Showing papers by "Urban Lendahl published in 2022"

The SARS-CoV-2 receptor ACE2 is expressed in mouse pericytes but not endothelial cells: Implications for COVID-19 vascular research

Abstract: Humanized mouse models and mouse-adapted SARS-CoV-2 virus are increasingly used to study COVID-19 pathogenesis, so it is important to learn where the SARS-CoV-2 receptor ACE2 is expressed. Here we mapped ACE2 expression during mouse postnatal development and in adulthood. Pericytes in the CNS, heart, and pancreas express ACE2 strongly, as do perineurial and adrenal fibroblasts, whereas endothelial cells do not at any location analyzed. In a number of other organs, pericytes do not express ACE2, including in the lung where ACE2 instead is expressed in bronchial epithelium and alveolar type II cells. The onset of ACE2 expression is organ specific: in bronchial epithelium already at birth, in brain pericytes before, and in heart pericytes after postnatal day 10.5. Establishing the vascular localization of ACE2 expression is central to correctly interpret data from modeling COVID-19 in the mouse and may shed light on the cause of vascular COVID-19 complications.

Identification, discrimination and heterogeneity of fibroblasts

Abstract: Abstract Fibroblasts, the principal cell type of connective tissue, secrete extracellular matrix components during tissue development, homeostasis, repair and disease. Despite this crucial role, the identification and distinction of fibroblasts from other cell types are challenging and laden with caveats. Rapid progress in single-cell transcriptomics now yields detailed molecular portraits of fibroblasts and other cell types in our bodies, which complement and enrich classical histological and immunological descriptions, improve cell class definitions and guide further studies on the functional heterogeneity of cell subtypes and states, origins and fates in physiological and pathological processes. In this review, we summarize and discuss recent advances in the understanding of fibroblast identification and heterogeneity and how they discriminate from other cell types.

Roles of Notch Signaling in the Tumor Microenvironment

Abstract: The Notch signaling pathway is an architecturally simple signaling mechanism, well known for its role in cell fate regulation during organ development and in tissue homeostasis. In keeping with its importance for normal development, dysregulation of Notch signaling is increasingly associated with different types of tumors, and proteins in the Notch signaling pathway can act as oncogenes or tumor suppressors, depending on the cellular context and tumor type. In addition to a role as a driver of tumor initiation and progression in the tumor cells carrying oncogenic mutations, it is an emerging realization that Notch signaling also plays a role in non-mutated cells in the tumor microenvironment. In this review, we discuss how aberrant Notch signaling can affect three types of cells in the tumor stroma—cancer-associated fibroblasts, immune cells and vascular cells—and how this influences their interactions with the tumor cells. Insights into the roles of Notch in cells of the tumor environment and the impact on tumor-stroma interactions will lead to a deeper understanding of Notch signaling in cancer and inspire new strategies for Notch-based tumor therapy.

Notch signalling in healthy and diseased vasculature

Abstract: Notch signalling is an evolutionarily highly conserved signalling mechanism governing differentiation and regulating homeostasis in many tissues. In this review, we discuss recent advances in our understanding of the roles that Notch signalling plays in the vasculature. We describe how Notch signalling regulates different steps during the genesis and remodelling of blood vessels (vasculogenesis and angiogenesis), including critical roles in assigning arterial and venous identities to the emerging blood vessels and regulation of their branching. We then proceed to discuss how experimental perturbation of Notch signalling in the vasculature later in development affects vascular homeostasis. In this review, we also describe how dysregulated Notch signalling, as a consequence of direct mutations of genes in the Notch pathway or aberrant Notch signalling output, contributes to various types of vascular disease, including CADASIL, Snedden syndrome and pulmonary arterial hypertension. Finally, we point out some of the current knowledge gaps and identify remaining challenges in understanding the role of Notch in the vasculature, which need to be addressed to pave the way for Notch-based therapies to cure or ameliorate vascular disease.

Active immunotherapy reduces NOTCH3 deposition in brain capillaries in a CADASIL mouse model

Abstract: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of familial small vessel disease and no preventive or curative therapy is available. CADASIL is caused by mutations in the NOTCH3 gene, resulting in a mutated NOTCH3 receptor, with aggregation of the NOTCH3 extracellular domain (ECD) around vascular smooth muscle cells. In this study we have developed a novel active immunization therapy specifically targeting CADASIL-like aggregated NOTCH3 ECD. Immunizing CADASIL TgN3R182C150 mice with aggregates composed of CADASIL-R133C mutated and wild type EGF1-5 repeats for a total of four months resulted in a marked reduction (38-48%) in NOTCH3 deposition around brain capillaries, increased microglia activation and lowered serum levels of NOTCH3 ECD. Active immunization did not impact body weight, general behavior or the number and integrity of vascular smooth muscle cells in the retina, suggesting that the therapy is tolerable. This is the first therapeutic study reporting a successful reduction of CADASIL-like NOTCH3 accumulation in mice supporting further development towards clinical application for the benefit of CADASIL patients.

100 plus years of stem cell research—20 years of ISSCR

Abstract: The International Society for Stem Cell Research (ISSCR) celebrates its 20th anniversary in 2022. This review looks back at some of the key developments in stem cell research as well as the evolution of the ISSCR as part of that field. Important discoveries from stem cell research are described, and how the improved understanding of basic stem cell biology translates into new clinical therapies and insights into disease mechanisms is discussed. Finally, the birth and growth of ISSCR into a leading stem cell society and a respected voice for ethics, advocacy, education and policy in stem cell research are described.

NOTCH3 active immunotherapy reduces NOTCH3 deposition in brain capillaries in a CADASIL mouse model

Abstract: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of familial small vessel disease and no preventive or curative therapy is available. CADASIL is caused by mutations in the NOTCH3 gene, resulting in a mutated NOTCH3 receptor, with aggregation of the NOTCH3 extracellular domain (ECD) around vascular smooth muscle cells. In this study we have developed a novel active immunization therapy specifically targeting CADASIL-like aggregated NOTCH3 ECD. Immunizing CADASIL TgN3R182C150 mice with aggregates composed of CADASIL-R133C mutated and wild type EGF1-5 repeats for a total of four months resulted in a marked reduction (38-48%) in NOTCH3 deposition around brain capillaries, increased microglia activation and lowered serum levels of NOTCH3 ECD. Active immunization did not impact body weight, general behavior or the number and integrity of vascular smooth muscle cells in the retina, suggesting that the therapy is tolerable. This is the first therapeutic study reporting a successful reduction of CADASIL-like NOTCH3 accumulation in mice supporting further development towards clinical application for the benefit of CADASIL patients.

Abstract 3351: Identification of a NOTCH transcriptomic signature for basal-like breast cancer

Abstract: Breast cancer is a heterogeneous disease, where different subtypes differ in terms of biology, treatment options and prognosis. It is an emerging view that dysregulation of major signaling pathways, including Notch signaling, contributes to breast cancer development and progression, but precisely how and in which subtypes Notch signaling is hyperactivated still largely remains to be determined. To gain further insights into dysregulation of Notch in cancer, we set out to identify and evaluate a novel Notch transcriptomic signature focusing initially on breast cancer. We first established Notch-regulated transcriptomes from six breast cancer cell of the basal subtype in response to activation of Notch (by culturing on immobilized Notch ligand) or blockade of Notch (by γ-secretase inhibitors) for 8 and 72 hours. Our data reveal that a core set of Notch-responsive genes can be identified from both time-points and we are validating the transcriptomic signature on a broader set of additional 19 breast cancer cell lines from various breast cancer subtypes. The Notch transcriptomic signature showed robust coherence scores in breast cancer patient data, and robust correlation with basal-like transcriptomes was demonstrated. Analysis of single cell transcriptomic data from breast cancer patients demonstrated that the Notch signature showed additionally good correlation with immune cells in the tumor stroma, notably tumor associated macrophages, indicating that Notch signaling is upregulated in specific cell types of the tumor stroma. Collectively, the data provide a robust transcriptional signature to read out activation of the Notch signaling pathway in basal-like breast cancer and the signature will be important to better stratify patients and to evaluate and predict outcome of future Notch-based therapies for breast cancer. Citation Format: Eike-Benjamin Braune, Felix Geist, Dirk Wienke, Anita Seshire, Urban Lendahl. Identification of a NOTCH transcriptomic signature for basal-like breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3351.