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• W3023519063 abstract "Of the large variety of technologies that can be used to study mammalian physiology and pathophysiology, confocal and two-photon intravital microscopy (IVM) is unique. For the past three decades, it has enabled researchers to monitor biological processes, live and in their true environment, all at high temporal and spatial resolutions. It is the only technology that provides single-cell (and even subcellular) information, while maintaining the complex environment that exists only in living organisms. As such, IVM has revealed not only how cells move and communicate in various healthy tissues, but also how these behaviors change under pathological conditions. The impact of IVM has been felt within many biomedical research areas, but particularly in fields of neuroscience, immunology, and in cancer research, where the technology has helped to elucidate the key mechanisms of immune cell communication and metastatic progression and has revealed new targets for therapeutic strategies. However, even with this success, advances that expand the utility of the technique and enable IVM to provide more complete information about in vivo pathophysiological phenomena at the single-cell level were still necessary and continue to be made.1 These recent developments include (1) expanding the spectral and spatiotemporal boundaries of the current technology,2-10 (2) retrieving more detailed molecular information on cellular and tissue functions within living organisms,11-18 and (3) translating basic science knowledge into clinically relevant information.19-21 The publications in this special issue, Intravital Microscopy: Innovations and Applications, review these recent achievements, as well as present new advances in the IVM of osteoimmunological cross talk, musculoskeletal development, infection biology, and cancer research. To begin this special issue, Coste et al. provide a comprehensive review of the wide variety of intravital imaging techniques used to access various tissues, from transdermal imaging to implantable chronic imaging windows. They then discuss how new advances in IVM have led to novel biological insights in the fields of immunology, metabolomics, and cancer metastasis, and how new instrumentation and clinical protocols are allowing the direct application of IVM to patient care. Next, Handschuh et al. review the ways in which IVM goes beyond looking at the cells of a single organism, but instead elucidates the mechanisms of host–pathogen interactions. They describe how IVM, in combination with advances in labeling and tracking of specific cell types and individual pathogens, has helped to dissect the sequence of events during the course of infections: from the early events of tissue invasion, where pathogens employ different strategies to establish themselves within the host and circumvent or evade immune defenses, to the induction of the immune response by pathogen–immune cell and immune cell–immune cell interactions, and finally to events implicated in the clearance of infections or the induction of immunopathology. Finally, the authors discuss the new advances, such as fluorescent reporter-based techniques, that will provide tools for extracting functional information on immune cell signaling and metabolism that could enhance our understanding of the mechanistic aspects of pathogen-mediated infections. As an example of this type of development, Okkelman et al. combine two commercially available dyes with FLIM imaging of live cultured cells and 3D organoids to create and validate fluorescent probes capable of the quantitative assessment of cell metabolism and mitochondrial function through the measurement of mitochondrial membrane potential. This technology offers a new way of viewing the metabolic processes of all cells, independent of their origin, phenotype, or state of differentiation, as respiration is fundamental to every cell type. The technology presented by Okkelman et al. may complement two other readouts of nutrition and respiration already employed in intravital imaging: the ubiquitous coenzyme-dependent (NAD(P)H and FAD) metabolism and oxygen availability.9, 13-15, 17, 18 However, the performance of the current technology has not been yet applied intravitally, the results presented by the authors convincingly demonstrate its power and feasibility for use with intravital imaging. In the manuscript by Stefanowski et al., the authors further develop and expand the utility of their recently published microendoscope for longitudinal two-photon intravital imaging of the murine femur.3 By using a modular construction, they make the technique capable of visualizing the spatiotemporal dynamics of bone healing and regeneration after osteotomy—a generally accepted long bone fracture model in rodents. This new technology, named LIMBOSTOMY, has a significantly increased observation volume compared to the original design3 as it uses a larger gradient refractive index (GRIN) lens (600 μm diameter). Particular attention was paid to correct the wave front distortions that typically compromise the optical performance of GRIN lenses. This approach results in subcellular resolution throughout the imaged cylindrical volume (400 μm diameter and 100 μm in height). The authors apply LIMBOSTOMY to monitor and quantify the neovascularization process within the callus of fracture sites after osteotomy. Being a chronic imaging technique capable of investigating the entire process of bone healing in one and the same individual, LIMBOSTOMY enables the authors to describe in detail the course of two phases of angiogenesis: first, rapid vessel sprouting pervades the field of view within 3–4 days after osteotomy, and second, the vessel network continues to be dynamically remodeled up to 14 days after osteotomy. Applications of this technology have the potential to go beyond bone healing research, to impact research into developmental bone biology as well as hematopoiesis within the marrow of long bones. Putting this work into its broader context is the review by Kim et al., which presents recent advances in multiphoton imaging technologies that have led to a greater understanding of bone tissue homeostasis, remodeling, and regeneration. This work thoroughly discusses the technologies that have helped to identify cellular phenomena, and their underlying signaling pathways, involved in the communication between different types of bone and bone marrow cells. As stated by Kim et al., bone is “a dynamic connective and supportive tissue”, and is “constantly sensing and responding to both external mechanical forces and internal systemic and local signals.” This specific feature of bone is eminently impactful not only when bone fractures occur (as was discussed in Stefanowski et al.), but also during the key processes of normal bone physiology. Kim et al. specifically focus on the dynamic interplay of osteoblasts, osteocytes, and osteoclasts, as well as on the challenges which a continuously changing vasculature and extracellular matrix impose on these cells. The authors present key IVM applications that have led to a better understanding of the dynamic molecular and cellular mechanisms underlying bone tissue homeostasis, remodeling, and regeneration under physiological and pathological conditions. The original research article by Servin-Vences et al. focuses on the application of two-photon microscopy (TPM) to investigate the molecular origins of osteoarthritis. The authors use linearly and circularly polarized two-photon excitation to look at the microscopic structure of femoral cartilage in 4–5 days old wild-type mice, and those lacking the polymodal ion-channel TRPV4 (TRPV4−/−). By looking at nonambulatory pups, the investigators aimed to gain insight into whether there are structural changes in the cartilage in Trpv4−/− mice at an age before the femoral heads have been affected by mechanical loading due to weight bearing and walking. Utilizing polarized excitation and detection, second-harmonic generation signals from all orientations of collagen fibers within the articular cartilage were collected and compared, enabling an in-depth characterization of the collagen's supramolecular alignment, morphology, and organization. Through these experiments, no statistically significant difference between the two structures was observed, indicating that the impact of a loss of TRPV4 on cartilage biology is likely not due to malformation of the cartilage but due to a slower process that occurs over time. The combination of in vivo TPM with other imaging modalities is an interesting, yet largely unexplored field, with relatively few, mostly not coregistered, examples.22, 23 In their publication, Rakhymzhan et al. present a coregistered nearly simultaneous large-volume multimodal IVM approach that combines TPM with optical coherence tomography (OCT), a technology which has already found broad application in the clinic, as exemplary highlighted by.24 They employ their imaging approach to visualize and link the morphology and specific cellular phenotypes in a broad variety of organs (i.e., lymph node, spleen, retina, and paws) in mice. Using this technology, the authors find that the morphology and motility of tissue-resident macrophages (CX3CR1+ cells), as revealed by TPM, correlates with the tissue organization, as captured by the OCT and second-harmonic generation signals. Their approach of coregistered OCT and TPM has the potential to simultaneously provide molecule-specific high-resolution imaging (TPM) and label-free visualization of tissue morphology (OCT), and thus build a bridge between basic research knowledge and clinical observations. The relevance of IVM for clinical applications is emphasized by the original article of Li et al., which is focused on the development and monitoring of therapeutics. Cellular heterogeneity may modify drug responses, as in the case of monoclonal antibody therapies within solid tumors. To address this question, the authors develop a confocal IVM approach that allows, within the solid tumor environment, visualization and tracking of the delivery and action of trastuzumab: a monoclonal antibody (against the growth factor receptor HER2) that is widely used in the clinic for treating breast and gastric cancer patients. To mimic the clinically observed cellular heterogeneity in tumors of patients the researchers implanted in mice mosaicked xenografts composed of a mixture of cancer cells with variable HER2 expression. In this way, the authors were able to show that, while trastuzumab accumulates to a greater extent in tumor cells expressing high levels of HER2 (as compared to HER2-low tumor cells), over time, most of the drug delivered to the animal actually accumulates within tumor-associated phagocytes. The findings presented here provide strong evidence of how environmental conditions lead to variations of drug therapy efficacy, demonstrating the potential of IVM in translational research. Taken together, the collection of articles within this special issue demonstrates the wide-ranging impact that IVM has in the biomedical sciences and in the clinic. Advances such as those presented here will provide the tools and the basic science knowledge to impact the next generation of clinical care." @default.
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• W3023519063 title "Life Through a Lens: Technological Development and Applications in Intravital Microscopy" @default.
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