scholarly journals Extensive phylogenies of human development reveal variable embryonic patterns

2020 ◽  
Author(s):  
Tim H. H. Coorens ◽  
Luiza Moore ◽  
Philip S. Robinson ◽  
Rashesh Sanghvi ◽  
Joseph Christopher ◽  
...  
Keyword(s):  
Progenitor Cell ◽  
Spatial Effect ◽  
Lineage Tracing ◽  
Substantial Variation ◽  
Normal Tissues ◽  
Multiple Organs ◽  
Naturally Occurring ◽  
Adult Body ◽  
Laser Capture ◽  
Laser Capture Microdissected

ABSTRACTStarting from the zygote, all cells in the developing and adult human body continuously acquire mutations. A mutation shared between two different cells implies a shared progenitor cell and can thus be used as a naturally occurring marker for lineage tracing. Here, we reconstruct extensive phylogenies of normal tissues from three adult individuals using whole-genome sequencing of 511 laser capture microdissected samples from multiple organs. Early embryonic progenitor cells inferred from the phylogenies often contribute in different proportions to the adult body and the extent of this asymmetry is variable between individuals, with ratios between the first two reconstructed cells ranging from 56:44 to 92:8. Asymmetries also pervade subsequent cell generations and can differ between tissues in the same individual. The phylogenies also resolve the spatial embryonic origins and patterning of tissues, revealing a spatial effect in the development of the human brain. Supplemented by data on eleven men, we timed the split between soma and germline, with the earliest observed segregation occurring at the first cell divisions. This research demonstrates that, despite reaching the same ultimate tissue patterns, early bottlenecks and lineage commitments lead to substantial variation in embryonic patterns both within and between individuals.

scholarly journals Differential stromal reprogramming in benign and malignant naturally occurring canine mammary tumours identifies disease-promoting stromal components

2019 ◽  
Author(s):  
Parisa Amini ◽  
Sina Nassiri ◽  
Alexandra Malbon ◽  
Enni Markkanen
Keyword(s):  
Screening Method ◽  
Malignant Tumours ◽  
Differential Abundance ◽  
Naturally Occurring ◽  
Mammary Tumours ◽  
Ffpe Specimen ◽  
Summary Statement ◽  
Benign Tumours ◽  
Laser Capture ◽  
Laser Capture Microdissected

AbstractThe importance of cancer-associated stroma (CAS) for initiation and progression of cancer is well accepted. However, as stromal changes in benign forms of naturally occurring tumours are poorly understood, it remains unclear how CAS from benign and malignant tumours compare. Spontaneous canine mammary tumours are viewed as excellent models of human mammary carcinomas (mCA). We have recently reported highly conserved stromal reprogramming between canine and human mCA based on transcriptome analysis of laser-capture-microdissected FFPE specimen. To identify stromal changes between benign and malignant mammary tumours, we have analysed CAS and matched normal stroma from 13 canine mammary adenomas and compared them to 15 canine mCA. Our analyses revealed distinct stromal reprogramming even in small benign tumours. While similarities in stromal reprogramming exist, the CAS signature clearly distinguished adenomas from mCA, suggesting that it may reliably discriminate between benign and malignant tumours. We identified strongly discriminatory genes and found strong differential enrichment in several hallmark signalling pathways between benign and malignant CAS. The distinction between CAS from adenoma and mCA was further substantiated by differential abundance in cellular composition. Finally, to determine key players in CAS reprograming between adenomas and mCA, a network-based gene screening method identified modules of co-expressing genes with distinct expression profile in benign and malignant CAS, and revealed several hub genes as potential molecular drivers in CAS. Given the relevance of canine CAS as a model for the human disease, our approach identifies potential stromal drivers of tumour malignancy with implications for human mCA.Summary statementRNAsequencing-based analysis of stromal reprogramming between benign and malignant naturally occurring canine mammary tumours identifies potential molecular drivers in cancer-associated stroma that support tumour growth and malignancy.

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 Heterogeneity of murine periosteum osteochondroprogenitors involved in fracture healing

2020 ◽  
Author(s):  
Brya G Matthews ◽  
Francesca V Sbrana ◽  
Sanja Novak ◽  
Jessica L. Funnell ◽  
Ye Cao ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Callus Formation ◽  
Lineage Tracing ◽  
Fracture Callus ◽  
Stem And Progenitor Cells ◽  
Periosteal Cells ◽  
Osteoblast Lineage

AbstractThe periosteum is the major source of cells involved in fracture healing. We sought to characterize differences in progenitor cell populations between periosteum and other bone compartments, and identify periosteal cells involved in fracture healing. The periosteum is highly enriched for progenitor cells, including Sca1+ cells, CFU-F and label-retaining cells. Lineage tracing with αSMACreER identifies periosteal cells that contribute to >80% of osteoblasts and ~40% of chondrocytes following fracture. A subset of αSMA+ cells are quiescent long-term injury-responsive progenitors. Ablation of αSMA+ cells impairs fracture callus formation. In addition, committed osteoblast-lineage cells contributed around 10% of osteoblasts, but no chondrocytes in fracture calluses. Most periosteal progenitors, particularly those that form osteoblasts, can be targeted by αSMACreER. We have demonstrated that the periosteum is highly enriched for skeletal stem and progenitor cells and there is heterogeneity in the populations of cells that contribute to mature lineages during periosteal fracture healing.

scholarly journals Osteocalcin expressing cells from tendon sheaths in mice contribute to tendon repair by activating Hedgehog signaling

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Yi Wang ◽  
Xu Zhang ◽  
Huihui Huang ◽  
Yin Xia ◽  
YiFei Yao ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Hedgehog Signaling ◽  
Progenitor Cell ◽  
Tendon Repair ◽  
Tendon Sheath ◽  
Lineage Tracing ◽  
Specific Marker ◽  
Molecular Function ◽  
Hh Signaling ◽  
Necessary And Sufficient

Both extrinsic and intrinsic tissues contribute to tendon repair, but the origin and molecular functions of extrinsic tissues in tendon repair are not fully understood. Here we show that tendon sheath cells harbor stem/progenitor cell properties and contribute to tendon repair by activating Hedgehog signaling. We found that Osteocalcin (Bglap) can be used as an adult tendon-sheath-specific marker in mice. Lineage tracing experiments show that Bglap-expressing cells in adult sheath tissues possess clonogenic and multipotent properties comparable to those of stem/progenitor cells isolated from tendon fibers. Transplantation of sheath tissues improves tendon repair. Mechanistically, Hh signaling in sheath tissues is necessary and sufficient to promote the proliferation of Mkx-expressing cells in sheath tissues, and its action is mediated through TGFβ/Smad3 signaling. Furthermore, co-localization of GLI1+ and MKX+ cells is also found in human tendinopathy specimens. Our work reveals the molecular function of Hh signaling in extrinsic sheath tissues for tendon repair.

scholarly journals Comparison of Ethanol Versus Formalin Fixation on Preservation of Histology and RNA in Laser Capture Microdissected Brain Tissues

2004 ◽  
Vol 14 (2) ◽  
pp. 175-182 ◽  
Author(s):  
Jack Meng Fen Su ◽  
Laszlo Perlaky ◽  
Xiao-Nan Li ◽  
Hon-Chiu Eastwood Leung ◽  
Barbara Antalffy ◽  
...  
Keyword(s):  
Formalin Fixation ◽  
Laser Capture ◽  
Laser Capture Microdissected ◽  
Brain Tissues

scholarly journals Proteomics Pipeline for Biomarker Discovery of Laser Capture Microdissected Breast Cancer Tissue

2012 ◽  
Vol 17 (2) ◽  
pp. 155-164 ◽  
Author(s):  
Ning Qing Liu ◽  
René B. H. Braakman ◽  
Christoph Stingl ◽  
Theo M. Luider ◽  
John W. M. Martens ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Biomarker Discovery ◽  
Breast Cancer Tissue ◽  
Cancer Tissue ◽  
Laser Capture ◽  
Laser Capture Microdissected

scholarly journals Spatially Resolved Proteome Mapping of Laser Capture Microdissected Tissue with Automated Sample Transfer to Nanodroplets

2018 ◽  
Vol 17 (9) ◽  
pp. 1864-1874 ◽  
Author(s):  
Ying Zhu ◽  
Maowei Dou ◽  
Paul D. Piehowski ◽  
Yiran Liang ◽  
Fangjun Wang ◽  
...  
Keyword(s):  
Spatially Resolved ◽  
Laser Capture ◽  
Sample Transfer ◽  
Laser Capture Microdissected

scholarly journals Mutations in thyroid hormone receptor α1 cause premature neurogenesis and progenitor cell depletion in human cortical development

2019 ◽  
Vol 116 (45) ◽  
pp. 22754-22763 ◽  
Author(s):  
Teresa G. Krieger ◽  
Carla M. Moran ◽  
Alberto Frangini ◽  
W. Edward Visser ◽  
Erik Schoenmakers ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Progenitor Cells ◽  
Hormone Receptor ◽  
Progenitor Cell ◽  
Thyroid Hormone Receptor ◽  
Cortical Development ◽  
Neural Progenitor Cell ◽  
Cortical Layer ◽  
Lineage Tracing

Mutations in the thyroid hormone receptor α 1 gene (THRA) have recently been identified as a cause of intellectual deficit in humans. Patients present with structural abnormalities including microencephaly, reduced cerebellar volume and decreased axonal density. Here, we show that directed differentiation of THRA mutant patient-derived induced pluripotent stem cells to forebrain neural progenitors is markedly reduced, but mutant progenitor cells can generate deep and upper cortical layer neurons and form functional neuronal networks. Quantitative lineage tracing shows that THRA mutation-containing progenitor cells exit the cell cycle prematurely, resulting in reduced clonal output. Using a micropatterned chip assay, we find that spatial self-organization of mutation-containing progenitor cells in vitro is impaired, consistent with down-regulated expression of cell–cell adhesion genes. These results reveal that thyroid hormone receptor α1 is required for normal neural progenitor cell proliferation in human cerebral cortical development. They also exemplify quantitative approaches for studying neurodevelopmental disorders using patient-derived cells in vitro.

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