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Neuro-mesodermal assembloids recapitulate aspects of peripheral nervous system development in vitro.Stem Cell Reports May 2023Here we describe a novel neuro-mesodermal assembloid model that recapitulates aspects of peripheral nervous system (PNS) development such as neural crest cell (NCC)...
Here we describe a novel neuro-mesodermal assembloid model that recapitulates aspects of peripheral nervous system (PNS) development such as neural crest cell (NCC) induction, migration, and sensory as well as sympathetic ganglion formation. The ganglia send projections to the mesodermal as well as neural compartment. Axons in the mesodermal part are associated with Schwann cells. In addition, peripheral ganglia and nerve fibers interact with a co-developing vascular plexus, forming a neurovascular niche. Finally, developing sensory ganglia show response to capsaicin indicating their functionality. The presented assembloid model could help to uncover mechanisms of human NCC induction, delamination, migration, and PNS development. Moreover, the model could be used for toxicity screenings or drug testing. The co-development of mesodermal and neuroectodermal tissues and a vascular plexus along with a PNS allows us to investigate the crosstalk between neuroectoderm and mesoderm and between peripheral neurons/neuroblasts and endothelial cells.
Topics: Humans; Endothelial Cells; Neural Stem Cells; Schwann Cells; Axons; Mesoderm; Neural Crest
PubMed: 37084722
DOI: 10.1016/j.stemcr.2023.03.012 -
Brain Research Bulletin Sep 2022In December 2019, the novel coronavirus disease (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection broke. With the gradual... (Review)
Review
In December 2019, the novel coronavirus disease (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection broke. With the gradual deepening understanding of SARS-CoV-2 and COVID-19, researchers and clinicians noticed that this disease is closely related to the nervous system and has complex effects on the central nervous system (CNS) and peripheral nervous system (PNS). In this review, we summarize the effects and mechanisms of SARS-CoV-2 on the nervous system, including the pathways of invasion, direct and indirect effects, and associated neuropsychiatric diseases, to deepen our knowledge and understanding of the relationship between COVID-19 and the nervous system.
Topics: COVID-19; Central Nervous System; Humans; Nervous System Diseases; Peripheral Nervous System; SARS-CoV-2
PubMed: 35772604
DOI: 10.1016/j.brainresbull.2022.06.014 -
International Journal of Molecular... Jun 2020We studied telocytes/CD34+ stromal cells in the normal and pathological peripheral nervous system (PNS), for which we reviewed the literature and contributed our... (Review)
Review
We studied telocytes/CD34+ stromal cells in the normal and pathological peripheral nervous system (PNS), for which we reviewed the literature and contributed our observations under light and electron microscopy in this field. We consider the following aspects: (A) general characteristics of telocytes and the terminology used for these cells (e.g., endoneurial stromal cells) in PNS; (B) the presence, characteristics and arrangement of telocytes in the normal PNS, including (i) nerve epi-perineurium and endoneurium (e.g., telopodes extending into the endoneurial space); (ii) sensory nerve endings (e.g., Meissner and Pacinian corpuscles, and neuromuscular spindles); (iii) ganglia; and (iv) the intestinal autonomic nervous system; (C) the telocytes in the pathologic PNS, encompassing (i) hyperplastic neurogenic processes (neurogenic hyperplasia of the appendix and gallbladder), highly demonstrative of telocyte characteristics and relations, (ii) PNS tumours, such as neurofibroma, schwannoma, granular cell tumour and nerve sheath myxoma, and interstitial cell of Cajal-related gastrointestinal stromal tumour (GIST), (iii) tumour-invaded nerves and (iv) traumatic, metabolic, degenerative or genetic neuropathies, in which there are fewer studies on telocytes, e.g., neuroinflammation and nerves in undescended testicles (cryptorchidism), Klinefelter syndrome, crush injury, mucopolysaccharidosis II (Hunter's syndrome) and Charcot-Marie-Tooth disease.
Topics: Animals; Biomarkers; Disease Susceptibility; Humans; Immunohistochemistry; Nerve Endings; Peripheral Nervous System; Peripheral Nervous System Diseases; Telocytes
PubMed: 32560571
DOI: 10.3390/ijms21124320 -
Glia Aug 2021To facilitate analyses of purinergic signaling in peripheral nerve glia, we review recent literature and catalog purinergic receptor mRNA expression in cultured mouse... (Review)
Review
To facilitate analyses of purinergic signaling in peripheral nerve glia, we review recent literature and catalog purinergic receptor mRNA expression in cultured mouse Schwann cells (SCs). Purinergic signaling can decrease developmental SC proliferation, and promote SC differentiation. The purinergic receptors P2RY2 and P2RX7 are implicated in nerve development and in the ratio of Remak SCs to myelinating SCs in differentiated peripheral nerve. P2RY2, P2RX7, and other receptors are also implicated in peripheral neuropathies and SC tumors. In SC tumors lacking the tumor suppressor NF1, the SC pathway that suppresses SC growth through P2RY2-driven β-arrestin-mediated AKT signaling is aberrant. SC-released purinergic agonists acting through SC and/or neuronal purinergic receptors activate pain responses. In all these settings, purinergic receptor activation can result in calcium-independent and calcium-dependent release of SC ATP and UDP, growth factors, and cytokines that may contribute to disease and nerve repair. Thus, current research suggests that purinergic agonists and/or antagonists might have the potential to modulate peripheral glia function in development and in disease.
Topics: Animals; Mice; Neuroglia; Peripheral Nervous System Diseases; Receptors, Purinergic; Schwann Cells; Signal Transduction
PubMed: 33507559
DOI: 10.1002/glia.23969 -
Cold Spring Harbor Perspectives in... Dec 2019The peripheral nervous system (PNS) is highly complicated and heterogenous. Conventional neuromodulatory approaches have revealed numerous essential biological functions... (Review)
Review
The peripheral nervous system (PNS) is highly complicated and heterogenous. Conventional neuromodulatory approaches have revealed numerous essential biological functions of the PNS and provided excellent tools to treat a large variety of human diseases. Yet growing evidence indicated the importance of cell-type-specific neuromodulation in the PNS in not only biological research using animal models but also potential human therapies. Optogenetics is a recently developed neuromodulatory approach combining optics and genetics that can effectively stimulate or silence neuronal activity with high spatial and temporal precision. Here, I review research regarding optogenetic manipulations for cell-type-specific control of the PNS, highlighting the advantages and challenges of current optogenetic tools, and discuss their potential future applications.
Topics: Animals; Animals, Genetically Modified; Humans; Neurons; Optogenetics; Peripheral Nervous System
PubMed: 30745289
DOI: 10.1101/cshperspect.a034397 -
Proceedings of the National Academy of... Apr 2023Fibromyalgia is a debilitating widespread chronic pain syndrome that occurs in 2 to 4% of the population. The prevailing view that fibromyalgia results from central...
Fibromyalgia is a debilitating widespread chronic pain syndrome that occurs in 2 to 4% of the population. The prevailing view that fibromyalgia results from central nervous system dysfunction has recently been challenged with data showing changes in peripheral nervous system activity. Using a mouse model of chronic widespread pain through hyperalgesic priming of muscle, we show that neutrophils invade sensory ganglia and confer mechanical hypersensitivity on recipient mice, while adoptive transfer of immunoglobulin, serum, lymphocytes, or monocytes has no effect on pain behavior. Neutrophil depletion abolishes the establishment of chronic widespread pain in mice. Neutrophils from patients with fibromyalgia also confer pain on mice. A link between neutrophil-derived mediators and peripheral nerve sensitization is already established. Our observations suggest approaches for targeting fibromyalgia pain via mechanisms that cause altered neutrophil activity and interactions with sensory neurons.
Topics: Humans; Chronic Pain; Fibromyalgia; Neutrophils; Hyperalgesia; Ganglia, Sensory
PubMed: 37071676
DOI: 10.1073/pnas.2211631120 -
Cells Feb 2021Surgery remains an essential therapeutic approach for most solid malignancies. Although for more than a century accumulating clinical and experimental data have... (Review)
Review
Surgery remains an essential therapeutic approach for most solid malignancies. Although for more than a century accumulating clinical and experimental data have indicated that surgical procedures themselves may promote the appearance and progression of recurrent and metastatic lesions, only in recent years has renewed interest been taken in the mechanism by which metastasizing of cancer occurs following operative procedures. It is well proven now that surgery constitutes a risk factor for the promotion of pre-existing, possibly dormant micrometastases and the acceleration of new metastases through several mechanisms, including the release of neuroendocrine and stress hormones and wound healing pathway-associated immunosuppression, neovascularization, and tissue remodeling. These postoperative consequences synergistically facilitate the establishment of new metastases and the development of pre-existing micrometastases. While only in recent years the role of the peripheral nervous system has been recognized as another contributor to cancer development and metastasis, little is known about the contribution of tumor-associated neuronal and neuroglial elements in the metastatic disease related to surgical trauma and wound healing. Specifically, although numerous clinical and experimental data suggest that biopsy- and surgery-induced wound healing can promote survival and metastatic spread of residual and dormant malignant cells, the involvement of the tumor-associated neuroglial cells in the formation of metastases following tissue injury has not been well understood. Understanding the clinical significance and underlying mechanisms of neuroimmune regulation of surgery-associated metastasis will not only advance the field of neuro-immuno-oncology and contribute to basic science and translational oncology research but will also produce a strong foundation for developing novel mechanism-based therapeutic approaches that may protect patients against the oncologically adverse effects of primary tumor biopsy and excision.
Topics: Animals; Disease Progression; Humans; Neoplasm Metastasis; Neoplasms; Nervous System; Peripheral Nervous System; Surgical Procedures, Operative
PubMed: 33672617
DOI: 10.3390/cells10020454 -
International Journal of Molecular... Feb 2021Pain can be induced by tissue injuries, diseases and infections. The interactions between the peripheral nervous system (PNS) and immune system are primary actions in... (Review)
Review
Pain can be induced by tissue injuries, diseases and infections. The interactions between the peripheral nervous system (PNS) and immune system are primary actions in pain sensitizations. In response to stimuli, nociceptors release various mediators from their terminals that potently activate and recruit immune cells, whereas infiltrated immune cells further promote sensitization of nociceptors and the transition from acute to chronic pain by producing cytokines, chemokines, lipid mediators and growth factors. Immune cells not only play roles in pain production but also contribute to PNS repair and pain resolution by secreting anti-inflammatory or analgesic effectors. Here, we discuss the distinct roles of four major types of immune cells (monocyte/macrophage, neutrophil, mast cell, and T cell) acting on the PNS during pain process. Integration of this current knowledge will enhance our understanding of cellular changes and molecular mechanisms underlying pain pathogenies, providing insights for developing new therapeutic strategies.
Topics: Animals; Chronic Pain; Humans; Immune System; Inflammation; Macrophages; Mast Cells; Mice; Monocytes; Neuroimmunomodulation; Neutrophils; Nociception; Pain Management; Peripheral Nervous System; Signal Transduction; T-Lymphocytes
PubMed: 33535595
DOI: 10.3390/ijms22031448 -
The Indian Journal of Medical ResearchThe COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been predominantly a respiratory manifestation. Currently, with... (Review)
Review
The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been predominantly a respiratory manifestation. Currently, with evolving literature, neurological signs are being increasingly recognized. Studies have reported that SARS-CoV-2 affects all aspects of the nervous system including the central nervous system (CNS), peripheral nervous system (PNS) and the muscular system as well. Not all patients have reverse transcription-polymerase chain reaction positive for the virus in the cerebrospinal fluid, and diagnosing the association of the virus with the myriad of neurological manifestations can be a challenge. It is important that clinicians have a high-index of suspicion for COVID-19 in patients presenting with new-onset neurological symptoms. This will lead to early diagnosis and specific management. Further studies are desired to unravel the varied neurological manifestations, treatment, outcome and long-term sequel in COVID-19 patients.
Topics: Betacoronavirus; COVID-19; Central Nervous System; Coronavirus Infections; Humans; Muscle, Skeletal; Nervous System Diseases; Pandemics; Peripheral Nervous System; Pneumonia, Viral; SARS-CoV-2
PubMed: 32859864
DOI: 10.4103/ijmr.IJMR_1395_20 -
Neuroscience Letters Nov 2021Our ability to quickly detect and respond to harmful environmental stimuli is vital for our safety and survival. This inherent acute pain detection is a "gift" because... (Review)
Review
Our ability to quickly detect and respond to harmful environmental stimuli is vital for our safety and survival. This inherent acute pain detection is a "gift" because it both protects our body from harm and allows healing of damaged tissues [1]. Damage to tissues from trauma or disease can result in distorted or amplified nociceptor signaling and sensitization of the spinal cord and brain (Central Nervous System; CNS) pathways to normal input from light touch mechanoreceptors. Together, these processes can result in nagging to unbearable chronic pain and extreme sensitivity to light skin touch (allodynia). Unlike acute protective pain, chronic pain and allodynia serve no useful purpose and can severely reduce the quality of life of an affected person. Chronic pain can arise from impairment to peripheral neurons, a phenomenon called "peripheral neuropathic pain." Peripheral neuropathic pain can be caused by many insults that directly affect peripheral sensory neurons, including mechanical trauma, metabolic imbalance (e.g., diabetes), autoimmune diseases, chemotherapeutic agents, viral infections (e.g., shingles). These insults cause "acquired" neuropathies such as small-fiber neuropathies, diabetic neuropathy, chemotherapy-induced peripheral neuropathy, and post herpetic neuralgia. Peripheral neuropathic pain can also be caused by genetic factors and result in hereditary neuropathies that include Charcot-Marie-Tooth disease, rare channelopathies and Fabry disease. Many acquired and hereditary neuropathies affect the skin, our largest organ and protector of nearly our entire body. Here we review how cutaneous nociception (pain perceived from the skin) is altered following diseases that affect peripheral nerves that innervate the skin. We provide an overview of how noxious stimuli are detected and encoded by molecular transducers on subtypes of cutaneous afferent endings and conveyed to the CNS. Next, we discuss several acquired and hereditary diseases and disorders that cause painful or insensate (lack of sensation) cutaneous peripheral neuropathies, the symptoms and percepts patients experience, and how cutaneous afferents and other peripheral cell types are altered in function in these disorders. We highlight exciting new research areas that implicate non-neuronal skin cells, particularly keratinocytes, in cutaneous nociception and peripheral neuropathies. Finally, we conclude with ideas for innovative new directions, areas of unmet need, and potential opportunities for novel cutaneous therapeutics that may avoid CNS side effects, as well as ideas for improved translation of mechanisms identified in preclinical models to patients.
Topics: Animals; Cell Communication; Disease Models, Animal; Humans; Keratinocytes; Nociception; Nociceptors; Pain; Peripheral Nerves; Peripheral Nervous System Diseases; Schwann Cells; Skin
PubMed: 34506882
DOI: 10.1016/j.neulet.2021.136233