Cellular differentiation of lymphoid subpopulations and their microenvironments in the human thymus.
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Acid Phosphatase↗
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Results for “Cellular Microenvironment”
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A new in vivo model to study the influence of the microenvironment in the regeneration of the central nervous system.
In order to study the 'in vivo' regenerative capacity of the central nervous system, a semipermeable tube was placed in the axis of the lesioned nigrostriatal pathway of adult rats. In spite of a correct positioning of the tube, no growing central nervous processes were observed within the tube after 3 to 6 weeks when it was left empty. However, when the lumen of the tube was previously filled with a pre-degenerated sciatic nerve, unmyelinated and myelinated fibers were observed growing in the peripheral graft. Since the content of the tube can be modified, it appears that this model can be used to test the capability of cellular or acellular microenvironments to promote the 'in vivo' regeneration of the mammalian central nervous system fibers.
Animals↗
Integrated single-cell and spatial transcriptomic analyses reveal malignant epithelial glycolytic heterogeneity and spatial niche remodeling during colorectal cancer progression.
Colorectal cancer (CRC) progression is shaped by metabolic reprogramming and complex interactions within the tumor microenvironment. However, the cellular heterogeneity, spatial organization, and clinical relevance of glycolytic activity in CRC remain incompletely understood. In this study, we integrated single-cell RNA sequencing, bulk transcriptomics, and spatial transcriptomics data to systematically characterize glycolytic heterogeneity in CRC. Glycolytic activity was quantified using five independent scoring methods, consistently showing that epithelial cells exhibited the highest glycolytic activity across the two single-cell cohorts. Stratification of CopyKAT-verified aneuploid malignant epithelial cells into high-glycolysis (HG) and low-glycolysis (LG) subgroups by glycolysis scores revealed that HG cells exhibited higher stemness scores and chromosomal copy number variations. Cell-cell communication analysis revealed that, compared with LG cells, HG cells exhibited increased interaction frequency and strength with immune and stromal populations, indicating enhanced malignant epithelial-microenvironment crosstalk. Spatial transcriptomics analyses further revealed that glycolytic activity varied across normal colorectal tissue, primary CRC, and colorectal liver metastases, accompanied by progressive remodeling of epithelial-associated spatial niches and MIF-mediated intercellular communication. Bulk transcriptomic analysis identified a glycolysis-related prognostic signature with robust predictive performance, which served as an independent prognostic factor for overall survival in CRC cohorts. Collectively, these findings indicate that glycolytic heterogeneity is a key feature of CRC malignant epithelial cells and is closely associated with tumor progression, microenvironmental remodeling, and clinical outcomes.
Humans↗
The development of the Xenopus retinofugal pathway: optic fibers join a pre-existing tract.
The developing optic nerve and tract have received considerable attention in recent years, but the cellular and subcellular microenvironment of the growing axons has not been described. In the belief that such a description is essential (though certainly not sufficient) for an understanding of pathway formation, we have examined the normal development of the retinofugal projection of Xenopus laevis. Optic fibers were labeled anterogradely at the retina with horseradish peroxidase (HRP) or the carbocyanine dye, DiI, at stages 32 to postmetamorphosis. The brains were examined both as whole mounts and in sections, light- and electron-microscopically, with the emphasis on tracts associated with the route of the optic fibers. At stage 32, two ventral commissures were present, the anterior and postoptic. They were immediately subjacent to the pia. All tracts and even isolated axons were in similarly superficial locations. The first deep pathway (separated from the pia by cell nuclei) was seen at stage 46; it was a dorsal commissure, probably the posterior. The first retinal axons passed from the optic stalk into the ventral part of the diencephalon, where they coursed along the rostral edge of the postoptic commissure, and maintained this position, relative to the other fibers in the tract of the commissure, throughout the remainder of their contralateral trajectory. They reached the presumptive thalamic and tectal termination sites and arborized. Subsequent optic axons followed this same route, thus enlarging the optic pathway relative to the more slowly growing nonoptic part of the commissure and its tract. Electron microscopy revealed, as early as stage 35, specialized contacts between cellular processes in the neuropil. These contacts had the form of symmetric membranous thickenings; some were associated with vesicles and were presumed to be synapses. We conclude that the early forebrain and midbrain have only two ventral commissural pathways, and most axons that grow out after these pathways have formed add to them rather than establish new tracts. The optic axons travel a stereotyped pathway alongside a pre-existing tract associated with the postoptic commissure. The possibility that optic fiber outgrowth is normally influenced by pre-existing tracts is discussed in relation to recent experimental investigations of fiber growth from ectopic eyes.
Animals↗
SCMO: a deep learning model integrating the single-cell resolution TME ecosystem and multi-omics for survival prediction in CRC patients.
BACKGROUND: Colorectal cancer (CRC) remains a leading cause of global cancer mortality, highlighting the need for precise survival prediction to guide clinical decisions. Although tissue-level multi-omics is widely utilized for survival prediction, its limited resolution cannot capture tumor heterogeneity. Single-cell RNA sequencing (scRNA-seq) enables dissection of the tumor microenvironment (TME) at cellular resolution, supporting personalized prognostic assessment. METHODS: We collected 213 CRC scRNA-seq samples and established a CRC-specific TME atlas comprising 339,060 cells. Using this atlas as a reference, we deconvolved bulk RNA-seq data from TCGA-CRC cohort with the EcoTyper algorithm to reconstruct TME features. Clinical, genomic, and transcriptomic data were obtained from the Xena platform; microbial data were sourced from the BIC database. We integrated TME and multi-omics features through a self-normalizing neural network to construct a deep learning model (single-cell resolution TME ecosystem with multi-omics data [SCMO]) for survival prediction. To enhance interpretability, we utilized the Integrated Gradients algorithm and spatial transcriptomic data to analyze multi-omics and TME features. We performed anticancer drug screening with tumor necrosis factor receptor-associated protein 1 (TRAP1), a critical feature according to the Integrated Gradients algorithm, as a potential target. RESULTS: We identified 13 survival-related TME features from the CRC-specific atlas: 12 cell states and one multi-cellular ecosystem. SCMO, which combined TME and multi-omics features, improved survival prediction and outperformed existing methods, achieving a concordance index of 0.762. The SCMO demonstrated robust performance for long-term predictions, achieving areas under the curve (AUCs) of 0.752, 0.772, and 0.869 for 1-, 3-, and 5-year predictions in the training set, with corresponding test set AUCs of 0.639, 0.756, and 0.772. TME features from the SCMO model revealed that ecosystem density increased with CRC malignancy. Multi-omics features included TRAP1 as a potential drug target. Drug screening identified saikosaponin A as a novel TRAP1 inhibitor, and its anticancer activity was validated in vitro. We developed SCMO-Lite, a simplified model incorporating 12 high-attribution-weight multi-omics features, which demonstrated robust risk stratification. CONCLUSIONS: SCMO combines analytical precision with biological interpretability, offering novel insights for oncology survival prediction.
Humans↗
Microenvironmental regulation of hematopoietic stem cells.
A major challenge in hematopoietic biology is the description and understanding of the molecular mechanisms responsible for the regulation of the primitive stem cell compartment. In one sense there exists a wealth of functional and physical properties which provide insight into the biology of the stem cell and its clonal progeny. However, much of this information is descriptive and available only as a function of complex in vivo assays. In order to move beyond these limitations, in vitro systems which accurately recapitulate the self-renewal, differentiation and proliferative behaviors of stem cells are required. We have approached this issue by focusing on the in vivo stem cell microenvironment. Dissection of this microenvironment into discrete cellular entities has yielded a cell line with in vitro stem cell supportive properties consistent with those which might be expected in a stem cell niche. Studies are summarized which suggest that a single stromal cell line provides a milieu which facilitates the in vitro maintenance of transplantable stem cells as well as the generation of large populations of committed progenitors. It is anticipated that this system will allow a direct analysis of stem cell regulatory pathways.
Animals↗
B cell memory and the long-lived plasma cell.
The germinal center reaction is pivotal to the induction of B cell memory. The signals that regulate this complex microenvironment, with their cellular and molecular consequences, underpin long-term protective immunity. Recent studies have identified many key regulators of the germinal center cycle and have revealed an array of cellular outcomes that further define the memory B cell compartment.
Animals↗
Volumetric DNA microscopy for mapping spatial transcriptomes in three dimensions.
The architecture and function of biological systems are inherently three-dimensional, yet most existing spatial transcriptomic technologies remain restricted to thin tissue sections, limiting their capacity to resolve cellular organization and microenvironments within intact tissue volumes. To address this limitation, we developed volumetric DNA microscopy, a scalable, optics-free approach for spatial transcriptome profiling directly within intact biological specimens. The method encodes spatial information into DNA molecules that form a dense intermolecular network in situ, enabling the reconstruction of three-dimensional spatial relationships through short-read sequencing and computational analysis. Here we detail the complete workflow including in situ cDNA synthesis, spatial encoding through DNA nanoball formation, dual-scale proximity bridging between neighboring nanoballs and spatial reconstruction via geodesic spectral embedding. Sequencing libraries can be generated within 7-8 d by a competent graduate-level molecular biologist, followed by standardized downstream computational analysis. Because the workflow requires only routine molecular biology reagents and a benchtop sequencer, volumetric DNA microscopy provides a versatile platform for exploring genetic and morphological features in intact tissues.
Spatial Transcriptomics↗
Hematopoietic activity of a stromal cell transmembrane protein containing epidermal growth factor-like repeat motifs.
Primitive hematopoietic stem cells are closely associated with discrete in vivo microenvironments. These "niches" are thought to provide the molecular signals that mediate stem cell differentiation and self-renewal. We have dissected the fetal liver microenvironment into distinct cellular components by establishing an extensive panel of stromal cell lines. One particular cell line maintains repopulating stem cells for prolonged in vitro culture periods. A subtraction cloning strategy has yielded a cDNA that encodes a cell surface glycoprotein with a restricted pattern of expression among stromal cell lines. This molecule, previously identified as delta-like/preadipocyte factor-1, contains epidermal growth factor-like repeats that are related to those in the notch/delta/serrate family of proteins. We have investigated the potential role of this molecule in hematopoietic stem/progenitor cell regulation. We show that the delta-like protein displays activity on purified stem cells by promoting the formation of "cobblestone areas" of proliferation. These cobblestone areas contain both primitive high-proliferative potential progenitors and in vivo repopulating stem cells.
Animals↗
Neuroendocrine control of the thymus.
Thymocytes undergo a complex process of differentiation, largely dependent on interactions with the thymic microenvironment, a tridimensional cellular network formed by epithelial cells, macrophages, dendritic cells, and fibroblasts. One key cellular interaction involves the TCR-CD3 complex expressed by thymocytes with MHC-peptide complexes present on microenvironmental cells. Additionally, thymic epithelial cells (TEC) interact with thymocytes via soluble polypeptides such as thymic hormones and interleukins, as well as through extracellular matrix (ECM) ligands and receptors. Such types of heterotypic interactions are under neuroendocrine control. For example, thymic endocrine function, represented by thymulin production, is up-regulated, both in vivo and in vitro, by thyroid and pituitary hormones, including prolactin and growth hormone. We also showed that these peptides enhance the expression of ECM ligands and receptors, as well as the degree of TEC-thymocyte adhesion. In addition, we studied the thymic nurse cell complex, used herein as an in vitro model for ECM-mediated intrathymic T-cell migration. We observed that T-cell migration is also hormonally regulated as ascertained by the thymocyte entrance into and exit from these lymphoepithelial complexes. Taken together these data clearly illustrate the concept that neuroendocrine circuits exert a pleiotropic control on thymus physiology. Lastly, the intrathymic production of classic hormones such as prolactin and growth hormone suggests that, in addition to endocrine circuits, paracrine and autocrine interactions mediated by these peptides and their respective receptors may exist in the thymus, thus influencing both lymphoid and microenvironmental compartments of the organ.
Animals↗
Cell and environment interactions in tumor microregions: the multicell spheroid model.
Abnormal vascularization of malignant tumors is associated with the development of microregions of heterogeneous cells and environments. Experimental models such as multicell spheroids and a variety of new techniques are being used to determine the characteristics of these microregions and to study the interactions of the cells and microenvironments. The special cellular microecology of tumors influences responsiveness to therapeutic agents and has implications for future directions in cancer research.
Antineoplastic Agents↗
Functional anatomy of lymph nodes. I. The paracortical cords.
Histological alterations in the paracortical zones of rabbit lymph nodes were produced by the intravenous injection of the acridine dye euchrysin. The paracortical parenchyma was reduced to narrow bands of lymphoid tissue which cuffed and outlined the venules against a distended and cell-filled sinus system. These perivenous lymphocyte cuffs, termed the paracortical cords, represented the basic anatomical unit of the thymus-dependent paracortical area. Both the paracortical cords and sinuses are cell traffic pathways, but during stages of antigen-induced lymphocyte trapping the cords retain more cells than do the sinuses. Proliferation of T cells and differentiation of B cells both occur within these cords in a microenvironment conductive to cellular cooperation.
Acridines↗
Marrow reticulo-fibroblastoid colonies (CFU-RF derived) spontaneously release an erythroid colony (BFU-E) enhancing factor.
The marrow microenvironment is composed of an extracellular matrix as well as a heterogeneous population of cells. Isolation of the various cell types and analysis of their function is necessary for a better understanding of their roles in hemopoiesis. We have recently reported a colony assay for a cellular component of the marrow microenvironment. The assay consists of a cellular component of the marrow microenvironment. The assay consists of a plasma clot-methylcellulose marrow culture. The stimulator is PHA-stimulated leukocyte conditioned medium (PHA-LCM) and hydrocortisone (5 x 10(-5)M). The fibrin strands appear to act as a substrate for the growth of Reticulo-Fibroblastoid colonies derived from the CFU-RF precursor. RF colonies can be subcultured forming adherent layers when transferred to liquid cultures. Confluent adherent layers can be maintained for long periods of time by changing medium every 3 to 5 days. Supernatants derived from unstimulated RF cultures (RF-CM) were tested for growth promotion of hemopoietic precursors. We found: (1) RF-CM by itself does not induce colony formation. (2) In the presence of erythropoietin, RF-CM enhances the growth of BFU-E. (3) Recombinant IL 4 also enhances BFU-E formation, but in our assays IL 4 induced fewer colonies than RF-CM and the colonies were smaller. (4) Because neither IL 4 nor RF-CM, by themselves, can stimulate colony formation, we compared the effect of RF-CM on assays that are known to show other IL 4 functions. RF-CM did not induce proliferation of PHA induced blast T cells, a known property of IL 4.(ABSTRACT TRUNCATED AT 250 WORDS)
B-Lymphocytes↗
Cellular and molecular regulation of an erythropoietic inductive microenvironment (EIM).
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Animals↗
Tumor-immune partitioning and clustering algorithm for identifying tumor-immune cell spatial interaction signatures within the tumor microenvironment.
BACKGROUND: Growing evidence supports the importance of characterizing the organizational patterns of various cellular constituents in the tumor microenvironment in precision oncology. Most existing data on immune cell infiltrates in tumors, which are based on immune cell counts or nearest neighbor-type analyses, have failed to fully capture the cellular organization and heterogeneity. METHODS: We introduce a computational algorithm, termed Tumor-Immune Partitioning and Clustering (TIPC), that jointly measures immune cell partitioning between tumor epithelial and stromal areas and immune cell clustering versus dispersion. As proof-of-principle, we applied TIPC to a prospective cohort incident tumor biobank containing 931 colorectal carcinoma cases. TIPC identified tumor subtypes with unique spatial patterns between tumor cells and T lymphocytes linked to certain molecular pathologic and prognostic features. T lymphocyte identification and phenotyping were achieved using multiplexed (multispectral) immunofluorescence. In a separate hepatocellular carcinoma cohort, we replaced the stromal component with specific immune cell types-CXCR3+CD68+ or CD8+-to profile their spatial relationships with CXCL9+CD68+ cells. RESULTS: Six unsupervised TIPC subtypes based on T lymphocyte distribution patterns were identified, comprising two cold and four hot subtypes. Three of the four hot subtypes were associated with significantly longer colorectal cancer (CRC)-specific survival compared to a reference cold subtype. Our analysis showed that variations in T-cell densities among the TIPC subtypes did not strictly correlate with prognostic benefits, underscoring the prognostic significance of immune cell spatial patterns. Additionally, TIPC revealed two spatially distinct and cell density-specific subtypes among microsatellite instability-high colorectal cancers, indicating its potential to upgrade tumor subtyping. TIPC was also applied to additional immune cell types, eosinophils and neutrophils, identified using morphology and supervised machine learning; here two tumor subtypes with similarly low densities, namely 'cold, tumor-rich' and 'cold, stroma-rich', exhibited differential prognostic associations. Lastly, we validated our methods and results using The Cancer Genome Atlas colon and rectal adenocarcinoma data (n = 570). Moreover, applying TIPC to hepatocellular carcinoma cases (n = 27) highlighted critical cell interactions like CXCL9-CXCR3 and CXCL9-CD8. CONCLUSIONS: Unsupervised discoveries of microgeometric tissue organizational patterns and novel tumor subtypes using the TIPC algorithm can deepen our understanding of the tumor immune microenvironment and likely inform precision cancer immunotherapy.
Humans↗
Hematopoietic microenvironment transfer by stromal fibroblasts derived from bone marrow varying in cellularity.
Autologous fibroblast derivatives of red and yellow marrow of rabbits were shown to differ in their capability to transfer a hematopoietic microenvironment upon implantation under the renal capsule. Although a heterotopic ossicle formed in each instance, the quality of the associated medullary tissue mirrored the quality of the bone marrow used to generate the stromal fibroblasts. Thus, fibroblasts cultured from a cellular marrow produced a stroma with numerous hematopoietic foci whereas those cultured from a severely hypocellular marrow produced a stroma with mainly fat cells. The results with 21 implants point to a transmittable regulatory role of a class of stromal fibroblasts.
Animals↗
The role of transforming growth factor-beta in hematopoiesis. A review.
The role of TGF beta hematopoiesis is currently being defined. It does appear that TGF beta and related polypeptides can modulate and regulate bone marrow and thymic-derived cells throughout their functional life span. The effects of TGF beta are pleiotropic and may depend on (a) cell lineage, (b) specific cellular phenotype, (c) stage of differentiation, (d) immediate microenvironment, (e) other cytokines and (f) cellular function. The understanding of TGF beta and its relationship to other cytokines should not only increase our understanding of hematopoiesis but may also have therapeutic implications.
Cell Differentiation↗
Uncovering Immune Niches in Health and Disease Using Spatial Transcriptomics.
Spatial transcriptomics allows for the investigation of complex cellular ecosystems directly in their native tissues and enables the dissection of immune niches as spatially organized and functionally diverse microenvironments across homeostatic, inflammatory, and malignant settings. In this review, we examine how spatial transcriptomics tools have been applied to interrogate the cellular and molecular architecture of immune niches, including the emerging studies of B and T cell clonal niches. We focus on immune niches in intestinal and tumor tissues due to their importance to both health and pathology, discuss pressing immunological questions these technologies may help to address, and highlight future developments in the field.
Humans↗