of Runx2 in peripheral nerve repair is unclear. Here, we analyzed Runx2 expression following injury and found that it was specifically up-regulated in Schwann cells. Furthermore, using Schwann cell-specific Runx2 knockout mice, we studied peripheral nerve development and regeneration and found that multiple steps in the regeneration process following sciatic nerve injury were Runx2-dependent. Changes observed in Runx2 knockout mice include increased proliferation of Schwann cells, impaired Schwann cell migration and axonal regrowth, reduced re-myelination of axons, and a block in macrophage clearance in the late stage of regeneration. Taken together, our findings indicate that Runx2 is a key regulator of Schwann cell plasticity, and therefore peripheral nerve repair. Thus, our study shows that Runx2 plays a major role in Schwann cell migration, re-myelination, and peripheral nerve functional recovery following injury.
PubMed: 38051902
DOI: 10.4103/1673-5374.387977 -
International Journal of Molecular... Dec 2023Exosomes are nanoscale-sized membrane vesicles released by cells into their extracellular milieu. Within these nanovesicles reside a multitude of bioactive molecules,... (Review)
Review
Exosomes are nanoscale-sized membrane vesicles released by cells into their extracellular milieu. Within these nanovesicles reside a multitude of bioactive molecules, which orchestrate essential biological processes, including cell differentiation, proliferation, and survival, in the recipient cells. These bioactive properties of exosomes render them a promising choice for therapeutic use in the realm of tissue regeneration and repair. Exosomes possess notable positive attributes, including a high bioavailability, inherent safety, and stability, as well as the capacity to be functionalized so that drugs or biological agents can be encapsulated within them or to have their surface modified with ligands and receptors to imbue them with selective cell or tissue targeting. Remarkably, their small size and capacity for receptor-mediated transcytosis enable exosomes to cross the blood-brain barrier (BBB) and access the central nervous system (CNS). Unlike cell-based therapies, exosomes present fewer ethical constraints in their collection and direct use as a therapeutic approach in the human body. These advantageous qualities underscore the vast potential of exosomes as a treatment option for neurological injuries and diseases, setting them apart from other cell-based biological agents. Considering the therapeutic potential of exosomes, the current review seeks to specifically examine an area of investigation that encompasses the development of Schwann cell (SC)-derived exosomal vesicles (SCEVs) as an approach to spinal cord injury (SCI) protection and repair. SCs, the myelinating glia of the peripheral nervous system, have a long history of demonstrated benefit in repair of the injured spinal cord and peripheral nerves when transplanted, including their recent advancement to clinical investigations for feasibility and safety in humans. This review delves into the potential of utilizing SCEVs as a therapy for SCI, explores promising engineering strategies to customize SCEVs for specific actions, and examines how SCEVs may offer unique clinical advantages over SC transplantation for repair of the injured spinal cord.
Topics: Humans; Spinal Cord; Spinal Cord Injuries; Schwann Cells; Peripheral Nerves; Neuroglia; Exosomes
PubMed: 38139147
DOI: 10.3390/ijms242417317 -
Neural Regeneration Research Jul 2023Charcot-Marie-Tooth neuropathies (CMT) constitute a group of common but highly heterogeneous, non-syndromic genetic disorders affecting predominantly the peripheral... (Review)
Review
Charcot-Marie-Tooth neuropathies (CMT) constitute a group of common but highly heterogeneous, non-syndromic genetic disorders affecting predominantly the peripheral nervous system. CMT type 1A (CMT1A) is the most frequent type and accounts for almost ~50% of all diagnosed CMT cases. CMT1A results from the duplication of the peripheral myelin protein 22 (PMP22) gene. Overexpression of PMP22 protein overloads the protein folding apparatus in Schwann cells and activates the unfolded protein response. This leads to Schwann cell apoptosis, dys- and de- myelination and secondary axonal degeneration, ultimately causing neurological disabilities. During the last decades, several different gene therapies have been developed to treat CMT1A. Almost all of them remain at the pre-clinical stage using CMT1A animal models overexpressing PMP22. The therapeutic goal is to achieve gene silencing, directly or indirectly, thereby reversing the CMT1A genetic mechanism allowing the recovery of myelination and prevention of axonal loss. As promising treatments are rapidly emerging, treatment-responsive and clinically relevant biomarkers are becoming necessary. These biomarkers and sensitive clinical evaluation tools will facilitate the design and successful completion of future clinical trials for CMT1A.
PubMed: 36571339
DOI: 10.4103/1673-5374.361538 -
EMBO Molecular Medicine Dec 2023Following peripheral nerve injury, successful axonal growth and functional recovery require Schwann cell (SC) reprogramming into a reparative phenotype, a process...
Following peripheral nerve injury, successful axonal growth and functional recovery require Schwann cell (SC) reprogramming into a reparative phenotype, a process dependent upon c-Jun transcription factor activation. Unfortunately, axonal regeneration is greatly impaired in aged organisms and following chronic denervation, which can lead to poor clinical outcomes. While diminished c-Jun expression in SCs has been associated with regenerative failure, it is unclear whether the inability to maintain a repair state is associated with the transition into an axonal growth inhibition phenotype. We here find that reparative SCs transition into a senescent phenotype, characterized by diminished c-Jun expression and secretion of inhibitory factors for axonal regeneration in aging and chronic denervation. In both conditions, the elimination of senescent SCs by systemic senolytic drug treatment or genetic targeting improved nerve regeneration and functional recovery, increased c-Jun expression and decreased nerve inflammation. This work provides the first characterization of senescent SCs and their influence on axonal regeneration in aging and chronic denervation, opening new avenues for enhancing regeneration and functional recovery after peripheral nerve injuries.
Topics: Humans; Aged; Peripheral Nerve Injuries; Schwann Cells; Aging; Gene Expression Regulation; Denervation
PubMed: 37860842
DOI: 10.15252/emmm.202317907 -
Tissue Engineering and Regenerative... Oct 2023Peripheral nerve damage mainly resulted from traumatic or infectious causes; the main signs of a damaged nerve are the loss of sensory and/or motor functions. The... (Review)
Review
BACKGROUND
Peripheral nerve damage mainly resulted from traumatic or infectious causes; the main signs of a damaged nerve are the loss of sensory and/or motor functions. The injured nerve has limited regenerative capacity and is recovered by the body itself, the recovery process depends on the severity of damage to the nerve, nowadays the use of stem cells is one of the new and advanced methods for treatment of these problems.
METHOD
Following our review, data are collected from different databases "Google scholar, Springer, Elsevier, Egyptian Knowledge Bank, and PubMed" using different keywords such as Peripheral nerve damage, Radial Nerve, Sciatic Nerve, Animals, Nerve regeneration, and Stem cell to investigate the different methods taken in consideration for regeneration of PNI.
RESULT
This review contains tables illustrating all forms and types of regenerative medicine used in treatment of peripheral nerve injuries (PNI) including different types of stem cells " adipose-derived stem cells, bone marrow stem cells, Human umbilical cord stem cells, embryonic stem cells" and their effect on re-constitution and functional recovery of the damaged nerve which evaluated by physical, histological, Immuno-histochemical, biochemical evaluation, and the review illuminated the best regenerative strategies help in rapid peripheral nerve regeneration in different animal models included horse, dog, cat, sheep, monkey, pig, mice and rat.
CONCLUSION
Old surgical attempts such as neurorrhaphy, autogenic nerve transplantation, and Schwann cell implantation have a limited power of recovery in cases of large nerve defects. Stem cell therapy including mesenchymal stromal cells has a high potential differentiation capacity to renew and form a new nerve and also restore its function.
Topics: Rats; Mice; Humans; Animals; Dogs; Horses; Sheep; Swine; Peripheral Nerve Injuries; Mesenchymal Stem Cell Transplantation; Sciatic Nerve; Schwann Cells; Nerve Regeneration; Models, Animal
PubMed: 37572269
DOI: 10.1007/s13770-023-00559-4 -
IScience Jun 2024Establishing robust models of human myelinating Schwann cells is critical for studying peripheral nerve injury and disease. Stem cell differentiation has emerged as a...
Establishing robust models of human myelinating Schwann cells is critical for studying peripheral nerve injury and disease. Stem cell differentiation has emerged as a key human cell model and disease motivating development of Schwann cell differentiation protocols. Human embryonic stem cells (hESCs) are considered the ideal pluripotent cell but ethical concerns regarding their use have propelled the popularity of human induced pluripotent stem cells (hiPSCs). Given that the equivalence of hESCs and hiPSCs remains controversial, we sought to compare the molecular and functional equivalence of hESC- and hiPSC-derived Schwann cells generated with our previously reported protocol. We identified only modest transcriptome differences by RNA sequencing and insignificant proteome differences by antibody array. Additionally, both cell types comparably improved nerve regeneration and function in a chronic denervation and regeneration animal model. Our findings demonstrate that Schwann cells derived from hESCs and hiPSCs with our protocol are molecularly comparable and functionally equivalent.
PubMed: 38770143
DOI: 10.1016/j.isci.2024.109855 -
Cell Feb 2024Myelin, the insulating sheath that surrounds neuronal axons, is produced by oligodendrocytes in the central nervous system (CNS). This evolutionary innovation, which...
Myelin, the insulating sheath that surrounds neuronal axons, is produced by oligodendrocytes in the central nervous system (CNS). This evolutionary innovation, which first appears in jawed vertebrates, enabled rapid transmission of nerve impulses, more complex brains, and greater morphological diversity. Here, we report that RNA-level expression of RNLTR12-int, a retrotransposon of retroviral origin, is essential for myelination. We show that RNLTR12-int-encoded RNA binds to the transcription factor SOX10 to regulate transcription of myelin basic protein (Mbp, the major constituent of myelin) in rodents. RNLTR12-int-like sequences (which we name RetroMyelin) are found in all jawed vertebrates, and we further demonstrate their function in regulating myelination in two different vertebrate classes (zebrafish and frogs). Our study therefore suggests that retroviral endogenization played a prominent role in the emergence of vertebrate myelin.
Topics: Animals; Gene Expression; Myelin Sheath; Oligodendroglia; Retroelements; RNA; Zebrafish; Anura
PubMed: 38364788
DOI: 10.1016/j.cell.2024.01.011 -
Current Opinion in Cell Biology Feb 2024Multiple Sclerosis (MS) is a common cause of impairment in working-aged adults. MS is characterized by neuroinflammation and infiltration of peripheral immune cells to... (Review)
Review
Multiple Sclerosis (MS) is a common cause of impairment in working-aged adults. MS is characterized by neuroinflammation and infiltration of peripheral immune cells to the brain, which cause myelin loss and death of oligodendrocytes and neurons. Many studies on MS have focused on the peripheral immune sources of demyelination and repair. However, recent studies revealed that a glial cell type, the astrocytes, undergo robust morphological and transcriptomic changes that contribute significantly to demyelination and myelin repair. Here, we discuss recent findings elucidating signaling modalities that astrocytes acquire or lose in MS and how these changes alter the interactions of astrocytes with other nervous system cell types.
Topics: Humans; Multiple Sclerosis; Astrocytes; Myelin Sheath; Oligodendroglia; Neurons
PubMed: 38145604
DOI: 10.1016/j.ceb.2023.102307