Background The bone marrow (BM) is a major reservoir of resting memory T cells and long-lived plasma cells, capable of providing protection against recurrent infections. Whether the age-related accumulation of adipose tissue in the BM affects the functionality and maintenance of memory cells is not well understood. Methods For the first time, we compare human femur marrow adipose tissue (fMAT) and subcutaneous white adipose tissue of the thigh (tsWAT) obtained from the same donors. Therefore, we used microarrays for comparative global gene expression analysis, and employed assays to analyse parameters of adipocyte biology, inflammation and oxidative stress. Findings We show that fMAT adipocytes differ significantly from tsWAT adipocytes regarding specific gene expression profiles including inflammatory responses and adipogenesis/adipocyte phenotype. Concomitant with considerably lower levels of CD36, a membrane-associated protein important for long-chain fatty acid uptake that is used as maturation marker, fMAT adipocytes are smaller and contain less triglycerides. fMAT adipocytes secrete similar levels of adiponectin and leptin as tsWAT adipocytes, and express increased levels of pro-inflammatory molecules concomitant with an elevated generation of reactive oxygen species (ROS) and impaired function of plasma cells in the BM. Interpretation Our findings suggest that fMAT is a unique type of adipose tissue containing small adipocytes with lower CD36 protein and triglyceride levels than tsWAT but high adipokine secretion. Moreover, fMAT adipocytes secrete high levels of pro-inflammatory cytokines, contributing to inflammation and impairment of plasma cell function in the BM, suggesting that fMAT has more immune regulatory functions than tsWAT.

Pharmacological HIV-1 reactivation to reverse latent infection has been extensively studied. However, HIV-1 reactivation also occurs naturally, as evidenced by occasional low-level viremia (“viral blips”) during antiretroviral treatment (ART). Clarifying where blips originate from and how they happen could provide clues to stimulate latency reversal more effectively and safely or to prevent viral rebound following ART cessation. We studied HIV-1 reactivation in the female genital tract, a dynamic anatomical target for HIV-1 infection throughout all disease stages. We found that primary endocervical epithelial cells from several women reactivated HIV-1 from latently infected T cells. The endocervical cells’ HIV-1 reactivation capacity further increased upon Toll-like receptor 3 stimulation with poly(I·C) double-stranded RNA or infection with herpes simplex virus 2 (HSV-2). Notably, acyclovir did not eliminate HSV-2-induced HIV-1 reactivation. While endocervical epithelial cells secreted large amounts of several cytokines and chemokines, especially tumor necrosis factor alpha (TNF-α), CCL3, CCL4, and CCL20, their HIV-1 reactivation capacity was almost completely blocked by TNF-α neutralization alone. Thus, immunosurveillance activities by columnar epithelial cells in the endocervix can cause endogenous HIV-1 reactivation, which may contribute to viral blips during ART or rebound following ART interruption. IMPORTANCE A reason that there is no universal cure for HIV-1 is that the virus can hide in the genome of infected cells in the form of latent proviral DNA. This hidden provirus is protected from antiviral drugs until it eventually reactivates to produce new virions. It is not well understood where in the body or how this reactivation occurs. We studied HIV-1 reactivation in the female genital tract, which is often the portal of HIV-1 entry and which remains a site of infection throughout the disease. We found that the columnar epithelial cells lining the endocervix, the lower part of the uterus, are particularly effective in reactivating HIV-1 from infected T cells. This activity was enhanced by certain microbial stimuli, including herpes simplex virus 2, and blocked by antibodies against the inflammatory cytokine TNF-α. Avoiding HIV-1 reactivation could be important for maintaining a functional HIV-1 cure when antiviral therapy is stopped.

Schizophrenia is a neuropsychiatric disorder, caused by a combination of genetic and environmental factors. Recently, metabolomic studies based on patients’ biofluids and post-mortem brain specimens have revealed altered levels of distinct metabolites between healthy individuals and patients with schizophrenia (SCZ). However, a putative link between dysregulated metabolites and distorted neurodevelopment has not been assessed and access to patients’ material is restricted. In this study, we aimed to investigate a presumed correlation between transcriptomics and metabolomics in a SCZ model using patient-derived induced pluripotent stem cells (iPSCs). iPSCs were differentiated towards cortical neurons and samples were collected longitudinally at defined developmental stages, such as neuroepithelium, radial glia, young and mature neurons. Samples were subsequently analyzed by bulk RNA-sequencing and targeted metabolomics. The transcriptomic analysis revealed dysregulations in several extracellular matrix-related genes in the SCZ samples observed in early neurogenesis, including members of the collagen superfamily. At the metabolic level, several lipid and amino acid discrepancies were correlated to the SCZ phenotype. By employing a novel in silico analysis, we correlated the transcriptome with the metabolome through the generation of integrative networks. The network comparison between SCZ and healthy controls revealed a number of consistently affected pathways in SCZ, related to early stages of cortical development, indicating abnormalities in membrane composition, lipid homeostasis and amino acid imbalances. Ultimately, our study suggests a novel approach of correlating in vitro metabolic and transcriptomic data obtained from a patient-derived iPSC model. This type of analysis will offer novel insights in cellular and genetic mechanisms underlying the pathogenesis of complex neuropsychiatric disorders, such as schizophrenia.