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Cells Jun 2024Preimplantation embryo culture, pivotal in assisted reproductive technology (ART), has lagged in innovation compared to embryo selection advancements. This review... (Review)
Review
Preimplantation embryo culture, pivotal in assisted reproductive technology (ART), has lagged in innovation compared to embryo selection advancements. This review examines the persisting gap between in vivo and in vitro embryo development, emphasizing the need for improved culture conditions. While in humans this gap is hardly estimated, animal models, particularly bovines, reveal clear disparities in developmental competence, cryotolerance, pregnancy and live birth rates between in vitro-produced (IVP) and in vivo-derived (IVD) embryos. Molecular analyses unveil distinct differences in morphology, metabolism, and genomic stability, underscoring the need for refining culture conditions for better ART outcomes. To this end, a deeper comprehension of oviduct physiology and embryo transport is crucial for grasping embryo-maternal interactions' mechanisms. Research on autocrine and paracrine factors, and extracellular vesicles in embryo-maternal tract interactions, elucidates vital communication networks for successful implantation and pregnancy. In vitro, confinement, and embryo density are key factors to boost embryo development. Advanced dynamic culture systems mimicking fluid mechanical stimulation in the oviduct, through vibration, tilting, and microfluidic methods, and the use of innovative softer substrates, hold promise for optimizing in vitro embryo development.
Topics: Animals; Humans; Embryo Culture Techniques; Embryo, Mammalian; Embryonic Development; Pregnancy; Female; Blastocyst
PubMed: 38920627
DOI: 10.3390/cells13120996 -
Oncoimmunology 2024Improving cancer immunotherapy efficacy hinges on identifying key T-cell populations critical for tumor control and response to Immune Checkpoint Blockade (ICB). We have...
Improving cancer immunotherapy efficacy hinges on identifying key T-cell populations critical for tumor control and response to Immune Checkpoint Blockade (ICB). We have recently reported that while the co-expression of PD-1 and CD28 is associated with impaired functionality in peripheral blood, it significantly enhances T-cell fitness in the tumor site of non-small cell lung cancer (NSCLC) patients. To uncover the underlying mechanisms, we explored the role of CD26, a key player in T-cell activation through its interaction with adenosine deaminase (ADA), a crucial intra/extracellular enzyme able to neutralize local adenosine (ADO). We found that an autocrine ADA/CD26 axis enhances CD8PD-1CD28 T-cell function, particularly within an immunosuppressive environment marked by CD39 expression. Then, we interrogated the TCGA and OAK datasets to gain insight into the prognostic/predictive potential of our findings. We identified a signature predicting overall survival (OS) in LUAD patients and response to atezolizumab in advanced LUAD cases. These findings suggest promising avenues for therapeutic intervention targeting the ADA/CD26 axis.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; CD8-Positive T-Lymphocytes; CD28 Antigens; Prognosis; Programmed Cell Death 1 Receptor; Dipeptidyl Peptidase 4; Adenosine Deaminase; Immune Checkpoint Inhibitors; Antibodies, Monoclonal, Humanized; Female; Male; Apyrase
PubMed: 38915783
DOI: 10.1080/2162402X.2024.2371051 -
Viruses May 2024The pathogenesis of viral infection is attributed to two folds: intrinsic cell death pathway activation due to the viral cytopathic effect, and immune-mediated extrinsic... (Review)
Review
The pathogenesis of viral infection is attributed to two folds: intrinsic cell death pathway activation due to the viral cytopathic effect, and immune-mediated extrinsic cellular injuries. The immune system, encompassing both innate and adaptive immunity, therefore acts as a double-edged sword in viral infection. Insufficient potency permits pathogens to establish lifelong persistent infection and its consequences, while excessive activation leads to organ damage beyond its mission to control viral pathogens. The innate immune response serves as the front line of defense against viral infection, which is triggered through the recognition of viral products, referred to as pathogen-associated molecular patterns (PAMPs), by host cell pattern recognition receptors (PRRs). The PRRs-PAMPs interaction results in the induction of interferon-stimulated genes (ISGs) in infected cells, as well as the secretion of interferons (IFNs), to establish a tissue-wide antiviral state in an autocrine and paracrine manner. Cumulative evidence suggests significant variability in the expression patterns of PRRs, the induction potency of ISGs and IFNs, and the IFN response across different cell types and species. Hence, in our understanding of viral hepatitis pathogenesis, insights gained through hepatoma cell lines or murine-based experimental systems are uncertain in precisely recapitulating the innate antiviral response of genuine human hepatocytes. Accordingly, this review article aims to extract and summarize evidence made possible with bona fide human hepatocytes-based study tools, along with their clinical relevance and implications, as well as to identify the remaining gaps in knowledge for future investigations.
Topics: Humans; Hepatitis D; Hepatitis Delta Virus; Hepatocytes; Host-Pathogen Interactions; Immunity, Innate; Interferons; Pathogen-Associated Molecular Pattern Molecules; Receptors, Pattern Recognition
PubMed: 38793622
DOI: 10.3390/v16050740 -
NPJ Precision Oncology May 2024Of all gynecologic cancers, epithelial-ovarian cancer (OCa) stands out with the highest mortality rates. Despite all efforts, 90% of individuals who receive standard...
Of all gynecologic cancers, epithelial-ovarian cancer (OCa) stands out with the highest mortality rates. Despite all efforts, 90% of individuals who receive standard surgical and cytotoxic therapy experience disease recurrence. The precise mechanism by which leukemia inhibitory factor (LIF) and its receptor (LIFR) contribute to the progression of OCa remains unknown. Analysis of cancer databases revealed that elevated expression of LIF or LIFR was associated with poor progression-free survival of OCa patients and a predictor of poor response to chemotherapy. Using multiple primary and established OCa cell lines or tissues that represent five subtypes of epithelial-OCa, we demonstrated that LIF/LIFR autocrine signaling is active in OCa. Moreover, treatment with LIFR inhibitor, EC359 significantly reduced OCa cell viability and cell survival with an IC ranging from 5-50 nM. Furthermore, EC359 diminished the stemness of OCa cells. Mechanistic studies using RNA-seq and rescue experiments unveiled that EC359 primarily induced ferroptosis by suppressing the glutathione antioxidant defense system. Using multiple in vitro, ex vivo and in vivo models including cell-based xenografts, patient-derived explants, organoids, and xenograft tumors, we demonstrated that EC359 dramatically reduced the growth and progression of OCa. Additionally, EC359 therapy considerably improved tumor immunogenicity by robust CD45 leukocyte tumor infiltration and polarizing tumor-associated macrophages (TAMs) toward M1 phenotype while showing no impact on normal T-, B-, and other immune cells. Collectively, our findings indicate that the LIF/LIFR autocrine loop plays an essential role in OCa progression and that EC359 could be a promising therapeutic agent for OCa.
PubMed: 38789520
DOI: 10.1038/s41698-024-00612-y -
Molecular Therapy : the Journal of the... May 2024Interleukin (IL)18 is a potent pro-inflammatory cytokine that is activated upon caspase 1 cleavage of the latent precursor, pro-IL18. Therapeutic T cell armoring with...
Interleukin (IL)18 is a potent pro-inflammatory cytokine that is activated upon caspase 1 cleavage of the latent precursor, pro-IL18. Therapeutic T cell armoring with IL18 promotes autocrine stimulation and positive modulation of the tumor microenvironment (TME). However, existing strategies are imperfect since they involve constitutive/poorly regulated activity or fail to modify the TME. Here, we have substituted the caspase 1 cleavage site within pro-IL18 with that preferred by granzyme B, yielding GzB-IL18. We demonstrate that GzB-IL18 is constitutively released but remains functionally latent unless chimeric antigen receptor (CAR) T cells are activated, owing to concomitant granzyme B release. Armoring with GzB-IL18 enhances cytolytic activity, proliferation, interferon (IFN)-γ release, and anti-tumor efficacy by a similar magnitude to constitutively active IL18. We also demonstrate that GzB-IL18 provides a highly effective armoring strategy for γδ CAR T cells, leading to enhanced metabolic fitness and significant potentiation of therapeutic activity. Finally, we show that constitutively active IL18 can unmask CAR T cell-mediated cytokine release syndrome in immunocompetent mice. By contrast, GzB-IL18 promotes anti-tumor activity and myeloid cell re-programming without inducing such toxicity. Using this stringent system, we have tightly coupled the biological activity of IL18 to the activation state of the host CAR T cell, favoring safer clinical implementation of this technology.
PubMed: 38745414
DOI: 10.1016/j.ymthe.2024.05.013 -
CNS Neuroscience & Therapeutics May 2024A bone-invasive pituitary adenoma exhibits aggressive behavior, leading to a worse prognosis. We have found that TNF-α promotes bone invasion by facilitating the...
AIMS
A bone-invasive pituitary adenoma exhibits aggressive behavior, leading to a worse prognosis. We have found that TNF-α promotes bone invasion by facilitating the differentiation of osteoclasts, however, before bone-invasive pituitary adenoma invades bone tissue, it needs to penetrate the dura mater, and this mechanism is not yet clear.
METHODS
We performed transcriptome microarrays on specimens of bone-invasive pituitary adenomas (BIPAs) and noninvasive pituitary adenomas (NIPAs) and conducted differential expressed gene analysis and enrichment analysis. We altered the expression of TNF-α through plasmids, then validated the effects of TNF-α on GH3 cells and verified the efficacy of the TNF-α inhibitor SPD304. Finally, the effects of TNF-α were validated in in vivo experiments.
RESULTS
Pathway act work showed that the MAPK pathway was significantly implicated in the pathway network. The expression of TNF-α, MMP9, and p-p38 is higher in BIPAs than in NIPAs. Overexpression of TNF-α elevated the expression of MAPK pathway proteins and MMP9 in GH3 cells, as well as promoted proliferation, migration, and invasion of GH3 cells. Flow cytometry indicated that TNF-α overexpression increased the G2 phase ratio in GH3 cells and inhibited apoptosis. The expression of MMP9 was reduced after blocking the P38 MAPK pathway; overexpression of MMP9 promoted invasion of GH3 cells. In vivo experiments confirm that the TNF-α overexpression group has larger tumor volumes. SPD304 was able to suppress the effects caused by TNF-α overexpression.
CONCLUSION
Bone-invasive pituitary adenoma secretes higher levels of TNF-α, which then acts on itself in an autocrine manner, activating the MAPK pathway and promoting the expression of MMP9, thereby accelerating the membrane invasion process. SPD304 significantly inhibits the effect of TNF-α and may be applied in the clinical treatment of bone-invasive pituitary adenoma.
Topics: Tumor Necrosis Factor-alpha; Pituitary Neoplasms; Humans; Adenoma; Neoplasm Invasiveness; Animals; Matrix Metalloproteinase 9; MAP Kinase Signaling System; Male; Cell Line, Tumor; Female; Mice; Mice, Nude; Autocrine Communication; Middle Aged; Bone Neoplasms; Adult; Rats; Cell Movement; Signal Transduction
PubMed: 38739004
DOI: 10.1111/cns.14749 -
IScience May 2024Excessive neuroinflammation after spinal cord injury (SCI) is a major hurdle during nerve repair. Although proinflammatory macrophage/microglia-mediated...
Excessive neuroinflammation after spinal cord injury (SCI) is a major hurdle during nerve repair. Although proinflammatory macrophage/microglia-mediated neuroinflammation plays important roles, the underlying mechanism that triggers neuroinflammation and aggravating factors remain unclear. The present study identified a proinflammatory role of semaphorin3C (SEMA3C) in immunoregulation after SCI. SEMA3C expression level peaked 7 days post-injury (dpi) and decreased by 14 dpi. and studies revealed that macrophages/microglia expressed SEMA3C in the local microenvironment, which induced neuroinflammation and conversion of proinflammatory macrophage/microglia. Mechanistic experiments revealed that RAGE/NF-κB was downstream target of SEMA3C. Inhibiting SEMA3C-mediated RAGE signaling considerably suppressed proinflammatory cytokine production, reversed polarization of macrophages/microglia shortly after SCI. In addition, inhibition of SEMA3C-mediated RAGE signaling suggested that the SEMA3C/RAGE axis is a feasible target to preserve axons from neuroinflammation. Taken together, our study provides the first experimental evidence of an immunoregulatory role for SEMA3C in SCI via an autocrine mechanism.
PubMed: 38638567
DOI: 10.1016/j.isci.2024.109649 -
Single-Cell Multi-Omics Map of Cell Type-Specific Mechanistic Drivers of Multiple Sclerosis Lesions.Neurology(R) Neuroimmunology &... May 2024In progressive multiple sclerosis (MS), compartmentalized inflammation plays a pivotal role in the complex pathology of tissue damage. The interplay between epigenetic...
BACKGROUND AND OBJECTIVES
In progressive multiple sclerosis (MS), compartmentalized inflammation plays a pivotal role in the complex pathology of tissue damage. The interplay between epigenetic regulation, transcriptional modifications, and location-specific alterations within white matter (WM) lesions at the single-cell level remains underexplored.
METHODS
We examined intracellular and intercellular pathways in the MS brain WM using a novel dataset obtained by integrated single-cell multi-omics techniques from 3 active lesions, 3 chronic active lesions, 3 remyelinating lesions, and 3 control WM of 6 patients with progressive MS and 3 non-neurologic controls. Single-nucleus RNA-seq and ATAC-seq were combined and additionally enriched with newly conducted spatial transcriptomics from 1 chronic active lesion. Functional gene modules were then validated in our previously published bulk tissue transcriptome data obtained from 73 WM lesions of patients with progressive MS and 25 WM of non-neurologic disease controls.
RESULTS
Our analysis uncovered an MS-specific oligodendrocyte genetic signature influenced by the KLF/SP gene family. This modulation has potential associations with the autocrine iron uptake signaling observed in transcripts of transferrin and its receptor . In addition, an inflammatory profile emerged within these oligodendrocytes. We observed unique cellular endophenotypes both at the periphery and within the chronic active lesion. These include a distinct metabolic astrocyte phenotype, the importance of FGF signaling among astrocytes and neurons, and a notable enrichment of mitochondrial genes at the lesion edge populated predominantly by astrocytes. Our study also identified B-cell coexpression networks indicating different functional B-cell subsets with differential location and specific tendencies toward certain lesion types.
DISCUSSION
The use of single-cell multi-omics has offered a detailed perspective into the cellular dynamics and interactions in MS. These nuanced findings might pave the way for deeper insights into lesion pathogenesis in progressive MS.
Topics: Humans; Multiple Sclerosis; Epigenesis, Genetic; Multiomics; Multiple Sclerosis, Chronic Progressive; White Matter
PubMed: 38564686
DOI: 10.1212/NXI.0000000000200213 -
Nature Apr 2024The immune system has a critical role in orchestrating tissue healing. As a result, regenerative strategies that control immune components have proved effective. This is...
The immune system has a critical role in orchestrating tissue healing. As a result, regenerative strategies that control immune components have proved effective. This is particularly relevant when immune dysregulation that results from conditions such as diabetes or advanced age impairs tissue healing following injury. Nociceptive sensory neurons have a crucial role as immunoregulators and exert both protective and harmful effects depending on the context. However, how neuro-immune interactions affect tissue repair and regeneration following acute injury is unclear. Here we show that ablation of the Na1.8 nociceptor impairs skin wound repair and muscle regeneration after acute tissue injury. Nociceptor endings grow into injured skin and muscle tissues and signal to immune cells through the neuropeptide calcitonin gene-related peptide (CGRP) during the healing process. CGRP acts via receptor activity-modifying protein 1 (RAMP1) on neutrophils, monocytes and macrophages to inhibit recruitment, accelerate death, enhance efferocytosis and polarize macrophages towards a pro-repair phenotype. The effects of CGRP on neutrophils and macrophages are mediated via thrombospondin-1 release and its subsequent autocrine and/or paracrine effects. In mice without nociceptors and diabetic mice with peripheral neuropathies, delivery of an engineered version of CGRP accelerated wound healing and promoted muscle regeneration. Harnessing neuro-immune interactions has potential to treat non-healing tissues in which dysregulated neuro-immune interactions impair tissue healing.
Topics: Animals; Mice; Autocrine Communication; Calcitonin Gene-Related Peptide; Diabetes Mellitus, Experimental; Efferocytosis; Macrophages; Monocytes; Muscle, Skeletal; NAV1.8 Voltage-Gated Sodium Channel; Neutrophils; Nociceptors; Paracrine Communication; Peripheral Nervous System Diseases; Receptor Activity-Modifying Protein 1; Regeneration; Skin; Thrombospondin 1; Wound Healing; Humans; Male; Female
PubMed: 38538784
DOI: 10.1038/s41586-024-07237-y -
Neuroimmunomodulation 2024The brain and the immune systems represent the two primary adaptive systems within the body. Both are involved in a dynamic process of communication, vital for the... (Review)
Review
BACKGROUND
The brain and the immune systems represent the two primary adaptive systems within the body. Both are involved in a dynamic process of communication, vital for the preservation of mammalian homeostasis. This interplay involves two major pathways: the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system.
SUMMARY
The establishment of infection can affect immunoneuroendocrine interactions, with functional consequences for immune organs, particularly the thymus. Interestingly, the physiology of this primary organ is not only under the control of the central nervous system (CNS) but also exhibits autocrine/paracrine regulatory circuitries mediated by hormones and neuropeptides that can be altered in situations of infectious stress or chronic inflammation. In particular, Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), impacts upon immunoneuroendocrine circuits disrupting thymus physiology. Here, we discuss the most relevant findings reported in relation to brain-thymic connections during T. cruzi infection, as well as their possible implications for the immunopathology of human Chagas disease.
KEY MESSAGES
During T. cruzi infection, the CNS influences thymus physiology through an intricate network involving hormones, neuropeptides, and pro-inflammatory cytokines. Despite some uncertainties in the mechanisms and the fact that the link between these abnormalities and chronic Chagasic cardiomyopathy is still unknown, it is evident that the precise control exerted by the brain over the thymus is markedly disrupted throughout the course of T. cruzi infection.
Topics: Humans; Chagas Disease; Animals; Brain; Thymus Gland; Trypanosoma cruzi; Hypothalamo-Hypophyseal System; Neuroimmunomodulation; Pituitary-Adrenal System
PubMed: 38527434
DOI: 10.1159/000538220