Product Citations: 7

Defining the Vascular Niche of Human Adipose Tissue Across Metabolic Conditions

Preprint on BioRxiv : the Preprint Server for Biology on 23 September 2024 by AlZaim, I., Hassan, M. N., et al.

Adipose tissue physiology and homeostasis depends on a healthy vascular network. Vascular malfunction is a hallmark of obesity, and vascular endothelial dysfunction, in particular, precipitates metabolic diseases, including obesity and type two diabetes. Although single-cell transcriptomics approaches have defined atlases of human white adipose tissue (WAT) cells, the associated adipose vascular cells remain relatively undefined. Specifically, there is limited information on their heterogeneity and function, and roles in metabolic disease. To address this gap, we created a single-cell transcriptome atlas of human subcutaneous adipose tissue (SAT), comprising nearly 70,000 vascular cells from 65 individuals. We identified eight adipose endothelial cell (AdEC) populations, comprising seven canonical subtypes and a previously undescribed, heterogeneous population we named sub-AdECs. Sub-AdECs exhibit gene signatures characteristic of multiple cell types, including mesenchymal, adipocytic, and immune cells, suggesting they possess diverse properties and identities. Furthermore, we compare the transcriptomes of vascular cells from individuals living with or without obesity and type two diabetes and find metabolic disease-associated inflammatory and fibrotic transcriptomic patterns. The atlas and accompanying analyses establish a solid foundation for future investigations into the biology of vascular cells within WAT and their contributions to metabolic diseases.

  • Biochemistry and Molecular biology
  • Cell Biology

GITR activation ex vivo impairs CD8 T cell function in people with HIV on antiretroviral therapy.

In IScience on 17 November 2023 by Gubser, C., Pascoe, R. D., et al.

Glucocorticoid-induced tumor necrosis factor related protein (GITR) is a co-stimulatory immune checkpoint molecule constitutively expressed on regulatory T cells (Tregs) and on activated T conventional cells (Tconv). In blood collected from PWH on suppressive ART, GITR expression was reduced in multiple activated CD4 and CD8 T cell subsets but was increased in Tregs. HIV specific CD8 T cells expressed higher levels of GITR and programmed cell death protein 1 (PD-1) compared to total CD8 T cells. Following stimulation with HIV peptides and GITR-ligand (L), we demonstrated a significant decrease in killing by HIV specific CD8 T cells and an increased exhausted profile. T cell receptor co-stimulation with GITR-L abrogated Treg suppression and induced expansion of CD4 Tconv. We conclude that GITR activation is an additional factor contributing to an impaired HIV immune response in PWH on ART and that GITR agonist antibodies should not be pursued for HIV cure strategies.
© 2023 The Authors.

  • Homo sapiens (Human)
  • Immunology and Microbiology

IL-7 receptor signaling drives human B-cell progenitor differentiation and expansion.

In Blood on 28 September 2023 by Kaiser, F. M. P., Janowska, I., et al.

Although absence of interleukin-7 (IL-7) signaling completely abrogates T and B lymphopoiesis in mice, patients with severe combined immunodeficiency caused by mutations in the IL-7 receptor α chain (IL-7Rα) still generate peripheral blood B cells. Consequently, human B lymphopoiesis has been thought to be independent of IL-7 signaling. Using flow cytometric analysis and single-cell RNA sequencing of bone marrow samples from healthy controls and patients who are IL-7Rα deficient, in combination with in vitro modeling of human B-cell differentiation, we demonstrate that IL-7R signaling plays a crucial role in human B lymphopoiesis. IL-7 drives proliferation and expansion of early B-cell progenitors but not of pre-BII large cells and has a limited role in the prevention of cell death. Furthermore, IL-7 guides cell fate decisions by enhancing the expression of BACH2, EBF1, and PAX5, which jointly orchestrate the specification and commitment of early B-cell progenitors. In line with this observation, early B-cell progenitors of patients with IL-7Rα deficiency still expressed myeloid-specific genes. Collectively, our results unveil a previously unknown role for IL-7 signaling in promoting the B-lymphoid fate and expanding early human B-cell progenitors while defining important differences between mice and humans. Our results have implications for hematopoietic stem cell transplantation strategies in patients with T- B+ severe combined immunodeficiency and provide insights into the role of IL-7R signaling in leukemogenesis.
© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

  • Homo sapiens (Human)
  • Cardiovascular biology
  • Immunology and Microbiology

Although tocilizumab treatment in severe and critical coronavirus disease 2019 (COVID-19) patients has proven its efficacy at the clinical level, there is little evidence supporting the effect of short-term use of interleukin-6 receptor blocking therapy on the B cell sub-populations and the cross-neutralization of SARS-CoV-2 variants in convalescent COVID-19 patients. We performed immunological profiling of 69 tocilizumab-treated and non-treated convalescent COVID-19 patients in total. We observed that SARS-CoV-2-specific IgG1 titers depended on disease severity but not on tocilizumab treatment. The plasma of both treated and non-treated patients infected with the ancestral variant exhibit strong neutralizing activity against the ancestral virus and the Alpha, Beta, and Delta variants of SARS-CoV-2, whereas the Gamma and Omicron viruses were less sensitive to seroneutralization. Overall, we observed that, despite the clinical benefits of short-term tocilizumab therapy in modifying the cytokine storm associated with COVID-19 infections, there were no modifications in the robustness of B cell and IgG responses to Spike antigens.
© 2023 The Authors.

  • FC/FACS
  • COVID-19

Progressive genetic modifications of porcine cardiac xenografts extend survival to 9 months.

In Xenotransplantation on 1 May 2022 by Mohiuddin, M. M., Goerlich, C. E., et al.

We report orthotopic (life-supporting) survival of genetically engineered porcine cardiac xenografts (with six gene modifications) for almost 9 months in baboon recipients. This work builds on our previously reported heterotopic cardiac xenograft (three gene modifications) survival up to 945 days with an anti-CD40 monoclonal antibody-based immunosuppression. In this current study, life-supporting xenografts containing multiple human complement regulatory, thromboregulatory, and anti-inflammatory proteins, in addition to growth hormone receptor knockout (KO) and carbohydrate antigen KOs, were transplanted in the baboons. Selective "multi-gene" xenografts demonstrate survival greater than 8 months without the requirement of adjunctive medications and without evidence of abnormal xenograft thickness or rejection. These data demonstrate that selective "multi-gene" modifications improve cardiac xenograft survival significantly and may be foundational for paving the way to bridge transplantation in humans.
© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  • FC/FACS
  • Sus scrofa domesticus (Domestic pig)
  • Papio anubis (Olive Baboon)
  • Cardiovascular biology
  • Genetics
  • Veterinary Research
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