Commun Biol. 2023 Jul 25;6(1):774. doi: 10.1038/s42003-023-05155-9.

ABSTRACT

Rare or de novo variants have substantial contribution to human diseases, but the statistical power to identify risk genes by rare variants is generally low due to rarity of genotype data. Previous studies have shown that risk genes usually have high expression in relevant cell types, although for many conditions the identity of these cell types are largely unknown. Recent efforts in single cell atlas in human and model organisms produced large amount of gene expression data. Here we present VBASS, a Bayesian method that integrates single-cell expression and de novo variant (DNV) data to improve power of disease risk gene discovery. VBASS models disease risk prior as a function of expression profiles, approximated by deep neural networks. It learns the weights of neural networks and parameters of Gamma-Poisson likelihood models of DNV counts jointly from expression and genetics data. On simulated data, VBASS shows proper error rate control and better power than state-of-the-art methods. We applied VBASS to published datasets and identified more candidate risk genes with supports from literature or data from independent cohorts. VBASS can be generalized to integrate other types of functional genomics data in statistical genetics analysis.

PMID:37491581 | DOI:10.1038/s42003-023-05155-9

Sci Rep. 2023 Jul 25;13(1):12028. doi: 10.1038/s41598-023-36099-z.

ABSTRACT

Animal sensory systems are tightly adapted to the demands of their environment. In the visual domain, research has shown that many species have circuits and systems that exploit statistical regularities in natural visual signals. The zebrafish is a popular model animal in visual neuroscience, but relatively little quantitative data is available about the visual properties of the aquatic habitats where zebrafish reside, as compared to terrestrial environments. Improving our understanding of the visual demands of the aquatic habitats of zebrafish can enhance the insights about sensory neuroscience yielded by this model system. We analyzed a video dataset of zebrafish habitats captured by a stationary camera and compared this dataset to videos of terrestrial scenes in the same geographic area. Our analysis of the spatiotemporal structure in these videos suggests that zebrafish habitats are characterized by low visual contrast and strong motion when compared to terrestrial environments. Similar to terrestrial environments, zebrafish habitats tended to be dominated by dark contrasts, particularly in the lower visual field. We discuss how these properties of the visual environment can inform the study of zebrafish visual behavior and neural processing and, by extension, can inform our understanding of the vertebrate brain.

PMID:37491571 | DOI:10.1038/s41598-023-36099-z

Sci Rep. 2023 Jul 25;13(1):12040. doi: 10.1038/s41598-023-38886-0.

ABSTRACT

Mammographic breast cancer screening is effective in reducing breast cancer mortality. Nevertheless, several limitations are known. Therefore, developing an alternative or complementary non-invasive tool capable of increasing the accuracy of the screening process is highly desirable. The objective of this study was to identify circulating microRNA (miRs) ratios associated with BC in women attending mammography screening. A nested case-control study was conducted within the ANDROMEDA cohort (women of age 46-67 attending BC screening). Pre-diagnostic plasma samples, information on life-styles and common BC risk factors were collected. Small-RNA sequencing was carried out on plasma samples from 65 cases and 66 controls. miR ratios associated with BC were selected by two-sample Wilcoxon test and lasso logistic regression. Subsequent assessment by RT-qPCR of the miRs contained in the selected miR ratios was carried out as a platform validation. To identify the most promising biomarkers, penalised logistic regression was further applied to candidate miR ratios alone, or in combination with non-molecular factors. Small-RNA sequencing yielded 20 candidate miR ratios associated with BC, which were further assessed by RT-qPCR. In the resulting model, penalised logistic regression selected seven miR ratios (miR-199a-3p_let-7a-5p, miR-26b-5p_miR-142-5p, let-7b-5p_miR-19b-3p, miR-101-3p_miR-19b-3p, miR-93-5p_miR-19b-3p, let-7a-5p_miR-22-3p and miR-21-5p_miR-23a-3p), together with body mass index (BMI), menopausal status (MS), the interaction term BMI * MS, life-style score and breast density. The ROC AUC of the model was 0.79 with a sensitivity and specificity of 71.9% and 76.6%, respectively. We identified biomarkers potentially useful for BC screening measured through a widespread and low-cost technique. This is the first study reporting circulating miRs for BC detection in a screening setting. Validation in a wider sample is warranted.Trial registration: The Andromeda prospective cohort study protocol was retrospectively registered on 27-11-2015 (NCT02618538).

PMID:37491482 | DOI:10.1038/s41598-023-38886-0

Nature. 2023 Jul 25. doi: 10.1038/s41586-023-06403-y. Online ahead of print.

NO ABSTRACT

PMID:37491470 | DOI:10.1038/s41586-023-06403-y

Nat Rev Microbiol. 2023 Jul 25. doi: 10.1038/s41579-023-00933-y. Online ahead of print.

ABSTRACT

Antibiotic-mediated perturbation of the gut microbiome is associated with numerous infectious and autoimmune diseases of the gastrointestinal tract. Yet, as the gut microbiome is a complex ecological network of microorganisms, the effects of antibiotics can be highly variable. With the advent of multi-omic approaches for systems-level profiling of microbial communities, we are beginning to identify microbiome-intrinsic and microbiome-extrinsic factors that affect microbiome dynamics during antibiotic exposure and subsequent recovery. In this Review, we discuss factors that influence restructuring of the gut microbiome on antibiotic exposure. We present an overview of the currently complex picture of treatment-induced changes to the microbial community and highlight essential considerations for future investigations of antibiotic-specific outcomes. Finally, we provide a synopsis of available strategies to minimize antibiotic-induced damage or to restore the pretreatment architectures of the gut microbial community.

PMID:37491458 | DOI:10.1038/s41579-023-00933-y

PLoS One. 2023 Jul 25;18(7):e0289098. doi: 10.1371/journal.pone.0289098. eCollection 2023.

ABSTRACT

Chronic smoking is a primary risk factor for breast cancer due to the presence of various toxins and carcinogens within tobacco products. Nicotine is the primary addictive component of tobacco products and has been shown to promote breast cancer cell proliferation and metastases. Nicotine activates nicotinic acetylcholine receptors (nAChRs) that are expressed in cancer cell lines. Here, we examine the role of the α7 nAChR in coupling to heterotrimeric G proteins within breast cancer MCF-7 cells. Pharmacological activation of the α7 nAChR using choline or nicotine was found to increase proliferation, motility, and calcium signaling in MCF-7 cells. This effect of α7 nAChR on cell proliferation was abolished by application of Gαi/o and Gαq protein blockers. Specifically, application of the Gαi/o inhibitor pertussis toxin was found to abolish choline-mediated cell proliferation and intracellular calcium transient response. These findings were corroborated by expression of a G protein binding dominant negative nAChR subunit (α7345-348A), which resulted in significantly attenuating calcium signaling and cellular proliferation in response to choline. Our study shows a new role for G protein signaling in the mechanism of α7 nAChR-associated breast cancer growth.

PMID:37490473 | DOI:10.1371/journal.pone.0289098

Bioinformatics. 2023 Jul 25:btad455. doi: 10.1093/bioinformatics/btad455. Online ahead of print.

ABSTRACT

SUMMARY: The Integrated Probabilistic Annotation (IPA) is an automated annotation method for LC-MS-based untargeted metabolomics experiments, that provides statistically rigorous estimates of the probabilities associated with each annotation. Here we introduce ipaPy2, a substantially improved and completely refactored Python implementation of the IPA method. The revised method is now able to integrate tandem MS fragmentation data, which increases the accuracy of the identifications. Moreover, ipaPy2 provides a much more user-friendly interface, and isotope peaks are no longer treated as individual features, but integrated into isotope fingerprints, greatly speeding up the calculations. The method has also been fully integrated with the mzMatch pipeline, so that the results of the annotation can be explored through the newly developed PeakMLViewerPy tool available at https://github.com/UoMMIB/PeakMLViewerPy.

AVAILABILITY AND IMPLEMENTATION: The source code, extensive documentation and tutorials are freely available on GitHub at https://github.com/francescodc87/ipaPy2.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:37490466 | DOI:10.1093/bioinformatics/btad455

Int Microbiol. 2023 Jul 25. doi: 10.1007/s10123-023-00408-3. Online ahead of print.

ABSTRACT

Indole is a typical heterocyclic compound derived from tryptophan widespread in nature. Pseudomonas aeruginosa is one of the most common opportunistic pathogens everywhere in the world. Indole and P. aeruginosa will encounter inevitably; however, the indole transformation process by P. aeruginosa remains unclear. Herein, an indole-degrading strain of P. aeruginosa Jade-X was isolated from activated sludge. Strain Jade-X could degrade 1 mmol/L indole within 48 h with the inoculum size of 1% (v/v). It showed high efficiency in indole degradation under the conditions of 30-42 °C, pH 5.0-9.0, and NaCl concentration less than 2.5%. The complete genome of strain Jade-X was sequenced which was 6508614 bp in length with one chromosome. Bioinformatic analyses showed that strain Jade-X did not contain the indole oxygenase gene. Three cytochrome P450 genes were identified and up-regulated in the indole degradation process by RT-qPCR analysis, while cytochrome P450 inhibitors did not affect the indole degradation process. It suggested that indole oxidation was catalyzed by an unraveled enzyme. An ant gene cluster was identified, among which the anthranilate 1,2-dioxygenase and catechol 1,2-dioxygenase genes were upregulated. An indole-anthranilate-catechol pathway was proposed in indole degradation by strain P. aeruginosa Jade-X. This study enriched our understanding of the indole biodegradation process in P. aeruginosa.

PMID:37490176 | DOI:10.1007/s10123-023-00408-3

Elife. 2023 Jul 25;12:e83659. doi: 10.7554/eLife.83659.

ABSTRACT

Effector T cells need to form immunological synapses (IS) with recognized target cells to elicit cytolytic effects. Facilitating IS formation is the principal pharmacological action of most T cell-based cancer immunotherapies. However, the dynamics of IS formation at the cell population level, the primary driver of the pharmacodynamics of many cancer immunotherapies, remains poorly defined. Using classic immunotherapy CD3/CD19 bispecific T cell engager (BiTE) as our model system, we integrate experimental and theoretical approaches to investigate the population dynamics of IS formation and their relevance to clinical pharmacodynamics and treatment resistance. Our models produce experimentally consistent predictions when defining IS formation as a series of spatiotemporally coordinated events driven by molecular and cellular interactions. The models predict tumor-killing pharmacodynamics in patients and reveal trajectories of tumor evolution across anatomical sites under BiTE immunotherapy. Our models highlight the bone marrow as a potential sanctuary site permitting tumor evolution and antigen escape. The models also suggest that optimal dosing regimens are a function of tumor growth, CD19 expression, and patient T cell abundance, which confer adequate tumor control with reduced disease evolution. This work has implications for developing more effective T cell-based cancer immunotherapies.

PMID:37490053 | DOI:10.7554/eLife.83659

mBio. 2023 Jul 25:e0141323. doi: 10.1128/mbio.01413-23. Online ahead of print.

ABSTRACT

For its replication within red blood cells, the malaria parasite depends on a highly active and regulated lipid metabolism. Enzymes involved in lipid metabolic processes such as phospholipases are, therefore, potential drug targets. Here, using reverse genetics approaches, we show that only 1 out of the 19 putative phospholipases expressed in asexual blood stages of Plasmodium falciparum is essential for proliferation in vitro, pointing toward a high level of redundancy among members of this enzyme family. Using conditional mislocalization and gene disruption techniques, we show that this essential phosphoinositide-specific phospholipase C (PI-PLC, PF3D7_1013500) has a previously unrecognized essential role during intracellular parasite maturation, long before its previously perceived role in parasite egress and invasion. Subsequent lipidomic analysis suggests that PI-PLC mediates cleavage of phosphatidylinositol bisphosphate (PIP2) in schizont-stage parasites, underlining its critical role in regulating phosphoinositide levels in the parasite. IMPORTANCE The clinical symptoms of malaria arise due to repeated rounds of replication of Plasmodium parasites within red blood cells (RBCs). Central to this is an intense period of membrane biogenesis. Generation of membranes not only requires de novo synthesis and acquisition but also the degradation of phospholipids, a function that is performed by phospholipases. In this study, we investigate the essentiality of the 19 putative phospholipase enzymes that the human malaria parasite Plasmodium falciparum expresses during its replication within RBCs. We not only show that a high level of functional redundancy exists among these enzymes but, at the same time, also identify an essential role for the phosphoinositide-specific phospholipase C in parasite development and cleavage of the phospholipid phosphatidylinositol bisphosphate.

PMID:37489900 | DOI:10.1128/mbio.01413-23

J Dev Biol. 2023 Jul 8;11(3):32. doi: 10.3390/jdb11030032.

ABSTRACT

Cells in a developing animal embryo become specified by the activation of cell-type-specific gene regulatory networks. The network that specifies the gut in the nematode Caenorhabditis elegans has been the subject of study for more than two decades. In this network, the maternal factors SKN-1/Nrf and POP-1/TCF activate a zygotic GATA factor cascade consisting of the regulators MED-1,2 → END-1,3 → ELT-2,7, leading to the specification of the gut in early embryos. Paradoxically, the MED, END, and ELT-7 regulators are present only in species closely related to C. elegans, raising the question of how the gut can be specified without them. Recent work found that ELT-3, a GATA factor without an endodermal role in C. elegans, acts in a simpler ELT-3 → ELT-2 network to specify gut in more distant species. The simpler ELT-3 → ELT-2 network may thus represent an ancestral pathway. In this review, we describe the elucidation of the gut specification network in C. elegans and related species and propose a model by which the more complex network might have formed. Because the evolution of this network occurred without a change in phenotype, it is an example of the phenomenon of Developmental System Drift.

PMID:37489333 | DOI:10.3390/jdb11030032

Nat Genet. 2023 Jul 24. doi: 10.1038/s41588-023-01450-7. Online ahead of print.

ABSTRACT

Comprehensive enhancer discovery is challenging because most enhancers, especially those contributing to complex diseases, have weak effects on gene expression. Our gene regulatory network modeling identified that nonlinear enhancer gene regulation during cell state transitions can be leveraged to improve the sensitivity of enhancer discovery. Using human embryonic stem cell definitive endoderm differentiation as a dynamic transition system, we conducted a mid-transition CRISPRi-based enhancer screen. We discovered a comprehensive set of enhancers for each of the core endoderm-specifying transcription factors. Many enhancers had strong effects mid-transition but weak effects post-transition, consistent with the nonlinear temporal responses to enhancer perturbation predicted by the modeling. Integrating three-dimensional genomic information, we were able to develop a CTCF-loop-constrained Interaction Activity model that can better predict functional enhancers compared to models that rely on Hi-C-based enhancer-promoter contact frequency. Our study provides generalizable strategies for sensitive and systematic enhancer discovery in both normal and pathological cell state transitions.

PMID:37488417 | DOI:10.1038/s41588-023-01450-7

Target Oncol. 2023 Jul 24. doi: 10.1007/s11523-023-00983-5. Online ahead of print.

ABSTRACT

BACKGROUND: There is growing evidence supporting multidisciplinary molecular tumor boards (MTB) in solid tumors whereas hematologic malignancies remain underrepresented in this regard.

OBJECTIVE: The present study aimed to assess the clinical relevance of MTBs in primary refractory diffuse large B-cell lymphomas/high-grade B-cell lymphomas with MYC and BCL2 rearrangements (prDLBCL/HGBL-MYC/BCL2) (n = 13) and HGBL, not otherwise specified (NOS), with MYC and BCL6 rearrangements (prHGBL, NOS-MYC/BCL6) (n = 6) based on our previously published whole-exome sequencing (WES) cohort.

PATIENTS AND METHODS: For genomic analysis, the institutional MTB WES pipeline (University Cancer Center Schleswig-Holstein: UCCSH), certified for routine clinical diagnostics, was employed and supplemented by a comprehensive immunohistochemical work-up. Consecutive database research and annotation according to established evidence levels for molecularly stratified therapies was performed (NCT-DKTK/ESCAT).

RESULTS: Molecularly tailored treatment options with NCT-DKTK evidence level of at least m2A were identified in each case. We classified mutations in accordance with biomarker/treatment baskets and detected a heterogeneous spectrum of targetable alterations affecting immune evasion (IE; n = 30), B-cell targets (BCT; n = 26), DNA damage repair (DDR; n = 20), tyrosine kinases (TK; n = 13), cell cycle (CC; n = 7), PI3K-MTOR-AKT pathway (PAM; n = 2), RAF-MEK-ERK cascade (RME; n = 1), and others (OTH; n = 11).

CONCLUSION: Our virtual MTB approach identified potential molecularly targeted treatment options alongside targetable genomic signatures for both prDLBCL/HGBL-MYC/BCL2 and prHGBL, NOS-MYC/BCL6. These results underline the potential of MTB consultations in difficult-to-treat lymphomas early in the treatment sequence.

PMID:37488307 | DOI:10.1007/s11523-023-00983-5

Sci Rep. 2023 Jul 24;13(1):11978. doi: 10.1038/s41598-023-39250-y.

ABSTRACT

The Neolithic burial of Grotta di Pietra Sant'Angelo (CS) represents a unique archaeological finding for the prehistory of Southern Italy. The unusual placement of the inhumation at a rather high altitude and far from inhabited areas, the lack of funerary equipment and the prone deposition of the body find limited similarities in coeval Italian sites. These elements have prompted wider questions on mortuary customs during the prehistory of Southern Italy. This atypical case requires an interdisciplinary approach aimed to build an integrated bioarchaeological profile of the individual. The paleopathological investigation of the skeletal remains revealed the presence of numerous markers that could be associated with craft activities, suggesting possible interpretations of the individual's lifestyle. CT analyses, carried out on the maxillary bones, showed the presence of a peculiar type of dental wear, but also a good density of the bone matrix. Biomolecular and micromorphological analyses of dental calculus highlight the presence of a rich Neolithic-like oral microbiome, the composition of which is consistent with the presence pathologies. Finally, paleogenomic data obtained from the individual were compared with ancient and modern Mediterranean populations, including unpublished high-resolution genome-wide data for 20 modern inhabitants of the nearby village of San Lorenzo Bellizzi, which provided interesting insights into the biodemographic landscape of the Neolithic in Southern Italy.

PMID:37488251 | DOI:10.1038/s41598-023-39250-y

Sci Rep. 2023 Jul 24;13(1):11931. doi: 10.1038/s41598-023-38860-w.

ABSTRACT

Varroa mites are serious pests of European honeybees (Apis mellifera). For detection of Varroa mite, a new molecular LAMP-based assay has been developed, which retains the body of the mite intact for morphological identification. Six novel Varroa LAMP primers were designed from existing DNA sequences of the COI locus to target V. destructor and V. jacobsoni, providing the ability to tell them apart from other non-target beehive associated mite and insect species. This LAMP assay is specific in detecting these Varroa species and has been tested on specimens originating from multiple countries. It produces amplification of V. destructor and V. jacobsoni in 16 ± 3.4 min with an anneal derivative of 78 ± 0.5 °C whilst another Varroa species,V. underwoodi, showed late amplification. A gBlock gene fragment, used here as a positive control has a different anneal derivative of 80 °C. Three non-destructive DNA extraction methods (HotShot, QuickExtract and Xtract) were tested and found to be suitable for use in the field. The LAMP assay was sensitive to very low levels of Varroa DNA, down to 0.24 picogram (~ 1 × 10 copies/µL of Varroa gBlock). This is a new molecular tool for rapid and accurate detection and identification of Varroa mites for pest management, in areas where these mites do not occur.

PMID:37488147 | DOI:10.1038/s41598-023-38860-w

Biosystems. 2023 Jul 22:104982. doi: 10.1016/j.biosystems.2023.104982. Online ahead of print.

ABSTRACT

In this work we present a systematic mathematical approximation scheme that exposes the way that information, about the evolutionary forces of selection and random genetic drift, is encoded within gene-frequency trajectories. We determine approximate, time-dependent, gene-frequency trajectory statistics, assuming additive selection. We use the probability of fixation to test and illustrate the approximation scheme introduced. For the case where the strength of selection and the effective population size have constant values, we show how a standard diffusion approximation result, for the probability of fixation, systematically emerges when increasing numbers of approximate trajectory statistics are taken into account. We then provide examples of how time-dependent parameters influence gene-frequency statistics.

PMID:37488034 | DOI:10.1016/j.biosystems.2023.104982

FEBS Lett. 2023 Jul 24. doi: 10.1002/1873-3468.14699. Online ahead of print.

ABSTRACT

The systematic identification of tumour vulnerabilities through perturbational experiments on cancer models, including genome editing and drug screens, is playing a crucial role in combating cancer. This collective effort is known as the Cancer Dependency Map (DepMap). The 1st European Cancer Dependency Map Symposium (EuroDepMap), held in Milan last May, featured talks, a roundtable discussion, and a poster session, showcasing the latest discoveries and future challenges related to the DepMap. The symposium aimed to facilitate interactions among participants across Europe, encourage idea exchange with leading experts, and present their work and future projects. Importantly, it sparked discussions on future endeavours, such as screening more complex cancer models and accounting for tumour evolution.

PMID:37487655 | DOI:10.1002/1873-3468.14699

Comput Biol Chem. 2023 Jul 21;106:107934. doi: 10.1016/j.compbiolchem.2023.107934. Online ahead of print.

ABSTRACT

Regeneration is a homeostatic process that involves the restoration of cells and body parts. Most of the molecular mechanisms and signalling pathways involved in wound healing, such as proliferation, have also been associated with cancer cell growth, suggesting that cancer is an over/unhealed wound. In this study, we examined differentially expressed genes in spinal cord samples from regenerative organisms (axolotl and zebrafish) and nonregenerative organisms (mouse and rat) compared to intact control spinal cord samples using publicly available transcriptomics data and bioinformatics analyses. Based on these gene signatures, we investigated 3 small compounds, namely cucurbitacin I, BMS-754807, and PHA-793887 as potential candidates for the treatment of cancer. The predicted target genes of the repositioned compounds were mainly enriched with the greatest number of genes in cancer pathways. The molecular docking results on the binding affinity between the repositioned compounds and their target genes are also reported. The repositioned 3 small compounds showed anticancer effect both in 2D and 3D cell cultures using the prostate cancer cell line as a model. We propose cucurbitacin I, BMS-754807, and PHA-793887 as potential anticancer drug candidates. Future studies on the mechanisms associated with the revealed gene signatures and anticancer effects of these three small compunds would allow scientists to develop therapeutic approaches to combat cancer. This research contributes to the evaluation of mechanisms and gene signatures that either limit or cause cancer, and to the development of new cancer therapies by establishing a link between regeneration and carcinogenesis.

PMID:37487250 | DOI:10.1016/j.compbiolchem.2023.107934

Proc Natl Acad Sci U S A. 2023 Aug;120(31):e2301972120. doi: 10.1073/pnas.2301972120. Epub 2023 Jul 24.

ABSTRACT

PARP1 (poly-ADP ribose polymerase 1) is recruited and activated by DNA strand breaks, catalyzing the generation of poly-ADP-ribose (PAR) chains from NAD+. PAR relaxes chromatin and recruits other DNA repair factors, including XRCC1 and DNA Ligase 3, to maintain genomic stability. Here we show that, in contrast to the normal development of Parp1-null mice, heterozygous expression of catalytically inactive Parp1 (E988A, Parp1+/A) acts in a dominant-negative manner to disrupt murine embryogenesis. As such, all the surviving F1 Parp1+/A mice are chimeras with mixed Parp1+/AN (neoR retention) cells that act similarly to Parp1+/-. Pure F2 Parp1+/A embryos were found at Mendelian ratios at the E3.5 blastocyst stage but died before E9.5. Compared to Parp1-/- cells, genotype and expression-validated pure Parp1+/A cells retain significant ADP-ribosylation and PARylation activities but accumulate markedly higher levels of sister chromatid exchange and mitotic bridges. Despite proficiency for homologous recombination and nonhomologous end-joining measured by reporter assays and supported by normal lymphocyte and germ cell development, Parp1+/A cells are hypersensitive to base damages, radiation, and Topoisomerase I and II inhibition. The sensitivity of Parp1+/A cells to base damages and Topo inhibitors exceed Parp1-/- controls. The findings show that the enzymatically inactive PARP1 dominant negatively blocks DNA repair in selective pathways beyond wild-type PARP1 and establishes a crucial physiological difference between PARP1 inactivation vs. deletion. As a result, the expression of enzymatically inactive PARP1 from one allele is sufficient to abrogate murine embryonic development, providing a mechanism for the on-target side effect of PARP inhibitors used for cancer therapy.

PMID:37487079 | DOI:10.1073/pnas.2301972120

Hepatol Commun. 2023 Jul 24;7(8):e0208. doi: 10.1097/HC9.0000000000000208. eCollection 2023 Aug 1.

ABSTRACT

BACKGROUND: Macrophages play an important role in maintaining liver homeostasis and regeneration. However, it is not clear to what extent the different macrophage populations of the liver differ in terms of their activation state and which other liver cell populations may play a role in regulating the same.

METHODS: Reverse transcription PCR, flow cytometry, transcriptome, proteome, secretome, single cell analysis, and immunohistochemical methods were used to study changes in gene expression as well as the activation state of macrophages in vitro and in vivo under homeostatic conditions and after partial hepatectomy.

RESULTS: We show that F4/80+/CD11bhi/CD14hi macrophages of the liver are recruited in a C-C motif chemokine receptor (CCR2)-dependent manner and exhibit an activation state that differs substantially from that of the other liver macrophage populations, which can be distinguished on the basis of CD11b and CD14 expressions. Thereby, primary hepatocytes are capable of creating an environment in vitro that elicits the same specific activation state in bone marrow-derived macrophages as observed in F4/80+/CD11bhi/CD14hi liver macrophages in vivo. Subsequent analyses, including studies in mice with a myeloid cell-specific deletion of the TGF-β type II receptor, suggest that the availability of activated TGF-β and its downregulation by a hepatocyte-conditioned milieu are critical. Reduction of TGF-βRII-mediated signal transduction in myeloid cells leads to upregulation of IL-6, IL-10, and SIGLEC1 expression, a hallmark of the activation state of F4/80+/CD11bhi/CD14hi macrophages, and enhances liver regeneration.

CONCLUSIONS: The availability of activated TGF-β determines the activation state of specific macrophage populations in the liver, and the observed rapid transient activation of TGF-β may represent an important regulatory mechanism in the early phase of liver regeneration in this context.

PMID:37486964 | DOI:10.1097/HC9.0000000000000208