TAMI-36. TAMEP ARE BRAIN TUMOR PARENCHYMAL CELLS CONTROLLING NEOPLASTIC ANGIOGENESIS AND PROGRESSION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi205-vi206
Author(s):  
Roland Kälin ◽  
Linzhi Cai ◽  
Yuping Li ◽  
Ines Hellmann ◽  
Rainer Glass
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Single Cell ◽  
Disease Progression ◽  
Progenitor Cell ◽  
Local Environment ◽  
Lineage Tracing ◽  
Immunofluorescence Analysis ◽  
Progenitor Cell Population ◽  
Parenchymal Cells

Abstract Aggressive brain tumors like glioblastoma depend on support by their local environment and subsets of tumor-parenchymal cells may promote specific phases of disease-progression. We investigated the glioblastoma microenvironment with transgenic lineage-tracing models, intravital imaging, single-cell transcriptomics, immunofluorescence analysis as well as histopathology and characterized a previously unacknowledged population of tumor-associated cells with a myeloid-like expression profile (TAMEP) that transiently appeared during glioblastoma growth. TAMEP of mice and humans were identified with specific markers. Strikingly, TAMEP did not derive from microglia or peripheral monocytes but were generated by a fraction of CNS-resident, SOX2-positive progenitors. Abrogation of this progenitor cell-population, by conditional Sox2-knockout, drastically reduced glioblastoma-vascularization and -size. TAMEP manipulation profoundly altered vessel function and strongly attenuated the blood-tumor barrier. Hence, our data indicate TAMEP and their progenitors as new targets for glioblastoma therapy.

scholarly journals OTME-1. TAMEP are brain tumor parenchymal cells controlling neoplastic angiogenesis and progression

2021 ◽  
Vol 3 (Supplement_2) ◽  
pp. ii13-ii13
Author(s):  
Roland Kälin ◽  
Linzhi Cai ◽  
Yuping Li ◽  
Louisa von Baumgarten ◽  
Christian Schulz ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Single Cell ◽  
Progenitor Cell ◽  
Local Environment ◽  
Lineage Tracing ◽  
Strong Impact ◽  
Immunofluorescence Analysis ◽  
Progenitor Cell Population ◽  
Parenchymal Cells

Abstract Aggressive brain tumors like glioblastoma depend on support by their local environment and subsets of tumor parenchymal cells may promote specific phases of disease progression. We investigated the glioblastoma microenvironment with transgenic lineage-tracing models, intravital imaging, single-cell transcriptomics, immunofluorescence analysis as well as histopathology and characterized a previously unacknowledged population of tumor-associated cells with a myeloid-like expression profile (TAMEP) that transiently appeared during glioblastoma growth. TAMEP of mice and humans were identified with specific markers. Notably, TAMEP did not derive from microglia or peripheral monocytes but were generated by a fraction of CNS-resident, SOX2-positive progenitors. Abrogation of this progenitor cell population, by conditional Sox2-knockout, drastically reduced glioblastoma vascularization and size. Hence, TAMEP emerge as a tumor parenchymal component with a strong impact on glioblastoma progression.

Local progenitor cells shape the neoplastic vasculature and promote brain tumor growth.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14044-e14044
Author(s):  
Roland Kälin ◽  
Linzhi Cai ◽  
Dongxu Zhao ◽  
Huabin Zhang ◽  
Wenlong Zhang ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Brain Tumor ◽  
Brain Tumors ◽  
Single Cell ◽  
Progenitor Cells ◽  
Cell Population ◽  
Expression Profile ◽  
Progenitor Cell ◽  
Myeloid Cells ◽  
Lineage Tracing

e14044 Background: Aggressive brain tumors like glioblastoma depend on support by their local environment. While the role of tumor-associated myeloid cells on glioblastoma progression is well-documented, we have only partial knowledge of the pathological impact of glioblastoma -parenchymal progenitor cells. Methods: We investigated the glioblastoma microenvironment with transgenic lineage-tracing models ( nestin-creER2, R26-tdTomato and sox2-creER2,R26-tdTomato), intravital imaging, single-cell transcriptomics, immunofluorescence and flow-cytometry as well as histopathology and characterized a previously unknown tumor-associated progenitor cell. In functional experiments, we studied the knockout of the transcription factor SOX2 in these tumor-associated cells. Results: Lineage-traced cells from mouse glioblastoma were obtained by flow-cytometry and single cell transcriptomes compared to established gene expression data from brain tumor parenchymal cells. The traced tumor-associated cells had a transcriptomic profile largely resembling myeloid cells and expressed microglia-/macrophage-markers on the protein-level. However, transgenic models and bone-marrow chimera revealed that the traced cells were clearly distinct from microglia or macrophages. The traced tumor associated cells with a myeloid expression profile derived from a SOX2-dependent progenitor cell. Consequently, conditional Sox2-knockout ablated the entire myeloid-like cell population. Remarkably, this tumor-associated cell population had a large impact on disease-progression causing significant reduction of glioblastoma –vascularization to 53%, changing vascular function and leading to a decrease in tumor volume to 42% as compared to controls. The myeloid-like progenitor cells were identified in human brain tumors by immunofluorescence and in scRNA-seq data. Conclusions: We identified a previously unacknowledged population of tumor-associated progenitor cells with a myeloid-like expression profile that transiently appeared during glioblastoma growth. These progenitors have strong impact on glioblastoma progression and point towards a new and promising therapeutic target in order to support anti-angiogenic regimen in glioblastoma.

scholarly journals The Role of Neurodevelopmental Pathways in Brain Tumors

2021 ◽  
Vol 9 ◽  
Author(s):  
Rachel N. Curry ◽  
Stacey M. Glasgow
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Disease Progression ◽  
Adult Brain ◽  
Signaling Cascades ◽  
Tumor Initiation ◽  
Developmental Factors ◽  
Developmental Signaling ◽  
Cell Signaling Pathways

Disruptions to developmental cell signaling pathways and transcriptional cascades have been implicated in tumor initiation, maintenance and progression. Resurgence of aberrant neurodevelopmental programs in the context of brain tumors highlights the numerous parallels that exist between developmental and oncologic mechanisms. A deeper understanding of how dysregulated developmental factors contribute to brain tumor oncogenesis and disease progression will help to identify potential therapeutic targets for these malignancies. In this review, we summarize the current literature concerning developmental signaling cascades and neurodevelopmentally-regulated transcriptional programs. We also examine their respective contributions towards tumor initiation, maintenance, and progression in both pediatric and adult brain tumors and highlight relevant differentiation therapies and putative candidates for prospective treatments.

scholarly journals Recent Advances in Single-Cell View of Mesenchymal Stem Cell in Osteogenesis

2022 ◽  
Vol 9 ◽  
Author(s):  
Fangyuan Shen ◽  
Yu Shi
Keyword(s):  
Stem Cell ◽  
Single Cell ◽  
Cell Fate ◽  
Progenitor Cell ◽  
Bone Development ◽  
Lineage Tracing ◽  
Research Progress ◽  
Bone Homeostasis ◽  
Differentiation Potential ◽  
Cell Technology

Osteoblasts continuously replenished by osteoblast progenitor cells form the basis of bone development, maintenance, and regeneration. Mesenchymal stem cells (MSCs) from various tissues can differentiate into the progenitor cell of osteogenic lineage and serve as the main source of osteoblasts. They also respond flexibly to regenerative and anabolic signals emitted by the surrounding microenvironment, thereby maintaining bone homeostasis and participating in bone remodeling. However, MSCs exhibit heterogeneity at multiple levels including different tissue sources and subpopulations which exhibit diversified gene expression and differentiation capacity, and surface markers used to predict cell differentiation potential remain to be further elucidated. The rapid advancement of lineage tracing methods and single-cell technology has made substantial progress in the characterization of osteogenic stem/progenitor cell populations in MSCs. Here, we reviewed the research progress of scRNA-seq technology in the identification of osteogenic markers and differentiation pathways, MSC-related new insights drawn from single-cell technology combined with experimental technology, and recent findings regarding the interaction between stem cell fate and niche in homeostasis and pathological process.

scholarly journals Single-cell lineage tracing in the mammary gland reveals stochastic clonal dispersion of stem/progenitor cell progeny

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Felicity M. Davis ◽  
Bethan Lloyd-Lewis ◽  
Olivia B. Harris ◽  
Sarah Kozar ◽  
Douglas J. Winton ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Single Cell ◽  
Progenitor Cell ◽  
Cell Lineage ◽  
Lineage Tracing

scholarly journals Single-cell analysis reveals effective siRNA delivery in brain tumors with microbubble-enhanced ultrasound and cationic nanoparticles

2021 ◽  
Vol 7 (18) ◽  
pp. eabf7390
Author(s):  
Yutong Guo ◽  
Hohyun Lee ◽  
Zhou Fang ◽  
Anastasia Velalopoulou ◽  
Jinhwan Kim ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Single Cell ◽  
Focused Ultrasound ◽  
Single Cell Analysis ◽  
Sirna Delivery ◽  
Cationic Lipid ◽  
Hybrid Nanoparticles ◽  
Tumor Cell Death ◽  
Tumor Microenvironments

RNA-based therapies offer unique advantages for treating brain tumors. However, tumor penetrance and uptake are hampered by RNA therapeutic size, charge, and need to be “packaged” in large carriers to improve bioavailability. Here, we have examined delivery of siRNA, packaged in 50-nm cationic lipid-polymer hybrid nanoparticles (LPHs:siRNA), combined with microbubble-enhanced focused ultrasound (MB-FUS) in pediatric and adult preclinical brain tumor models. Using single-cell image analysis, we show that MB-FUS in combination with LPHs:siRNA leads to more than 10-fold improvement in siRNA delivery into brain tumor microenvironments of the two models. MB-FUS delivery of Smoothened (SMO) targeting siRNAs reduces SMO protein production and markedly increases tumor cell death in the SMO-activated medulloblastoma model. Moreover, our analysis reveals that MB-FUS and nanoparticle properties can be optimized to maximize delivery in the brain tumor microenvironment, thereby serving as a platform for developing next-generation tunable delivery systems for RNA-based therapy in brain tumors.

scholarly journals Longitudinal single cell transcriptomics reveals Krt8+ alveolar epithelial progenitors in lung regeneration

2019 ◽  
Author(s):  
Maximilian Strunz ◽  
Lukas M. Simon ◽  
Meshal Ansari ◽  
Laura F. Mattner ◽  
Ilias Angelidis ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Lung Injury ◽  
Single Cell ◽  
Progenitor Cell ◽  
Terminal Differentiation ◽  
Lineage Tracing ◽  
Alveolar Type ◽  
Cell State ◽  
Lung Regeneration

Lung injury activates quiescent stem and progenitor cells to regenerate alveolar structures. The sequence and coordination of transcriptional programs during this process has largely remained elusive. Using single cell RNA-seq, we first generated a whole-organ bird’s-eye view on cellular dynamics and cell-cell communication networks during mouse lung regeneration from ∼30,000 cells at six timepoints. We discovered an injury-specific progenitor cell state characterized by Krt8 in flat epithelial cells covering alveolar surfaces. The number of these cells peaked during fibrogenesis in independent mouse models, as well as in human acute lung injury and fibrosis. Krt8+ progenitors featured a highly distinct connectome of receptor-ligand pairs with endothelial cells, fibroblasts, and macrophages. To ‘sky dive’ into epithelial differentiation dynamics, we sequenced >30,000 sorted epithelial cells at 18 timepoints and computationally derived cell state trajectories that were validated by lineage tracing genetic reporter mice. Airway stem cells within the club cell lineage and alveolar type-2 cells underwent transcriptional convergence onto the same Krt8+ progenitor cell state, which later resolved by terminal differentiation into alveolar type-1 cells. We derived distinct transcriptional regulators as key switch points in this process and show that induction of TNF-alpha/NFkappaB, p53, and hypoxia driven gene expression programs precede a Sox4, Ctnnb1, and Wwtr1 driven switch towards alveolar type-1 cell fate. We show that epithelial cell plasticity can induce non-gradual transdifferentiation, involving intermediate progenitor cell states that may persist and promote disease if checkpoint signals for terminal differentiation are perturbed.

scholarly journals Single-cell analysis defines the lineage plasticity of stem cells in cervix epithelium

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Zixian Zhao ◽  
Yujia Wang ◽  
Yingchuan Wu ◽  
Dandan Li ◽  
Ting Zhang ◽  
...  
Keyword(s):  
Single Cell ◽  
Progenitor Cell ◽  
Cell Function ◽  
Cultured Cells ◽  
Dynamic Change ◽  
Lineage Tracing ◽  
Genetic Lineage ◽  
Time Analysis ◽  
Cervical Epithelium

AbstractInformation about the dynamic change and post-injury regeneration of cervical epithelium is relatively rare, even though it is tightly related to gynecologic malignancy. Here, using a feeder cell-based culturing system, we stably cloned mouse and human P63 and KRT5 expressing cells from the adult cervix as putative cervical stem/progenitor cells (CVSCs). When subjected to differentiation, the cultured cells gave rise to mature cervical epithelium by differentiating into squamous or glandular cells. The ability of endogenous mouse CVSCs to reconstitute cervical epithelium after injury was also evident from the genetic lineage tracing experiments. Single-cell transcriptomic analysis further classified the CVSCs into three subtypes and delineated their bi-lineage differentiation roadmap by pseudo-time analysis. We also tracked the real-time differentiation routes of two representing single CVSC lines in vitro and found that they recapitulated the predicted roadmap in pseudo-time analysis. Signaling pathways including Wnt, TGF-beta, Notch and EGFR were found to regulate the cervical epithelial hierarchy and implicated the different roles of distinct types of cells in tissue homeostasis and tumorigenesis. Collectively, the above data provide a cloning system to achieve stable in vitro culture of a bi-lineage stem/progenitor cell population in the cervix, which has profound implications for our understanding of the cervix stem/progenitor cell function in homeostasis, regeneration, and disease and could be helpful for developing stem cell-based therapies in future.

Sign in / Sign up

Export Citation Format

Share Document