reticular cells
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2022 ◽  
Vol 12 ◽  
Author(s):  
Liwei Jiang ◽  
Mine Yilmaz ◽  
Mayuko Uehara ◽  
Cecilia B. Cavazzoni ◽  
Vivek Kasinath ◽  
...  

Lymph node (LN)-resident stromal cells play an essential role in the proper functioning of LNs. The stromal compartment of the LN undergoes significant compensatory changes to produce a milieu amenable for regulation of the immune response. We have identified a distinct population of leptin receptor-expressing (LepR+) stromal cells, located in the vicinity of the high endothelial venules (HEVs) and lymphatics. These LepR+ stromal cells expressed markers for fibroblastic reticular cells (FRCs), but they lacked markers for follicular dendritic cells (FDCs) and marginal reticular cells (MRCs). Leptin signaling deficiency led to heightened inflammatory responses within the LNs of db/db mice, leakiness of HEVs, and lymphatic fragmentation. Leptin signaling through the JAK/STAT pathway supported LN stromal cell survival and promoted the anti-inflammatory properties of these cells. Conditional knockout of the LepR+ stromal cells in LNs resulted in HEV and extracellular matrix (ECM) abnormalities. Treatment of ob/ob mice with an agonist leptin fusion protein restored the microarchitecture of LNs, reduced intra-LN inflammatory responses, and corrected metabolic abnormalities. Future studies are needed to study the importance of LN stomal cell dysfunction to the pathogenesis of inflammatory responses in type 2 diabetes (T2D) in humans.


JBMR Plus ◽  
2021 ◽  
Author(s):  
Branden R. Sosa ◽  
Ziqi Wang ◽  
John H. Healey ◽  
Meera Hameed ◽  
Matthew B. Greenblatt
Keyword(s):  

2021 ◽  
Author(s):  
Joshua D'Rozario ◽  
Konstantin Knoblich ◽  
Mechthild Luetge ◽  
Christian Perez Shibayama ◽  
Hung-Wei Cheng ◽  
...  

The lymph node (LN) is home to resident macrophage populations that are essential for immune function and homeostasis. The T cell paracortical zone is a major site of macrophage efferocytosis of apoptotic cells, but key factors controlling this niche are undefined. Here we show that fibroblastic reticular cells (FRCs) are an essential component of the LN macrophage niche. Macrophages co-localised with FRCs in human LNs, and murine single-cell RNA-sequencing revealed that most reticular cells expressed master macrophage regulator CSF1. Functional assays showed that CSF1R signalling was sufficient to support macrophage development. In the presence of LPS, FRCs underwent a mechanistic switch and maintained support through CSF1R-independent mechanisms. These effects were conserved between mouse and human systems. Rapid loss of macrophages and monocytes from LNs was observed upon genetic ablation of FRCs. These data reveal a critically important role for FRCs in the creation of the parenchymal macrophage niche within LNs.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 447-447
Author(s):  
Yoshiaki Abe ◽  
Mamiko Sakata-Yanagimoto ◽  
Manabu Fujisawa ◽  
Hiroaki Miyoshi ◽  
Yasuhito Suehara ◽  
...  

Abstract Background: Activities of nonhematopoietic cells (NHCs) reportedly underlie lymphomagenesis. In follicular lymphoma (FL), mesenchymal stromal cells (SCs) including follicular dendritic cells (FDCs) have been shown to facilitate FL expansion. However, comprehensive understanding of lymphoma NHC activities have been hampered by indefinite NHC heterogeneity even in normal human lymph node (LN). Indeed, human LN blood endothelial cells (BECs) and non-endothelial stromal cells (NESCs) have not been analyzed at single-cell resolution. Here, we aimed to construct a single-cell atlas of NHCs in human LN applicable to lymphoma researches. We also sought to reveal the landscape of stromal remodeling in lymphomas, particularly in FL, to advance understanding of stromal contributions in lymphomagenesis. Methods: We prospectively performed single-cell RNA sequencing of NHCs (>100,000 cells) extracted from 27 human samples including metastasis-free LN (MFLN; n=9), nodal FL (n=10), peripheral T-cell lymphoma (PTCL; n=5), and diffuse large B-cell lymphoma transformed from FL (tDLBCL; n=3). Data from MFLN samples were used for the construction of NHC atlas. Immunofluorescence (IF) staining was performed to investigate the existence and topological localizations of each NHC subcluster in the LN. Using the NHC atlas, we performed comprehensive comparative analysis with FL NHCs by differentially-expressed gene (DEG) and intercellular ligand-receptor analyses. We also investigated the prognostic impact of putative stroma-derived biomarkers using deposited microarray data of FL patients. Finally, we examined the applicability of the atlas to NHCs from other lymphoma subtypes by analyzing PTCL and tDLBCL NHCs. Data analysis was performed through multiple pipelines including Seurat, Monocle3, and CellphoneDB. Results: Graph-based clustering analysis revealed that the transcriptional features of NHC subpopulations in MFLN are detectable in FL NHCs. Unsupervised sub-clustering analysis of BECs, lymphatic endothelial cells (LECs), and NESCs revealed 10, 8, and 12 subclusters, respectively, including some lacking mouse counterpart. IF staining successfully identified each NHC subcluster and its localization in the LN. In FL NHCs, the proportion of arterial BEC subclusters markedly increased relative to MFLN, while the proportion of LECs decreased. In FL NESCs, the proportion of marginal reticular cells (MRCs) as well as FDCs greatly increased. DEG analysis revealed that the greatest changes in gene expression occurs in NESC subclusters, particularly in MRCs, T-zone reticular cells (TRCs), pericytes, and FDCs. Notably, in some NESC subclusters, we observed marked upregulation of genes relevant to solid cancers but previously not described in lymphomas (e.g. POSTN, EGFL6, and FAP). Combined interactome and DEG analysis revealed 60 FL-specific interactions between NHC subclusters and malignant B cells. For example, interactions mediated through stroma-derived CD70 were enhanced at medullary SC subclusters and SCs at LN capsule adventitia. Additionally, the CCR7-CCL19 interaction and interactions via B-cell activating factor (BAFF) were unexpectedly upregulated at non-TRC SC and medullary SC subclusters, respectively. Also, the CXCL13-CXCR5 axis was highly activated in MRCs, collectively indicating that non-FDC SCs vigorously participate in FL cell expansion and/or infiltration into extra-follicular lesions. Some intercellular interactions were functionally validated by in vitro binding assays. Based on this dataset, we identified putative stroma-derived biomarkers linked to unfavorable prognosis in FL patients including TDO2, encoding immune-modulators, and LY6H and LOX, tip cell markers. We finally confirmed that NHC subclusters identified in our atlas were also detectable in NHCs of more aggressive lymphoma subtypes including PTCL and tDLBCL. Notably, we found that extra-follicular SCs had further differentiated into follicular SCs in tDLBCL, likely representing a terminal form of stromal remodeling in FL. Conclusion: We constructed a comprehensive single-cell atlas of NHCs in human LN highly applicable to lymphoma NHC researches and revealed a total of 30 NHC subclusters. Our study largely updates NHC taxonomy in LNs and provides a rich resource and deeper insights into lymphoma biology, a contribution that should advance lymphoma management and therapy. Figure 1 Figure 1. Disclosures Usuki: Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Research Funding, Speakers Bureau; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K.: Research Funding; Celgene K.K.: Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Nippon-Boehringer-Ingelheim Co., Ltd.: Research Funding; Mundipharma K.K.: Research Funding; Amgen-Astellas Biopharma K.K.: Research Funding; Nippon-Shinyaku Co., Ltd.: Research Funding, Speakers Bureau; Kyowa-Kirin Co., Ltd.: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Research Funding, Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; MSD K.K.: Research Funding, Speakers Bureau; PharmaEssentia Japan KK: Research Funding, Speakers Bureau; Yakult Honsha Co., Ltd.: Research Funding, Speakers Bureau; Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; Sumitomo-Dainippon Pharma Co., Ltd.: Research Funding; SymBio Pharmaceuticals Ltd.: Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Research Funding; Bristol-Myers-Squibb K.K.: Research Funding, Speakers Bureau; Apellis Pharmaceuticals, Inc.: Research Funding; AbbVie GK: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Incyte Biosciences Japan G.K.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sanofi K.K.: Speakers Bureau; Amgen K.K.: Research Funding.


Author(s):  
Rahel Gerosa ◽  
Steffen Boettcher ◽  
Larisa Vladimirovna Kovtonyuk ◽  
Annika Hausmann ◽  
Wolf-Dietrich Hardt ◽  
...  

Hematopoiesis is maintained by hematopoietic stem and progenitor cells (HSPCs) that are located in the bone marrow (BM) where they are embedded within a complex supportive microenvironment, consisting of a multitude of various non-hematopoietic and hematopoietic cell types. The BM microenvironment not only regulates steady-state hematopoiesis by provision of growth factors, cytokines and cell-cell contact but is also an emerging key player during the adaptation to infectious and inflammatory insults (emergency hematopoiesis). Through a combination of gene expression analyses in prospectively isolated non-hematopoietic BM cell populations and various mouse models we have revealed that BM CXCL12-abundant reticular (CAR) cells are a major source of systemic and local BM IL-6 levels during emergency hematopoiesis following lipopolysaccharide (LPS) stimulation. Importantly, while IL-6 is dispensable during the initial phase of LPS-induced emergency hematopoiesis, it is required to sustain an adequate hematopoietic output during chronic-repetitive inflammation. Our data highlight the essential role of the non-hematopoietic BM microenvironment for the sensing and integration of pathogen-derived signals into sustained demand-adapted hematopoietic responses.


2021 ◽  
Vol 218 (10) ◽  
Author(s):  
Balthasar A. Heesters ◽  
Kyah van Megesen ◽  
Ilhan Tomris ◽  
Robert P. de Vries ◽  
Giuliana Magri ◽  
...  

Stromal-derived follicular dendritic cells (FDCs) are essential for germinal centers (GCs), the site where B cells maturate their antibodies. FDCs present native antigen to B cells and maintain a CXCL13 gradient to form the B cell follicle. Yet despite their essential role, the transcriptome of human FDCs remains undefined. Using single-cell RNA sequencing and microarray, we provided the transcriptome of these enigmatic cells as a comprehensive resource. Key genes were validated by flow cytometry and microscopy. Surprisingly, marginal reticular cells (MRCs) rather than FDCs expressed B cell activating factor (BAFF). Furthermore, we found that human FDCs expressed TLR4 and can alter antigen availability in response to pathogen-associated molecular patterns (PAMPs). High expression of PD-L1 and PD-L2 on FDCs activated PD1 on T cells. In addition, we found expression of genes related to T cell regulation, such as HLA-DRA, CD40, and others. These data suggest intimate contact between human FDCs and T cells.


2021 ◽  
Vol 8 (9) ◽  
pp. 1419
Author(s):  
Ashraf Alakkad ◽  
Mohamed Alakkad

A lady from Sudan was referred to our medical clinic as a case of cervical lymphadenopathy with gradual enlargement. She had no complaint. The cervical lymphadenopathy was not associated with pain, fever, weight loss, cough, neither bleeding nor other associated swellings. There was no history of chronic medical problems including TB and underwent thorough investigations including LN biopsy. Lymphoma was initially suspected. Fine-needle aspiration and excision biopsy were undertaken. Histological analysis later suggested Kikuchi-Fujimoto disease, also known as histiocytic necrotizing lymphadenitis. Kikuchi-Fujimoto disease (KFD) was described in 1972 as lymphadenitis with focal proliferation of reticular cells accompanied by numerous histiocytes and extensive nuclear debris. KFD, frequently found in East Asian countries, is rare in the UK. No definite etiology of KFD is known despite autoimmune and infection factors being suggested. The diagnostic hallmark is histological findings from lymph nodes. Steroid therapy could be used in severe cases. KFD is relatively unknown and this case report aims to highlight its occurrence in our population.


2021 ◽  
Author(s):  
Frank P. Assen ◽  
Miroslav Hons ◽  
Robert Hauschild ◽  
Shayan Shamipour ◽  
Jun Abe ◽  
...  

Lymph nodes (LNs) comprise two main structural elements: Fibroblastic reticular cells (FRCs) that form dedicated niches for immune cell interaction and capsular fibroblasts that build a shell around the organ. While LNs are fairly stable in size during homeostatic conditions, immunological challenge causes more than 10-fold increase in size within only a few days. How a solid organ can accommodate such extreme volumetric changes is poorly understood. Here, we characterize the biomechanics of LN swelling on the cellular and organ scale. We identify lymphocyte trapping by influx and proliferation as drivers of an outward pressure force, causing FRCs and their associated conduits to stretch. After an initial phase of relaxation, FRCs sense the resulting strain via cell matrix adhesions, which coordinates local growth and remodeling of the stromal network. While the expanded FRC network adopts its typical configuration, a massive fibrotic reaction of the organ capsule sets in and counters further organ expansion. Thus, different fibroblast populations mechanically control LN swelling in a multi-tier fashion.


Author(s):  
K. Balasundaram ◽  
S. Sivagnanam ◽  
S. Paramasivan

The white pulp of the spleen in adult goats was thoroughly screened under the scanning electron microscope (VEGA3 TESCAN). The study revealed the presence of lymphoid and non-lymphoid cells. The T lymphocytes and B lymphocytes could morphologically be differentiated under the magnification of 8000 to 20000 times by Scanning electron microscopy. The changes in number of cells in relation to the age was also recorded. The peri arterial lymphatic sheath and its structural connections with Reticular cells and other non-lymphoid cells were clearly demonstrated. The types of lymphoid cells and their arrangement around the central arteries upto the marginal zones were observed in detail. A conclusion about the type of circulation in the spleen of goats was arrived after three dimentional observation of the tissue under scanning electron microscope.


Author(s):  
Lushen Li ◽  
Jing Wu ◽  
Reza Abdi ◽  
Christopher M. Jewell ◽  
Jonathan S. Bromberg

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