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Glial cells are the most abundant cells in both the peripheral and central nervous systems. During the past decade, a subpopulation of immature peripheral glial cells, namely, embryonic Schwann cell-precursors, have been found to perform important functions related to development. These cells have properties resembling those of the neural crest and...
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Animal models are useful to study the molecular, cellular, and morphogenetic mechanisms underlying normal and pathological development. Cell‐based study models have emerged as an alternative approach to study many aspects of human embryonic development and disease. The neural crest (NC) is a transient, multipotent, and migratory embryonic cell popu...
Citations
... NT3 knockout mice lose over 70% of their neurons in the sensory ganglia, suggesting that NT3 is necessary for neuronal subpopulation survival (Krimm, Davis, Albers, 2000). The pattern of NT3 expression has been investigated, and it has been revealed that it is strongly expressed during rapid process phases growth in locations near growing ganglionic neurons and during glial cell development (Pöyhönen, Er, Domanskyi, Airavaara, 2019;Milichko Dyachuk, 2020). ...
... Nevertheless, similar to BDNF, NT4/5 enhances sensory neuron and retinal ganglion cell survival. NT4/5 also supports muscular activity and enhances the survival of motor neurons by promoting axonal sprouting (Houlton et al., 2019;Milichko Dyachuk, 2020). ...
... It has a vast range of actions, functioning on various neuronal populations. Glial cells, speci c astrocytes in the CNS and Schwann cells in the PNS, express the CNTF (Milichko Dyachuk, 2020). In the PNS, CNTF improves the survival of parasympathetic ganglionic neurons and sensory and sympathetic neurons (Milichko Dyachuk, 2020). ...
Growth factors play critical roles in the growth and maintenance of the nervous system. Their robust survival and functional capacities make them the “powerhouse” in both physiological and pathological processes in the peripheral and central nervous systems. Indeed, it has been proposed that the aberration in the expressions of the growth factors played significant roles in the pathogenesis of neurodegenerative diseases and psychiatric disorders, which makes them ideal therapeutic options. Despite the great interest in employing growth factors to prevent and/or mitigate the neurodegeneration and atrophy observed in experiments on these diseases, considerable challenges remain. Therefore, this chapter examines the role of growth factor members that bind to receptor tyrosine kinase and their partaking in neurodegeneration and provides roadmaps for future translational research.
... NT3 knockout mice lose over 70% of their neurons in the sensory ganglia, suggesting that NT3 is necessary for neuronal subpopulation survival (Krimm, Davis, Albers, 2000). The pattern of NT3 expression has been investigated, and it has been revealed that it is strongly expressed during rapid process phases growth in locations near growing ganglionic neurons and during glial cell development (Pöyhönen, Er, Domanskyi, Airavaara, 2019;Milichko Dyachuk, 2020). ...
... Nevertheless, similar to BDNF, NT4/5 enhances sensory neuron and retinal ganglion cell survival. NT4/5 also supports muscular activity and enhances the survival of motor neurons by promoting axonal sprouting (Houlton et al., 2019;Milichko Dyachuk, 2020). ...
... It has a vast range of actions, functioning on various neuronal populations. Glial cells, speci c astrocytes in the CNS and Schwann cells in the PNS, express the CNTF (Milichko Dyachuk, 2020). In the PNS, CNTF improves the survival of parasympathetic ganglionic neurons and sensory and sympathetic neurons (Milichko Dyachuk, 2020). ...
The majority fraction of growth factors exert their signaling through the cellular microenvironment (outer cell surface) and evoke responses with extensive involvement, particularly in the early stages of cellular development. A series of targeted ligands from the growth factor family bind to cell surface receptors, in the case of most receptors, via membrane spanning receptor tyrosine kinases. This eventually stimulates various cellular activities in the nervous system. Most growth factors are members of numerous superfamilies, including neurotrophins, transforming growth factor, neurokine, fibroblast growth factor, epidermal growth factor, insulin-like growth factor, and others.
RTK activation initiates signaling pathways that affect biological processes such as cell proliferation, differentiation, migration, and survival. Therefore, to prevent signaling errors, which may eventually lead to abnormal cellular activity and illness, cellular mechanisms have developed to secure that adequate signaling thresholds are established and maintained within the appropriate timespan. This prevents signaling errors, leading to abnormal cellular behavior and disease. RTK are proteins with inherent kinase activity and have a single transmembrane domain.
In response to ligand binding, the kinase is activated and autophosphorylates itself on tyrosine residues within the cytoplasmic tail. This creates docking sites for proteins containing phospho-tyrosine-binding domains and serves as the starting point for various signaling cascades regulating cellular functions.
... Recently, a study by Su D et al. (15) demonstrated that IL-1b secreted from pancreatic ductal adenocarcinoma cells led to aberrant activation of the NF-kB pathway in SCs in the interaction between pancreatic cancer and SCs. Indeed, SCs are remarkable in their ability to naturally (adaptively) reprogram and reprogram the surrounding environment (25). In our study, the classical inflammatory pathway NF-kB is activated in SCs among the TME of CRC and induced the enrichment of IL-8. ...
Background
Evidence has shown neurons and glial cells were closely related to tumor progression. As the predominant glial cells in the external innervated nerves of the gastrointestinal, the role of Schwann cells (SCs) in colorectal cancer (CRC) has not been well explored.
Methods
HCT-116 and HT-29 CRC cells were treated with conditioned medium (CM) from SCs, and the cells’ proliferative and migrating capacities were examined. Cytokine array analysis was used to identify the tumor-promoting-cytokines from SCs-CM. Molecular changes from SCs after being co-cultured with tumor cells were detected by ELISA and reverse transcription-quantitative PCR. The activation of the nuclear factor kappa B (NF-κB) signaling pathway in SCs was demonstrated by immunofluorescence staining. Neutralizing antibody was used to verify the tumor-promoting effects of key cytokine.
Results
Migration and invasion of CRC cells were markedly aided by CM from SCs in vitro. Interleukin-8 (IL-8) was identified as an effective factor. SCs co-cultured with CRC cells upregulated IL-8 expression, which may be related to its activated NF-κB signaling pathway. Neutralization of IL-8 attenuated the tumor-promoting effect of SCs.
Conclusion
The present study identified a new mechanism of tumor-neuroglia interaction, enriching the concept of the tumor-neural axis in the tumor microenvironment of CRC, which also inspired potential targets for anti-cancer therapies.
... Besides SGCs, SCs are also a much-touted cell type with stem cell properties in the peripheral nervous system. Increasing evidence suggests that SC precursors and even adult SCs can give rise to several cell types including those of parasympathetic ganglia during neurodevelopment as well as after injury, highlighting the broad developmental potential of these cells [80][81][82][83][84][85][86]. Studies showed that SC precursors, unlike SCs, die when separated from axons in vitro. ...
... Considering that SGCs are multipotent, these studies suggest that SGCs might represent a subpopulation of SC precursors; however, a recent singlecell RNA-sequencing study indicated that SGCs are molecularly distinct from SCs [9]. Studies also suggest that SGCs adopt the morphology of SCs when cultured for extended period of time [18, 28] and SCs exhibit, to some extent, plasticity upon nerve injury [84,92] raising an interesting possibility concerning the lineage of SGCs with respect to SC precursors or SCs. ...
Satellite glial cells (SGCs) that surround sensory neurons in the peripheral nervous system ganglia originate from neural crest cells. Although several studies have focused on SGCs, the origin and characteristics of SGCs are unknown, and their lineage remains unidentified. Traditionally, it has been considered that SGCs regulate the environment around neurons under pathological conditions, and perform functions of supporting, nourishing, and protecting neurons. However, recent studies demonstrated that SGCs may have the characteristics of stem cells. After nerve injury, SGCs up-regulate the expression of stem cell markers and can differentiate into functional sensory neurons. Moreover, SGCs express several markers of Schwann cell precursors and Schwann cells, such as CDH19, MPZ, PLP1, SOX10, ERBB3, and FABP7. Schwann cell precursors have also been proposed as a potential source of neurons in the peripheral nervous system. The similarity in function and markers suggests that SGCs may represent a subgroup of Schwann cell precursors. Herein, we discuss the roles and functions of SGCs, and the lineage relationship between SGCs and Schwann cell precursors. We also describe a new perspective on the roles and functions of SGCs.
Graphical Abstract
In the DRG located on the posterior root of spinal nerves, satellite glial cells wrap around each sensory neuron to form an anatomically and functionally distinct unit with the sensory neurons. Following nerve injury, satellite glial cells up-regulate the expression of progenitor markers, and can differentiate into neurons.
... Since EMID causes not only tissue injury but also nerve injury, naturally SCs should be viewed as a highvalue suspect in causing adenomyosis. Indeed, when peripheral nerves are injured, SCs can dedifferentiate et al. 2014), and parasympathetic, sympathetic, enteric, GABAergic, glycinergic, serotoninergic, and cholinergic neurons (Dyachuk et al. 2014, Espinosa-Medina et al. 2014, Su et al. 2014, Milichko & Dyachuk 2020. In view of their pleiotropic roles after injury, there is reason to believe that EMID may cause injury to peripheral nerves residing in the EMI region, resulting in SC dedifferentiation. ...
In brief
Traditionally viewed as enigmatic and elusive, adenomyosis is a fairly common gynecological disease but is under-recognized and under-researched. This review summarizes the latest development on the pathogenesis and pathophysiology of adenomyosis, which have important implications for imaging diagnosis of the disease and for the development of non-hormonal therapeutics.
Abstract
Traditionally considered as an enigmatic disease, adenomyosis is a uterine disease that affects many women of reproductive age and is a contributing factor for pelvic pain, heavy menstrual bleeding (HMB), and subfertility. In this review, the new development in the pathogenesis and pathophysiology of adenomyosis has been summarized, along with their clinical implications. After reviewing the progress in our understanding of the pathogenesis and describing the prevailing theories, in conjunction with their deficiencies, a new hypothesis, called endometrial–myometrial interface disruption (EMID), which is backed by extensive epidemiologic data and demonstrated by a mouse model, is reviewed, along with recent data implicating the role of Schwann cells in the EMI area in the genesis of adenomyosis. Additionally, the natural history of adenomyotic lesions is elaborated and underscores that, in essence, adenomyotic lesions are fundamentally wounds undergoing repeated tissue injury and repair (ReTIAR), which progress to fibrosis through epithelial–mesenchymal transition, fibroblast-to-myofibroblast transdifferentiation, and smooth muscle metaplasia. Increasing lesional fibrosis propagates into the neighboring EMI and endometrium. The increased endometrial fibrosis, with ensuing greater tissue stiffness, results in attenuated prostaglandin E2, hypoxia signaling and glycolysis, impairing endometrial repair and causing HMB. Compared with adenomyosis-associated HMB, the mechanisms underlying adenomyosis-associated pain are less understood but presumably involve increased uterine contractility, hyperinnervation, increased lesional production of pain mediators, and central sensitization. Viewed through the prism of ReTIAR, a new imaging technique can be used to diagnose adenomyosis more accurately and informatively and possibly help to choose the best treatment modality.
... After nerve injury, Schwann cells assume a proregenerative function Mirsky, 2016, 2021;FIGURE 10 A summary of activated and inhibited transcriptional programs detected in the proximal nerve stumps 24 h post-axotomy in female and male mice. Merrell and Stanger, 2016;Milichko and Dyachuk, 2020), exhibiting an exceptional phenotypic plasticity (Jessen and Arthur-Farraj, 2019;Stierli et al., 2019;Nocera and Jacob, 2020) that supports their de-differentiation, proliferation, and re-differentiation into myelinating and non-myelinating phenotype to facilitate repair of the respective axons. Schwann cell reprogramming is controlled by a set of TFs (Balakrishnan et al., 2021), including Myt1l, Pou3f1/Oct6, Myrf, Olig1/2, Jun, Sox-, Hox-, and Fox-family members TFs upregulated at 24 h post-axotomy predominantly in males. ...
The convergence of transcriptional and epigenetic changes in the peripheral nervous system (PNS) reshapes the spatiotemporal gene expression landscape in response to nerve transection. The control of these molecular programs exhibits sexually dimorphic characteristics that remain not sufficiently characterized. In the present study, we recorded genome-wide and sex-dependent early-phase transcriptional changes in regenerating (proximal) sciatic nerve 24 h after axotomy. Male nerves exhibited more extensive transcriptional changes with male-dominant upregulation of cytoskeletal binding and structural protein genes. Regulation of mRNAs encoding ion and ionotropic neurotransmitter channels displayed prominent sexual dimorphism consistent with sex-specific mRNA axonal transport in an early-phase regenerative response. Protein kinases and axonal transport genes showed sexually dimorphic regulation. Genes encoding components of synaptic vesicles were at high baseline expression in females and showed post-injury induction selectively in males. Predictive bioinformatic analyses established patterns of sexually dimorphic regulation of neurotrophic and immune genes, including activation of glial cell line-derived neurotrophic factor Gfra1 receptor and immune checkpoint cyclin D1 (Ccnd1) potentially linked to X-chromosome encoded tissue inhibitor of matrix metallo proteinases 1 (Timp1). Regulatory networks involving Olig1, Pou3f3/Oct6, Myrf, and Myt1l transcription factors were linked to sex-dependent reprogramming in regenerating nerves. Differential expression patterns of non-coding RNAs motivate a model of sexually dimorphic nerve regenerative responses to injury determined by epigenetic factors. Combined with our findings in the corresponding dorsal root ganglia (DRG), unique early-phase sex-specific molecular triggers could enrich the mechanistic understanding of peripheral neuropathies.
... When the peripheral nerves are injured, SCs can dedifferentiate into immature SCs and acquire stemness [26,31,32]. In addition, SCs can also transdifferentiate into endoneurial fibroblasts [33], chromaffin cells [34], melanocytes [35], mesenchymal cells [36], and parasympathetic, sympathetic, enteric, GABAergic, glycinergic, serotoninergic and cholinergic neurons [37][38][39][40][41]. In view of their multifaceted roles after injury, we speculated that dedifferentiated SCs resulting from EMID might be coaxed and differentiated into endometrial epithelial cells through increased local production of estrogens due to platelet aggregation and hypoxia [42], and inflammatory cytokines and growth factors following tissue injury [43]. ...
We have recently demonstrated that endometrial–myometrial interface (EMI) disruption (EMID) can cause adenomyosis in mice, providing experimental evidence for the well-documented epidemiological finding that iatrogenic uterine procedures increase the risk of adenomyosis. To further elucidate its underlying mechanisms, we designed this study to test the hypothesis that Schwann cells (SCs) dedifferentiating after EMID facilitate the genesis of adenomyosis, but the suppression of SC dedifferentiation perioperatively reduces the risk. We treated mice perioperatively with either mitogen-activated protein kinase kinase (MEK)/extracellular-signal regulated protein kinase (ERK) or c-Jun N-terminal kinase (JNK) inhibitors or a vehicle 4 h before and 24 h, 48 h and 72 h after the EMID procedure. We found that EMID resulted in progressive SCs dedifferentiation, concomitant with an increased abundance of epithelial cells in the myometrium and a subsequent epithelial–mesenchymal transition (EMT). This EMID-induced change was abrogated significantly with perioperative administration of JNK or MEK/ERK inhibitors. Consistently, perioperative administration of a JNK or a MEK/ERK inhibitor reduced the incidence by nearly 33.5% and 14.3%, respectively, in conjunction with reduced myometrial infiltration of adenomyosis and alleviation of adenomyosis-associated hyperalgesia. Both treatments significantly decelerated the establishment of adenomyosis and progression of EMT, fibroblast-to-myofibroblast trans-differentiation and fibrogenesis in adenomyotic lesions. Thus, we provide the first piece of evidence strongly implicating the involvement of SCs in the pathogenesis of adenomyosis induced by EMID.
... eir high plasticity and absolute abundance enable them to recruit several immune cells, regulate the microenvironment, and assist regeneration [24,25]. ese factors make them perfect candidates hijacked by tumor cells to form and maintain a unique TME [26][27][28]. Some groundbreaking articles focused on the characteristics of SCs in the TME and their supporting effects on cancer, which adds an exciting new dimension to the interaction between tumors and the TME [28][29][30][31][32][33]. ...
... ese SCPs can differentiate into abnormally diverse cell types, including immature SCs, and subsequently into myelinated and unmyelinated SCs. is ability implies the plastic potential of SCs, which makes them a pluripotent cell pool to develop and regenerate PNS [47]. In fact, SCs are eminent in their ability to naturally (adaptively) reprogram and reprogram the surrounding environment [26]. After peripheral nerve injury, myelinated SCs dedifferentiate into "repair SCs" (rSCs) with an unmyelinated phenotype, change the local signal environment through matrix remodeling and release of proinflammatory mediators, recruit macrophages to cooperatively eliminate the myelin fragments, and guide the axon genesis, thus carving out the way for subsequent nerve regeneration [48][49][50][51]. is process of SC activation and transdifferentiation into a repair phenotype in nerve injury is a typical representative of natural (adaptive) reprogramming [26]. ...
... In fact, SCs are eminent in their ability to naturally (adaptively) reprogram and reprogram the surrounding environment [26]. After peripheral nerve injury, myelinated SCs dedifferentiate into "repair SCs" (rSCs) with an unmyelinated phenotype, change the local signal environment through matrix remodeling and release of proinflammatory mediators, recruit macrophages to cooperatively eliminate the myelin fragments, and guide the axon genesis, thus carving out the way for subsequent nerve regeneration [48][49][50][51]. is process of SC activation and transdifferentiation into a repair phenotype in nerve injury is a typical representative of natural (adaptive) reprogramming [26]. Transcriptomics revealed that genes encoding structural proteins such as myelin transcription factor Egr2, myelin protein zero, and myelin basic protein were downregulated. ...
The tumor microenvironment (TME), which is composed of various cell components and signaling molecules, plays an important role in the occurrence and progression of tumors and has become the central issue of current cancer research. In recent years, as a part of the TME, the peripheral nervous system (PNS) has attracted increasing attention. Moreover, emerging evidence shows that Schwann cells (SCs), which are the most important glial cells in the PNS, are not simply spectators in the TME. In this review article, we focused on the up-to-date research progress on SCs in the TME and introduced our point of view. In detail, we described that under two main tumor-nerve interaction patterns, perineural invasion (PNI) and tumor innervation, SCs were reprogrammed and acted as important participants. We also investigated the newest mechanisms between the interactions of SCs and tumor cells. In addition, SCs can have profound impacts on other cellular components in the TME, such as immune cells and cancer-associated fibroblasts (CAFs), involving immune regulation, tumor-related pain, and nerve remodeling. Overall, these innovative statements can expand the scope of the TME, help fully understand the significant role of SCs in the tumor-nerve-immune axis, and propose enlightenments to innovate antitumor therapeutic methods and future research.
Schwann cells are glial cells of the peripheral nervous system. They exist in several subtypes and perform a variety of functions in nerves. Their derivation and culture in vitro are interesting for applications ranging from disease modeling to tissue engineering. Since primary human Schwann cells are challenging to obtain in large quantities, in vitro differentiation from other cell types presents an alternative. Here, we first review the current knowledge on the developmental signaling mechanisms that determine neural crest and Schwann cell differentiation in vivo. Next, an overview of studies on the in vitro differentiation of Schwann cells from multipotent stem cell sources is provided. The molecules frequently used in those protocols and their involvement in the relevant signaling pathways are put into context and discussed. Focusing on hiPSC- and hESC-based studies, different protocols are described and compared, regarding cell sources, differentiation methods, characterization of cells, and protocol efficiency. A brief insight into developments regarding the culture and differentiation of Schwann cells in 3D is given. In summary, this contribution provides an overview of the current resources and methods for the differentiation of Schwann cells, it supports the comparison and refinement of protocols and aids the choice of suitable methods for specific applications.
Proper functioning of the digestive system is ensured by coordinated action of the central and peripheral nervous systems (PNS). Peripheral innervation of the digestive system can be viewed as intrinsic and extrinsic. The intrinsic portion is mainly composed of the neurons and glia of the enteric nervous system (ENS), while the extrinsic part is formed by sympathetic, parasympathetic, and sensory branches of the PNS. Glial cells are a crucial component of digestive tract innervation, and a great deal of research evidence highlights the important status of ENS glia in health and disease. In this review, we shift the focus a bit and discuss the functions of Schwann cells (SCs), the glial cells of the extrinsic innervation of the digestive system. For more context, we also provide information on the basic findings regarding the function of innervation in disorders of the digestive organs. We find diverse SC roles described particularly in the mouth, the pancreas, and the intestine. We note that most of the scientific evidence concerns the involvement of SCs in cancer progression and pain, but some research identifies stem cell functions and potential for regenerative medicine.
