InterCellar enables interactive analysis and exploration of cell−cell communication in single-cell transcriptomic data

Deciphering cell−cell communication is a key step in understanding the physiology and pathology of multicellular systems. Recent advances in single-cell transcriptomics have contributed to unraveling the cellular composition of tissues and enabled the development of computational algorithms to predict cellular communication mediated by ligand−receptor interactions. Despite the existence of various tools capable of inferring cell−cell interactions from single-cell RNA sequencing data, the analysis and interpretation of the biological signals often require deep computational expertize. Here we present InterCellar, an interactive platform empowering lab-scientists to analyze and explore predicted cell−cell communication without requiring programming skills. InterCellar guides the biological interpretation through customized analysis steps, multiple visualization options, and the possibility to link biological pathways to ligand−receptor interactions. Alongside convenient data exploration features, InterCellar implements data-driven analyses including the possibility to compare cell−cell communication from multiple conditions. By analyzing COVID-19 and melanoma cell−cell interactions, we show that InterCellar resolves data-driven patterns of communication and highlights molecular signals through the integration of biological functions and pathways. We believe our user-friendly, interactive platform will help streamline the analysis of cell−cell communication and facilitate hypothesis generation in diverse biological systems.

The matrix in focus: new directions in extracellular matrix research from the 2021 ASMB hybrid meeting

ABSTRACT The extracellular matrix (ECM) is a complex assembly of macromolecules that provides both architectural support and molecular signals to cells and modulate their behaviors. Originally considered a passive mechanical structure, decades of research have since demonstrated how the ECM dynamically regulates a diverse set of cellular processes in development, homeostasis, and disease progression. In September 2021, the American Society for Matrix Biology (ASMB) organized a hybrid scientific meeting, integrating in-person and virtual formats, to discuss the latest developments in ECM research. Here, we highlight exciting scientific advances that emerged from the meeting including (1) the use of model systems for fundamental and translation ECM research, (2) ECM-targeting approaches as therapeutic modalities, (3) cell-ECM interactions, and (4) the ECM as a critical component of tissue engineering strategies. In addition, we discuss how the ASMB incorporated mentoring, career development, and diversity, equity, and inclusion initiatives in both virtual and in-person events. Finally, we reflect on the hybrid scientific conference format and how it will help the ASMB accomplish its mission moving forward.

Biosemiotics and Body Signifier Theory: a way to understand High Dilutions

Since the 80´s Madeleine Bastide and Agnès Lagache have worked on the idea of the Body Signifier Theory, in which the living systems could be defined as “sensible” systems not only able to self-organize, but also to receive and process non-molecular information according to the Pierce semiotic triad: matrix, receiver and carrier. These ideas were built along 20 years of experimental observations, whose results presented some kind of stereotyped pattern that emerged from cells or animals exposed to high dilutions, according to the similia principle. Curiously, at the same time, classical scientific communities have developed the concept of biosemiotics after the observation that living systems are semiotics entities able to deal with codes and meanings, even in molecule-driven processes. Not only the genetic code, but all regulatory functions in living systems represent coding processes. The development of methodologies to identify and understand these codes and its outputs is the aim of biosemiotic science. Putting both concepts together (body signifiers and biosemiotics), it is possible to recognize strong similarities between their approaches and methodology, allowing logical connections between non-molecular signals and changes in cell interactions patterns. Thus, the general concept of biosemiotic could be a theoretical platform on which the construction of a solid phenomenological description of high dilutions effects could be done.

Genome evolution in an agricultural pest following adoption of transgenic crops

Replacing synthetic insecticides with transgenic crops for pest management has been economically and environmentally beneficial, but these benefits erode as pests evolve resistance. It has been proposed that novel genomic approaches could track molecular signals of emerging resistance to aid in resistance management. To test this, we quantified patterns of genomic change in Helicoverpa zea, a major lepidopteran pest and target of transgenic Bacillus thuringiensis (Bt) crops, between 2002 and 2017 as both Bt crop adoption and resistance increased in North America. Genomic scans of wild H. zea were paired with quantitative trait locus (QTL) analyses and showed the genomic architecture of field-evolved Cry1Ab resistance was polygenic, likely arising from standing genetic variation. Resistance to pyramided Cry1A.105 and Cry2Ab2 toxins was controlled by fewer loci. Of the 11 previously described Bt resistance genes, 9 showed no significant change over time or major effects on resistance. We were unable to rule out a contribution of aminopeptidases (apns), as a cluster of apn genes were found within a Cry-associated QTL. Molecular signals of emerging Bt resistance were detectable as early as 2012 in our samples, and we discuss the potential and pitfalls of whole-genome analysis for resistance monitoring based on our findings. This first study of Bt resistance evolution using whole-genome analysis of field-collected specimens demonstrates the need for a more holistic approach to examining rapid adaptation to novel selection pressures in agricultural ecosystems.

Complex sphingolipids: Vital determinants of drug susceptibility, membrane integrity and pathogenesis of Candida glabrata

Complex Sphingolipids (SLs) are unique to fungi, which apart from being novel drug targets, also appear to act as molecular signals, in diverse biological processes. In this study, we have specifically blocked the key synthesis step of SLs metabolism by disruption of the uncharacterized CgIPT1 gene, which based on homology with other Candida spp., predicted to mediate the conversion of MIPC to M(IP)2C. We followed fusion based PCR homologous recombination method for IPT1 deletion by using dominant markerNAT1. The knockout was selected on a nourseothricin drug plate and confirmed by gene specific PCR and by checking M(IP)2C levels. We observed that the specific accumulation of MIPC or lack of M(IP)2C in C. glabrata displayed increased susceptibility to both imidazole’s (ketoconazole, miconazole and clotrimazole) and triazoles (fluconazole, itraconazole and posaconazole). RNA Sequencing of Cgipt1Δcells revealed no major impact on of expression levels of common MDR determinants albeit a distinct imbalances in expression of lipid homeostasis genes was evident. The Fluorescence Recovery after Photobleaching (FRAP) experiments confirmed that plasma membrane in Cgipt1Δ cells display a reduction in micro-viscosity leading to increase in drug diffusion and susceptibility of Cgipt1Δcells. Interestingly, the Cgipt1Δ also exhibit attenuated virulence in a murine model. Together, our data confirms the relevance of M(IP)2C in governing drug susceptibility and virulence in C. glabrata.

Identification of Genes Associated with Nitrogen Stress Responses in Apple Leaves

Nitrogen (N) is an essential macronutrient that regulates diverse physiological processes for plant survival and development. In apple orchards, inappropriate N conditions can cause imbalanced growth and subsequent physiological disorders in trees. In order to investigate the molecular basis underlying the physiological signals for N stress responses, we examined the metabolic signals responsive to contrasting N stress conditions (deficient/excessive) in apple leaves using transcriptome approaches. The clustering of differentially expressed genes (DEGs) showed the expression dynamics of genes associated with each N stress group. Functional analyses of gene ontology and pathway enrichments revealed the potential candidates of metabolic signals responsible for N-deficient/excessive stress responses. The functional interactions of DEGs in each cluster were further explored by protein–protein interaction network analysis. Our results provided a comprehensive insight into molecular signals responsive to N stress conditions, and will be useful in future research to enhance the nutrition tolerance of tree crops.

Uric Acid in Inflammation and the Pathogenesis of Atherosclerosis

Hyperuricemia is a common metabolic syndrome. Elevated uric acid levels are risk factors for gout, hypertension, and chronic kidney diseases. Furthermore, various epidemiological studies have also demonstrated an association between cardiovascular risks and hyperuricemia. In hyperuricemia, reactive oxygen species (ROS) are produced simultaneously with the formation of uric acid by xanthine oxidases. Intracellular uric acid has also been reported to promote the production of ROS. The ROS and the intracellular uric acid itself regulate several intracellular signaling pathways, and alterations in these pathways may result in the development of atherosclerotic lesions. In this review, we describe the effect of uric acid on various molecular signals and the potential mechanisms of atherosclerosis development in hyperuricemia. Furthermore, we discuss the efficacy of treatments for hyperuricemia to protect against the development of atherosclerosis.

Regulation of Limbal Epithelial Stem Cells: Importance of the Niche

Limbal epithelial stem/progenitor cells (LSCs) reside in a niche that contains finely tuned balances of various signaling pathways including Wnt, Notch, BMP, Shh, YAP, and TGFβ. The activation or inhibition of these pathways is frequently dependent on the interactions of LSCs with various niche cell types and extracellular substrates. In addition to receiving molecular signals from growth factors, cytokines, and other soluble molecules, LSCs also respond to their surrounding physical structure via mechanotransduction, interaction with the ECM, and interactions with other cell types. Damage to LSCs or their niche leads to limbal stem cell deficiency (LSCD). The field of LSCD treatment would greatly benefit from an understanding of the molecular regulation of LSCs in vitro and in vivo. This review synthesizes current literature around the niche factors and signaling pathways that influence LSC function. Future development of LSCD therapies should consider all these niche factors to achieve improved long-term restoration of the LSC population.

Monocytes, Macrophages, and Their Potential Niches in Synovial Joints – Therapeutic Targets in Post-Traumatic Osteoarthritis?

Synovial joints are complex structures that enable normal locomotion. Following injury, they undergo a series of changes, including a prevalent inflammatory response. This increases the risk for development of osteoarthritis (OA), the most common joint disorder. In healthy joints, macrophages are the predominant immune cells. They regulate bone turnover, constantly scavenge debris from the joint cavity and, together with synovial fibroblasts, form a protective barrier. Macrophages thus work in concert with the non-hematopoietic stroma. In turn, the stroma provides a scaffold as well as molecular signals for macrophage survival and functional imprinting: “a macrophage niche”. These intricate cellular interactions are susceptible to perturbations like those induced by joint injury. With this review, we explore how the concepts of local tissue niches apply to synovial joints. We introduce the joint micro-anatomy and cellular players, and discuss their potential interactions in healthy joints, with an emphasis on molecular cues underlying their crosstalk and relevance to joint functionality. We then consider how these interactions are perturbed by joint injury and how they may contribute to OA pathogenesis. We conclude by discussing how understanding these changes might help identify novel therapeutic avenues with the potential of restoring joint function and reducing post-traumatic OA risk.