Search Results (267)

Heterotopic ossification (HO) refers to the pathological formation of bone in soft tissues, typically following trauma, surgical procedures, or as a result of genetic disorders. Notably, injuries to the central nervous system significantly increase the risk of HO, a condition referred to as neurogenic HO (NHO). This review outlines the cellular and molecular mechanisms driving HO, focusing on the inflammatory response, progenitor cell reprogramming, and current treatment strategies. HO is primarily fuelled by a prolonged and dysregulated inflammatory response, characterized by sustained expression of osteoinductive cytokines secreted by M1 macrophages. These cytokines promote the aberrant differentiation of fibro-adipogenic progenitor cells (FAPs) into osteoblasts, leading to ectopic mineralization. Additional factors such as hypoxia, BMP signalling, and mechanotransduction pathways further contribute to extracellular matrix (ECM) remodelling and osteogenic reprogramming of FAPs. In the context of NHO, neuroendocrine mediators enhance ectopic bone formation by influencing both local inflammation and progenitor cell fate decisions. Current treatment options such as nonsteroidal anti-inflammatory drugs (NSAIDs), radiation therapy, and surgical excision offer limited efficacy and are associated with significant risks. Novel therapeutic strategies targeting inflammation, neuropeptide signalling, and calcium metabolism may offer more effective approaches to preventing or mitigating HO progression. Full article

Central nervous system (CNS) disorders present significant therapeutic challenges due to the limited regenerative capacity of neural tissues, resulting in long-term disability for many patients. Consequently, the development of novel therapeutic strategies is urgently warranted. Stem cell therapies show considerable potential for mitigating brain damage and restoring neural connectivity, owing to their multifaceted properties, including anti-apoptotic, anti-inflammatory, neurogenic, and vasculogenic effects. Recent research has also identified exosomes—small vesicles enclosed by a lipid bilayer, secreted by stem cells—as a key mechanism underlying the therapeutic effects of stem cell therapies, and given their enhanced stability and superior blood–brain barrier permeability compared to the stem cells themselves, exosomes have emerged as a promising alternative treatment for CNS disorders. A key challenge in the application of both stem cell and exosome-based therapies for CNS diseases is the method of delivery. Currently, several routes are being investigated, including intracerebral, intrathecal, intravenous, intranasal, and intra-arterial administration. Intracerebral injection can deliver a substantial quantity of stem cells directly to the brain, but it carries the potential risk of inducing additional brain injury. Conversely, intravenous transplantation is minimally invasive but results in limited delivery of cells and exosomes to the brain, which may compromise the therapeutic efficacy. With advancements in catheter technology, intra-arterial administration of stem cells and exosomes has garnered increasing attention as a promising delivery strategy. This approach offers the advantage of delivering a significant number of stem cells and exosomes to the brain while minimizing the risk of additional brain damage. However, the investigation into the therapeutic potential of intra-arterial transplantation for CNS injury is still in its early stages. In this comprehensive review, we aim to summarize both basic and clinical research exploring the intra-arterial administration of stem cells and exosomes for the treatment of CNS diseases. Additionally, we will elucidate the underlying therapeutic mechanisms and provide insights into the future potential of this approach. Full article

Myeloid-derived growth factor (MYDGF), named in reference to its secretion from myeloid cells in bone marrow, is a novel protein with anti-apoptotic and tissue-repairing properties. MYDGF is found in various human tissues affected by different diseases. To date, however, MYDGF expression has yet to be reported in the nervous system. Herein, we demonstrate for the first time that MYDGF mRNA levels increased in the zebrafish retina 1 h after optic nerve injury (ONI). MYDGF-producing cells were located in the photoreceptors and infiltrating leukocytic cells. We prepared the retina for MYDGF gene knockdown by performing intraocular injections using either MYDGF-specific morpholino or the CRISPR/Cas9 system. Under these MYDGF-knockdown retinal conditions, anti-apoptotic Bcl-2 mRNA was suppressed; in comparison, apoptotic caspase-3 and inflammatory TNFα mRNA were significantly upregulated in the zebrafish retina after ONI compared to the control. Furthermore, heat shock factor 1 (HSF1) was evidently suppressed under these conditions, leading to a significant number of apoptotic neurons. These findings indicate that MYDGF is a key molecule in the stimulation of neuronal regeneration in the central nervous system. Full article

In recent years, a long list of relevant studies has highlighted the engagement of the nervous system in the fine-tuning of tumor development and progression. Several authors have shown that different types of nerve fibres (sympathetic, parasympathetic/vagal or somatosensory fibres) may contribute to tumor innervation affecting cancer initiation, progression and metastasis. A large presence of nerve fibres is frequently observed in tumors with respect to the corresponding healthy tissues. In this regard, it is worth noting that in some cases a reduced innervation may associate with slow tumor growth in a tissue-specific manner. Current studies have begun to shed light over the role played in this specific process by Schwann cells (SCs), the most abundant glial cells of the peripheral nervous system. SCs observed in cancer tissues share strong similarities with repair SCs that appear after nerve injury. A large body of research indicates that SCs may have a role in shaping the microenvironment of tumors by regulating the immune response and influencing their invasiveness. In this review, we summarize data relevant to the role of peripheral innervation in general, and of SCs in particular, in defining the progression of different tumors: melanoma that originate in the skin with mainly sensory innervation; pancreatic and liver-derived tumors (e.g., pancreatic adenocarcinoma and cholangiocarcinoma) with mainly autonomous innervation. We conclude by summarizing data regarding hepatocarcinoma (with anatomical predominance of small autonomic nerve fibres) in which the potential relationship between innervation and tumor progression has been little explored, and largely remains to be defined. Full article

In the treatment of ischemic stroke, an innovative approach is the use of neuroprotective compounds. Natural peptides, including adrenocorticotropic hormone (ACTH), can serve as the basis for such drugs. Previously, a significant effect of non-hormonal ACTH(4-7)PGP (Semax) and ACTH(6-9)PGP peptides on the functions of the nervous system was shown. Also, while using RNA-Seq, we firstly revealed differentially expressed genes (DEGs) that associated with peptides in the penumbra-associated region of the frontal cortex (FC) of rats at 24 h after transient middle cerebral artery occlusion (tMCAO) model. Peptides significantly reduced profile disturbances caused by ischemia for almost two-thousand DEGs in FC related to the neurotransmitter and inflammatory response. Here, we studied how peptides affected the expression of genes in the striatum with an ischemic focus, predominantly. The same animals from which we previously acquired FC were used to collect striatum samples. Peptides generated fewer DEGs in the striatum than in the FC. Both peptides tended to normalize the profile of disturbances caused by ischemia for hundreds of DEGs, whereas 152 genes showed an even more affected profile in the striatum under ACTH(6-9)PGP action. These DEGs were associated with inflammation, predominantly. About hundred genes were overlapped between both peptides in both tissues and were associated with neuroactive ligand-receptor interaction, predominantly. Thus, genes that are associated with the ACTH-like peptide action in rat brain regions with varying levels of ischemia injury were identified. Moreover, differential spatial regulation of the ischemia process in the rat brain at the transcriptome levels was discovered under peptides with different ACTH structures. We suppose that our results may be useful for selecting more effective neuroprotective drug structures in accordance with their specific tissue/damage therapeutic impact. Full article

Adhesion between Schwann cells (SCs, a type of glial cell in the peripheral nervous system) and their underlying substrates is a fundamental process that holds critical importance for the proper functioning of the peripheral nervous system. Conducting further in-depth research into the adhesion mechanisms of nerve cells is of paramount significance, as it can pave the way for the development of highly effective biomaterials and facilitate the repair of nerve injuries. Thyroid Receptor Interaction Protein 6 (TRIP6), a member of the ZYXIN family of LIM domain-containing proteins, serves as a key component of focal adhesions. It plays a pivotal role in regulating a diverse array of cellular responses, including the reorganization of the actin cytoskeleton and cell adhesion. Accumulated data indicate that RSC96 cells (rat Schwann cells), which are rat Schwann cells, exhibit integrin-based mechanosensitivity during the initial phase of adhesion, specifically within the first 24 h. This enables the cells to sense and respond to alterations in matrix stiffness. The results of immunofluorescence staining experiments revealed intriguing findings. An increase in matrix stiffness not only led to significant changes in the morphological parameters of RSC96 ells, such as circularity, aspect ratio, and cell spreading area, but also enhanced the expression levels of TRIP6, focal adhesion kinase (FAK), and vinculin within these cells. These changes collectively promoted the adhesion of RSC96 cells to the matrix. Furthermore, when TRIP6 expression was silenced in RSC96 cells cultured on hydrogels, a notable decrease in the expression of both FAK and vinculin was observed. This, in turn, had a detrimental impact on cell adhesion. In summary, the present study strongly suggests that TRIP6 may play a crucial role in promoting the adhesion of RSC96 cells to polyacrylamide hydrogels with varying stiffness. This research not only offers a fresh perspective on the study of the integrin-mediated force regulation of cell adhesion but also lays a solid foundation for potential applications in tissue engineering, regenerative medicine, and other related fields. Full article

ABCC6, a key regulator in ectopic calcification, plays a crucial role in mineralization through the modulation of extracellular purinergic pathways and production of inorganic pyrophosphate (PPi), which inhibits calcification. Inherited deficiencies in ABCC6 lead to pseudoxanthoma elasticum (PXE) and related conditions, characterized by calcification in various tissues, particularly affecting the skin, eyes, and cardiovascular system. Although PXE does not directly impact the nervous system, secondary neurological issues arise from cerebrovascular complications, increasing the risk of strokes linked to arterial blockages resembling atherosclerosis. This review investigates the connection between ABCC6 mutations and cerebral small vessel disease (SVD), expanding the understanding of PXE and related phenotypes. Mutations in ABCC6, identified as causing PXE, contribute to systemic metabolic dysfunction, with significant implications for cerebrovascular health. An association between ABCC6 mutations and cerebral SVD has been suggested in various studies, particularly in populations with distinct genetic backgrounds. Emerging evidence indicates that pathogenic mutations increase the risk of ischemic strokes, with both homozygous and heterozygous carriers showing susceptibility. Mechanistically, ABCC6 deficiency is implicated in dyslipidemia and atherosclerosis, further exacerbating cerebrovascular risks. Increased arterial pulsatility, linked to carotid siphon calcification, may also contribute to microvascular damage and subsequent brain injury. Understanding these mechanisms is vital for developing targeted diagnostic and therapeutic strategies for managing cerebrovascular risks in PXE patients. This review emphasizes the need for comprehensive genetic screening and the consideration of traditional vascular risk factors in patient management, highlighting the complex interplay between genetic mutations and environmental influences affecting cerebrovascular health. Future research should focus on longitudinal studies to elucidate the causal pathways linking arterial calcification, pulsatility, and brain damage in PXE. Full article

The central nervous system (CNS) is highly susceptible to damage due to its limited ability to regenerate. Injuries to the CNS, whether from trauma, ischemia, or neurodegenerative diseases, disrupt both cellular and vascular structures, leading to immediate (primary) and subsequent (secondary) damage. Primary damage involves the physical disruption of cells and blood vessels, weakening the blood–brain barrier (BBB) and triggering excitotoxicity and calcium overload. Secondary damage develops over hours to days and is marked by ionic imbalance, mitochondrial dysfunction, oxidative stress, and chronic inflammation, which further aggravates tissue damage. Inflammation plays a dual role: acute inflammation helps in repair, while chronic inflammation accelerates neurodegeneration. Microglia and astrocytes play key roles in this inflammatory response, with M1-like microglia promoting pro-inflammatory responses and M2-like microglia supporting anti-inflammatory and repair processes. Neurodegenerative diseases are characterized by the accumulation of misfolded proteins such as Tau, amyloid-beta, TDP-43, and α-synuclein, which impair cellular function and lead to neuronal loss. Neurodegenerative diseases are characterized by the accumulation of misfolded proteins and influenced by genetic risk factors (e.g., APOE4, TARDBP). Despite the CNS’s limited regenerative abilities, processes like synaptogenesis, neurogenesis, axonal regeneration, and remyelination offer potential for recovery. Therapeutic approaches aim to target inflammatory pathways, enhance repair mechanisms, and develop neuroprotective treatments to counter excitotoxicity, oxidative stress, and apoptosis. Advances in stem cell therapy, gene therapy, and personalized medicine hold promise for improving outcomes. Future research should focus on combining strategies, utilizing advanced technologies, and conducting translational studies to bridge the gap between preclinical research and clinical application. By better understanding and leveraging the complex processes of CNS injury and repair, researchers hope to develop effective therapies to restore function and enhance the quality of life for individuals with CNS disorders. Full article

The skin is the body’s largest organ. It serves various functions, including protection and metabolism. Due to its structure and location, it is more vulnerable to external physical and chemical damage than internal organs. Additionally, certain endogenous diseases can cause pathological changes to appear on the skin and nerves. When skin tissue breaks down or sustains severe trauma, the cells, blood vessels, and nerves across all layers can suffer varying degrees of damage. This often results in pain, itching, sensory disturbances, and other discomforts, causing significant distress to patients. Stem-cell-derived exosome therapy has emerged as a promising treatment for skin injuries due to its safety, non-toxicity, and precision medicine benefits. Research has shown that stem-cell-derived exosomes regulate nerve cells by mediating MicroRNA (miRNA) transport and expression between cells, promoting axon growth. This exosome-driven miRNA exchange serves as a vital mode of intercellular communication, playing a crucial role in nervous system repair. Nerves play a critical role in skin wound healing and tissue regeneration, with sensory and autonomic nerves influencing key skin functions such as inflammation, immune defense, apoptosis, proliferation, and wound repair. Exosomes may aid in treating cutaneous nerve injuries by directly or indirectly promoting axon regeneration, nerve cell proliferation, and the release of protective neurofactors. Full article

Spinal cord injury (SCI) is a prevalent central nervous system disorder that causes significant disability and mortality. Unfortunately, due to the complex pathophysiological mechanisms involved, there remains a critical paucity of effective therapeutic interventions capable of achieving neural tissue regeneration and functional recovery enhancement in SCI patients. The advancements in extracellular vesicles (EVs) as a cell-free therapy for SCI have displayed notable benefits. These include their small size, low immunogenicity, capacity to target specific areas, and ability to cross the blood‒brain barrier (BBB). EVs offer the potential to not only repair tissue damage and stimulate regeneration but also effectively deliver and release them at the site of SCI when combined with diverse biomaterials. This review explores the biological role and importance of EVs in treating SCI, highlighting the combined use of modified EVs with different biomaterials and their potential for future applications. It presents new and hopeful treatment approaches for individuals afflicted with SCI. Full article

Acute brain injury includes different pathologies: stroke, traumatic injury, subarachnoidale haemorhhage. In the pathophysiology of acute brain injury, secondary injury with hyperactivation of glia plays a crucial role. Activated glial cells induce prolonged inflammation that impacts the recovery and further cognitive functions of patients. In our study, we have examined the neuroprotective impact of exogenous neuropeptides—Cerebrolysin on astrocytes under different conditions. In a model that simulates central nervous system damage associated with brain injury, stroke, and subarachnoid hemorrhage, the U87MG human brain cancer (glioblastoma astrocytoma like) cells were treated with Cerebrolysin and exposed to conditions of continuous and cyclic hypoxia and red blood cell lysate overload. The activity and expression of cyclooxygenases COX-1 and COX-2 and on cytokines (IL-8, IL-1β, IL-6, IL-10) and chemokines (CCL5/RANTES, CXCL9/MIG, CCL2/MCP-1, and CXCL10/IP-10) concentration were assessed. Cerebrolysin lowers IL-1β and IL-6 and increases IL-10 under all conditions. Cerebrolysin may exhibit a neuroimmunotrophic function, reducing inflammation under conditions that replicate traumatic brain injury and hemorrhagic insults to the central nervous system. By modulating both pro-inflammatory and anti-inflammatory cytokines, Cerebrolysin can help create a more balanced immune response conducive to tissue repair and reduced secondary damage. Its ability to lower harmful mediators like IL-1β and IL-6 while enhancing protective factors such as IL-10 suggests a promising therapeutic strategy in stroke, traumatic brain injury, and subarachnoid hemorrhage. Alongside other mechanisms such as neurotrophic factor enhancement and glial cell regulation, this cytokine modulation underscores the therapeutic potential of Cerebrolysin in a variety of central nervous system disorders. Full article

Penetrating traumatic injuries of the brain have a poor clinical prognosis necessitating development of new therapies to improve neurological outcomes. Laboratory research is hampered by reliance on highly invasive experimental approaches in living animals to simulate penetrating injuries e.g., by cutting/crushing the brain tissue, with a range of associated ethical, technical and logistical challenges. Accordingly, there is a critical need to develop neuromimetic in vitro alternative neural models to reduce harm to animals. However, most in vitro, reductionist simulations of brain injury are too simplistic to simulate the complex environment of the injured nervous system. We recently reported a complex, two-dimensional in vitro mouse model of neurotrauma containing five major brain cell types to replicate neural architecture, grown on a “hard” glass substrate in a brain cell sheet. We now demonstrate the translation of this approach into a three-dimensional tissue injury model, by propagating the entire cellular network in a “soft” compliant collagen hydrogel, similar to native brain tissue stiffness (an important determinant of cell fate). A multicellular network of neural cells was observed to form in the polymer matrix containing all major brain cell populations, including the immune cells (microglia). We demonstrate that it is feasible to create a reproducible, focal traumatic injury in the synthesised neural tissue construct. Importantly, key pathological features of neurological injury, such as astrocyte scarring, immune cell (microglial) activation, impeded axonal outgrowth and stem/progenitor cell migration, can be successfully induced. We also prove that it is feasible to implant a biomaterial into the lesion gap to study neural cell responses for screening applications. The findings support the concept that the model can be used in a versatile manner for advanced neural modelling. Full article

Measurement of circulating lactate is an essential diagnostic tool in pediatric medicine, playing a crucial role in assessing metabolic status and tissue oxygenation. Initially regarded as a byproduct of anaerobic metabolism, recent research has expanded our understanding of lactate’s roles across various physiological systems, from energy metabolism to immune modulation and neurological health. Elevated lactate levels are widely utilized to monitor critical conditions such as sepsis, trauma, and hypoxic–ischemic injury, offering valuable prognostic information in intensive care settings. Notably, lactate dynamics—particularly trends in serial measurements—are more effective than single readings for predicting clinical outcomes, especially in sepsis and trauma. Measurement of circulating lactate in different body fluids (blood, cerebrospinal fluid, and umbilical blood) provides critical insights into neonatal health and central nervous system involvement. However, challenges remain, including the need for non-invasive and rapid point-of-care testing, particularly in neonatal populations. Our aim was to review and synthesize the current literature on the role and particularities of measurement of circulating lactate in pediatric pathology. Emerging technologies, such as machine learning models and small molecule inhibitors, show promise in advancing lactate regulation and predicting hemodynamic instability. As the role of lactate in pediatric pathology continues to evolve, optimizing measurement protocols and exploring new therapeutic strategies will enhance early detection, intervention, and clinical outcomes for critically ill children. Full article

We aimed to determine whether transient global amnesia (TGA) is associated with alterations in central nervous system (CNS) injury biomarkers—serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP). In a prospective cohort of TGA patients, blood samples were obtained within 24–48 h of TGA onset (t0) and 6 weeks thereafter (t1). We assessed sNfL and sGFAP levels using the highly sensitive single-molecule array assay and calculated Z-scores adjusted for age, gender, and body mass index (BMI). Demographics, electroencephalography (EEG), and cerebral magnetic resonance imaging (cMRI) findings were also collected. A total of 20 patients were included (median age: 66 years, 70% women). No significant changes in sNfL or sGFAP levels associated with TGA at t0 and t1 were observed. Median sNfL Z-scores were 0.45 (interquartile range [IQR] −0.09, 1.19) at t0 and 0.60 (IQR −0.61, 1.19) at t1. Median sGFAP Z-scores were 0.27 (IQR −0.45, 0.76) at t0 and 0.44 (IQR −0.27, 0.75) at t1. Similarly, in the subgroup of patients with diffusion-weighted imaging (DWI)-positive hippocampal lesions (n = 5/20[25%]), no elevations in blood biomarkers were detected. Our pilot study on neurological blood biomarkers supports the benign nature of TGA, indicating that no CNS tissue damage occurs. Full article

Tendon injuries pose a clinical challenge due to tendons’ limited recovery. Emerging evidence points to the nervous system’s critical role in tendon healing, with neural markers NGF, NF-200, NPY, CGRP, and GAL modulating inflammation, cell proliferation, and extracellular matrix (ECM) remodeling. This study investigates the predictive role of selected neural markers in a validated ovine Achilles tendon injury model, comparing spatio-temporal expression patterns in regenerating tendons transplanted with amniotic epithelial stem cells (AECs) versus spontaneous healing (CTR) 14 and 28 days post-injury (p.i.). AEC-treated tissues showed a spatio-temporal modulation of NF-200, NGF, NPY, CGRP, GAL, and enhanced ECM remodeling, with greater cell alignment, lower angle deviation, and accelerated collagen maturation, with a favorable Collagen type 1 (COL1) to Collagen type 3 (COL3) ratio. Pearson’s matrix analysis revealed significant positive correlations between NGF, CGRP, and GAL expression, along a positive correlation between the three neural markers and cell alignment and angle deviation. As opposed to CTR, in AEC-treated tendons, lower levels of NGF, CGRP, and GAL correlated positively with improved tissue organization, suggesting these markers may predict successful tendon regeneration. The findings highlight the neuro-mediated activity of AECs in tendon regeneration, with NGF, CGRP, and GAL emerging as key predictive biomarkers for tendon healing. Full article