scholarly journals Sequential Exposure to Antenatal Microbial Triggers Attenuates Alveolar Growth and Pulmonary Vascular Development and Impacts Pulmonary Epithelial Stem/Progenitor Cells

2021 ◽  
Vol 8 ◽  
Author(s):  
Helene Widowski ◽  
Niki L. Reynaert ◽  
Daan R. M. G. Ophelders ◽  
Matthias C. Hütten ◽  
Peter G. J. Nikkels ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Preterm Delivery ◽  
Lung Development ◽  
Morphological Changes ◽  
Vascular Development ◽  
Neutrophil Infiltration ◽  
Cell Populations ◽  
Basal Cells ◽  
Proliferating Cells ◽  
Pulmonary Vascular Development

Perinatal inflammatory stress is strongly associated with adverse pulmonary outcomes after preterm birth. Antenatal infections are an essential perinatal stress factor and contribute to preterm delivery, induction of lung inflammation and injury, pre-disposing preterm infants to bronchopulmonary dysplasia. Considering the polymicrobial nature of antenatal infection, which was reported to result in diverse effects and outcomes in preterm lungs, the aim was to examine the consequences of sequential inflammatory stimuli on endogenous epithelial stem/progenitor cells and vascular maturation, which are crucial drivers of lung development. Therefore, a translational ovine model of antenatal infection/inflammation with consecutive exposures to chronic and acute stimuli was used. Ovine fetuses were exposed intra-amniotically to Ureaplasma parvum 42 days (chronic stimulus) and/or to lipopolysaccharide 2 or 7 days (acute stimulus) prior to preterm delivery at 125 days of gestation. Pulmonary inflammation, endogenous epithelial stem cell populations, vascular modulators and morphology were investigated in preterm lungs. Pre-exposure to UP attenuated neutrophil infiltration in 7d LPS-exposed lungs and prevented reduction of SOX-9 expression and increased SP-B expression, which could indicate protective responses induced by re-exposure. Sequential exposures did not markedly impact stem/progenitors of the proximal airways (P63+ basal cells) compared to single exposure to LPS. In contrast, the alveolar size was increased solely in the UP+7d LPS group. In line, the most pronounced reduction of AEC2 and proliferating cells (Ki67+) was detected in these sequentially UP + 7d LPS-exposed lambs. A similar sensitization effect of UP pre-exposure was reflected by the vessel density and expression of vascular markers VEGFR-2 and Ang-1 that were significantly reduced after UP exposure prior to 2d LPS, when compared to UP and LPS exposure alone. Strikingly, while morphological changes of alveoli and vessels were seen after sequential microbial exposure, improved lung function was observed in UP, 7d LPS, and UP+7d LPS-exposed lambs. In conclusion, although sequential exposures did not markedly further impact epithelial stem/progenitor cell populations, re-exposure to an inflammatory stimulus resulted in disturbed alveolarization and abnormal pulmonary vascular development. Whether these negative effects on lung development can be rescued by the potentially protective responses observed, should be examined at later time points.

scholarly journals SOX21 modulates SOX2-initiated differentiation of epithelial cells in the extrapulmonary airways

2020 ◽  
Author(s):  
Evelien Eenjes ◽  
Marjon Buscop-van Kempen ◽  
Anne Boerema-de Munck ◽  
Lisette de Kreij-de Bruin ◽  
J. Marco Schnater ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Progenitor Cells ◽  
Airway Epithelium ◽  
Lung Development ◽  
Fetal Lung ◽  
Basal Cells ◽  
Induced Differentiation ◽  
Bronchial Epithelial ◽  
Sox2 Expression ◽  
Submucosal Glands

ABSTRACTSOX2 expression levels are crucial for the balance between maintenance and differentiation of airway progenitor cells during development and regeneration. Here, we describe SOX21 patterning of the proximal airway epithelium which coincides with high levels of SOX2. Airway progenitor cells in this SOX2+/SOX21+ zone show differentiation to basal cells, specifying cells for the extrapulmonary airways. We show that loss of SOX21 results in increased differentiation of progenitor cells during murine lung development. SOX21 inhibits SOX2-induced differentiation by antagonizing SOX2 binding on different promotors. SOX21 remains expressed in adult tracheal epithelium and submucosal glands, where SOX21 modulates SOX2-induced differentiation in a similar fashion. Using fetal lung organoids and adult bronchial epithelial cells, we show that SOX2+SOX21+ regionalization is conserved in human. Thus SOX21 modulates SOX2-initiated differentiation in extrapulmonary epithelial cells during development and regeneration after injury.

Bone Marrow Niches for Skeletal Progenitor Cells and their Inhabitants in Health and Disease

2019 ◽  
Vol 14 (4) ◽  
pp. 305-319 ◽  
Author(s):  
Marietta Herrmann ◽  
Franz Jakob
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Adult Stem Cells ◽  
Current Knowledge ◽  
Cell Populations ◽  
Surface Markers ◽  
Bone Marrow Niches

The bone marrow hosts skeletal progenitor cells which have most widely been referred to as Mesenchymal Stem or Stromal Cells (MSCs), a heterogeneous population of adult stem cells possessing the potential for self-renewal and multilineage differentiation. A consensus agreement on minimal criteria has been suggested to define MSCs in vitro, including adhesion to plastic, expression of typical surface markers and the ability to differentiate towards the adipogenic, osteogenic and chondrogenic lineages but they are critically discussed since the differentiation capability of cells could not always be confirmed by stringent assays in vivo. However, these in vitro characteristics have led to the notion that progenitor cell populations, similar to MSCs in bone marrow, reside in various tissues. MSCs are in the focus of numerous (pre)clinical studies on tissue regeneration and repair.Recent advances in terms of genetic animal models enabled a couple of studies targeting skeletal progenitor cells in vivo. Accordingly, different skeletal progenitor cell populations could be identified by the expression of surface markers including nestin and leptin receptor. While there are still issues with the identity of, and the overlap between different cell populations, these studies suggested that specific microenvironments, referred to as niches, host and maintain skeletal progenitor cells in the bone marrow. Dynamic mutual interactions through biological and physical cues between niche constituting cells and niche inhabitants control dormancy, symmetric and asymmetric cell division and lineage commitment. Niche constituting cells, inhabitant cells and their extracellular matrix are subject to influences of aging and disease e.g. via cellular modulators. Protective niches can be hijacked and abused by metastasizing tumor cells, and may even be adapted via mutual education. Here, we summarize the current knowledge on bone marrow skeletal progenitor cell niches in physiology and pathophysiology. We discuss the plasticity and dynamics of bone marrow niches as well as future perspectives of targeting niches for therapeutic strategies.

Tissue Ki67 proliferative index expression and pathological changes in hemodialysis arteriovenous fistulae: Preliminary single-center results

2021 ◽  
pp. 112972982110154
Author(s):  
Raffaella Mauro ◽  
Cristina Rocchi ◽  
Francesco Vasuri ◽  
Alessia Pini ◽  
Anna Laura Croci Chiocchini ◽  
...  
Keyword(s):  
Morphological Changes ◽  
Hot Spot ◽  
Wall Thickening ◽  
Proliferating Cells ◽  
Ki 67 ◽  
Group A ◽  
The Mean ◽  
Set Up ◽  
Group B

Background: Arteriovenous fistula (AVF) for hemodialysis integrates outward remodeling with vessel wall thickening in response to drastic hemodynamic changes. Aim of this study is to determine the role of Ki67, a well-established proliferative marker, related to AVF, and its relationship with time-dependent histological morphologic changes. Materials and methods: All patients were enrolled in 1 year and stratified in two groups: (A) pre-dialysis patients submitted to first AVF and (B) patients submitted to revision of AVF. Morphological changes: neo-angiogenesis (NAG), myointimal thickening (MIT), inflammatory infiltrate (IT), and aneurysmatic fistula degeneration (AD). The time of AVF creation was recorded. A biopsy of native vein in Group A and of arterialized vein in Group B was submitted to histological and immunohistochemical (IHC) analysis. IHC for Ki67 was automatically performed in all specimens. Ki67 immunoreactivity was assessed as the mean number of positive cells on several high-power fields, counted in the hot spots. Results: A total of 138 patients were enrolled, 69 (50.0%) Group A and 69 (50.0%) Group B. No NAG or MIT were found in Group A. Seven (10.1%) Group A veins showed a mild MIT. Analyzing the Group B, a moderate-to-severe MIT was present in 35 (50.7%), IT in 19 (27.5%), NAG in 37 (53.6%); AD was present in 10 (14.5%). All AVF of Group B with the exception of one (1.4%) showed a positivity for Ki67, with a mean of 12.31 ± 13.79 positive cells/hot spot (range 0–65). Ki67-immunoreactive cells had a subendothelial localization in 23 (33.3%) cases, a myointimal localization in SMC in 35 (50.7%) cases. The number of positive cells was significantly correlated with subendothelial localization of Ki67 ( p = 0.001) and with NA ( p = 0.001). Conclusions: Native veins do not contain cycling cells. In contrast, vascular cell proliferation starts immediately after AVF creation and persists independently of the time the fistula is set up. The amount of proliferating cells is significantly associated with MIT and subendothelial localization of Ki67-immunoreactive cells, thus suggesting a role of Ki-67 index in predicting AVF failure.

TAMI-70. METABOLIC VULNERABILITY TO GPX4 INHIBITION AND FERROPTOSIS OF QUIESCENT ASTROCYTE-LIKE GLIOMA CELL POPULATIONS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi212-vi213
Author(s):  
Matei Banu ◽  
Athanassios Dovas ◽  
Michael Argenziano ◽  
Wenting Zhao ◽  
Dominique Higgins ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Glioma Cell ◽  
Ex Vivo ◽  
Tricarboxylic Acid Cycle ◽  
Cellular Heterogeneity ◽  
Cell Populations ◽  
Acid Oxidation ◽  
Astrocytic Tumor ◽  
Proliferating Cells ◽  
Novel Treatments

Abstract Diversity is a key feature in the glioma ecosystem. Adaptation to a changing tumor microenvironment is achieved through cellular and metabolic plasticity. Here we show that slow-cycling, astrocyte-like glioma cell subpopulations activate distinct metabolic programs, rendering them susceptible to novel treatments. We performed multi-omics analysis on transgenic murine glioma models to characterize cellular heterogeneity. Bulk RNAseq on targeted time-dependent biopsies combined with scRNAseq uncovered distinct tumor cell populations, including a quiescent, astrocyte-like population relatively insensitive to conventional chemotherapy targeting proliferating cells. Using scRNAseq, we identified a persistently conserved astrocytic population in human IDH1-mt/wt high-grade gliomas. This astrocytic tumor population was more abundant in mouse models with constitutive Notch activation, however it was associated with alterations in several other transcriptional programs, suggesting that targeted therapies would likely be ineffective at eradicating it. Gene ontology analysis revealed enrichment in mitochondrial genes specifically regulating oxidative phosphorylation and tricarboxylic acid cycle. Energetic, lipidomic and metabolomic analyses revealed significant mitochondrial β-fatty acid oxidation and lipid catabolism, with less effective oxygen consumption rate and higher basal oxidative stress. Furthermore, this astrocytic tumor population had depleted levels of basal GSH and was more sensitive to reactive oxygen species. Leveraging this metabolic vulnerability, we performed drug screens and found that therapeutic inhibition of complex I or GPX4 was highly effective and synergistic. GPX4 inhibition induced ferroptosis, a newly-discovered form of programmed non-necroptotic cell death mediated by iron-driven lipid peroxidation. Using scRNAseq and RNAscope on ex vivo slice cultures from murine and human gliomas, we found that GPX4 inhibition and ferroptosis induction in the glioma microenvironment selectively eradicated the quiescent astrocytic subpopulation whereas proliferating glioma were less sensitive. Our data therefore supports a novel treatment paradigm, employing metabolic strategies, such as ferroptosis, in conjunction with chemotherapy and RT to target distinct tumor cell populations with different therapeutic vulnerabilities.

Fontan Hepatic Fibrosis and Pulmonary Vascular Development

2014 ◽  
Vol 36 (3) ◽  
pp. 657-661 ◽  
Author(s):  
William N. Evans ◽  
Ruben J. Acherman ◽  
Brody J. Winn ◽  
Noel S. Yumiaco ◽  
Alvaro Galindo ◽  
...  
Keyword(s):  
Hepatic Fibrosis ◽  
Vascular Development ◽  
Pulmonary Vascular Development

scholarly journals The Use of Endothelial Progenitor Cells for the Regeneration of Musculoskeletal and Neural Tissues

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Naosuke Kamei ◽  
Kivanc Atesok ◽  
Mitsuo Ochi
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Endothelial Cells ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Tissue Repair ◽  
Cell Populations ◽  
Neural Tissues ◽  
Cell Source ◽  
Stem Cell Populations

Endothelial progenitor cells (EPCs) derived from bone marrow and blood can differentiate into endothelial cells and promote neovascularization. In addition, EPCs are a promising cell source for the repair of various types of vascularized tissues and have been used in animal experiments and clinical trials for tissue repair. In this review, we focused on the kinetics of endogenous EPCs during tissue repair and the application of EPCs or stem cell populations containing EPCs for tissue regeneration in musculoskeletal and neural tissues including the bone, skeletal muscle, ligaments, spinal cord, and peripheral nerves. EPCs can be mobilized from bone marrow and recruited to injured tissue to contribute to neovascularization and tissue repair. In addition, EPCs or stem cell populations containing EPCs promote neovascularization and tissue repair through their differentiation to endothelial cells or tissue-specific cells, the upregulation of growth factors, and the induction and activation of endogenous stem cells. Human peripheral blood CD34(+) cells containing EPCs have been used in clinical trials of bone repair. Thus, EPCs are a promising cell source for the treatment of musculoskeletal and neural tissue injury.

scholarly journals Basal stem cell fate specification is mediated by SMAD signaling in the developing human lung

2018 ◽  
Author(s):  
Alyssa J. Miller ◽  
Qianhui Yu ◽  
Michael Czerwinski ◽  
Yu-Hwai Tsai ◽  
Renee F. Conway ◽  
...  
Keyword(s):  
Single Cell ◽  
Progenitor Cells ◽  
Cell Fate ◽  
Basal Cell ◽  
Human Lung ◽  
Branching Morphogenesis ◽  
Basal Cells ◽  
Smad Signaling ◽  
Cell Fate Decisions ◽  
Cell Transition

AbstractBasal stem cells (basal cells), located in the bronchi and trachea of the human lung epithelium, play a critical role in normal airway homeostasis and repair, and have been implicated in the development of diseases such as cancer1-4. Additionally, basal-like cells contribute to alveolar regeneration and fibrosis following severe injury5-8. However, the developmental origin of basal cells in humans is unclear. Previous work has shown that specialized progenitor cells exist at the tips of epithelial tubes during lung branching morphogenesis, and in mice, give rise to all alveolar and airway lineages9,10. These ‘bud tip progenitor cells’ have also been described in the developing human lung11-13, but the mechanisms controlling bud tip differentiation into specific cell lineages, including basal cells, are unknown. Here, we interrogated the bud tip-to-basal cell transition using human tissue specimens, bud tip progenitor organoid cultures11, and single-cell transcriptomics. We used single-cell mRNA sequencing (scRNAseq) of developing human lung specimens from 15-21 weeks gestation to identify molecular signatures and cell states in the developing human airway epithelium. We then inferred differentiation trajectories during bud tip-to-airway differentiation, which revealed a previously undescribed transitional cell state (‘hub progenitors’) and implicated SMAD signaling as a regulator of the bud tip-to-basal cell transition. We used bud tip progenitor organoids to show that TGFT1 and BMP4 mediated SMAD signaling robustly induced the transition into functional basal-like cells, and these in vitro-derived basal cells exhibited clonal expansion, self-renewal and multilineage differentiation. This work provides a framework for deducing and validating key regulators of cell fate decisions using single cell transcriptomics and human organoid models. Further, the identification of SMAD signaling as a critical regulator of newly born basal cells in the lung may have implications for regenerative medicine, basal cell development in other organs, and understanding basal cell misregulation in disease.

scholarly journals Placental development during early pregnancy in sheep: vascular growth and expression of angiogenic factors in maternal placenta

Reproduction ◽  
2010 ◽  
Vol 140 (1) ◽  
pp. 165-174 ◽  
Author(s):  
Anna T Grazul-Bilska ◽  
Pawel P Borowicz ◽  
Mary Lynn Johnson ◽  
Megan A Minten ◽  
Jerzy J Bilski ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fetal Growth ◽  
Early Pregnancy ◽  
Vascular Development ◽  
Hypoxia Inducible Factor ◽  
Angiogenic Factors ◽  
Placental Development ◽  
Proliferating Cells ◽  
Placental Angiogenesis ◽  
Tissue Area

Placental vascular development (angiogenesis) is critical for placental function and thus for normal embryonic/fetal growth and development. Specific environmental factors or use of assisted reproductive techniques may result in poor placental angiogenesis, which may contribute to embryonic losses and/or fetal growth retardation. Uterine tissues were collected on days 14, 16, 18, 20, 22, 24, 26, 28, and 30 after mating and on day 10 after estrus (nonpregnant controls) to determine vascular development and expression of several factors involved in the regulation of angiogenesis in the endometrium. Compared with controls, several measurements of endometrial vascularity increased (P<0.001) including vascular labeling index (LI; proportion of proliferating cells), the tissue area occupied by capillaries, area per capillary (capillary size), total capillary circumference per unit of tissue area, and expression of factor VIII (marker of endothelial cells), but capillary number decreased (P<0.001). Compared with controls, mRNA for placental growth factor, vascular endothelial growth factor receptors, angiopoietins (ANGPT) 1 and 2, ANGPT receptorTEK, endothelial nitric oxide synthase, and hypoxia-inducible factor 1α increased (P<0.05) during early pregnancy. Vascular LI was positively correlated (P<0.05) with several measurements of vascularity and with mRNA expression of angiogenic factors. These data indicate that endometrial angiogenesis, manifested by increased vascularity and increased expression of several factors involved in the regulation of angiogenesis, is initiated very early in pregnancy. This more complete description of early placental angiogenesis may provide the foundation for determining whether placental vascular development is altered in compromised pregnancies.

Abstract 011: Transcriptional Basis Of Epicardial Progenitor Cell Activation During Heart Development, Regeneration And Repair

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Guo N Huang ◽  
Jeffrey E Thatcher ◽  
John McAnally ◽  
Yongli Kong ◽  
Xiaoxia Qi ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Heart Development ◽  
Progenitor Cell ◽  
Cell Activation ◽  
Cardiac Development ◽  
Expression System ◽  
Neutrophil Infiltration ◽  
Developmental Gene ◽  
Paracrine Factors ◽  
Multipotent Progenitor Cells

The epicardium encapsulates the heart and functions as a source of multipotent progenitor cells and paracrine factors essential for cardiac development and repair. Injury of the adult heart results in reactivation of epicardial progenitor cells, which reengages a developmental gene program, but the underlying transcriptional basis has not been delineated. We established a mouse embryonic heart organ culture and gene expression system that facilitated the identification of epicardial enhancers activated during heart development and injury. Epicardial activation of these enhancers depends on a combinatorial transcriptional code centered on C/EBP, HOX, MEIS, and GRAINYHEAD families of transcription factors. Furthermore, disruption of C/EBP signaling in the adult epicardium reduced injury-induced neutrophil infiltration and improved cardiac function. These findings reveal a transcriptional basis for epicardial progenitor cell activation during heart development and injury, providing a platform for enhancing cardioprotection and regeneration.

Mouse Lung Organoid Responses to Reduced, Increased, and Cyclic Stretch

2021 ◽  
Author(s):  
Rashika Joshi ◽  
Matthew R. Batie ◽  
Qiang Fan ◽  
Brian Michael Varisco
Keyword(s):  
Lung Development ◽  
Histone Deacetylases ◽  
Cyclic Strain ◽  
Cyclic Stretch ◽  
Mouse Lung ◽  
Proliferating Cells ◽  
Double Positive ◽  
Cross Sectional ◽  
Static Stretch

Most lung development occurs in the context of cyclic stretch. Alteration of the mechanical microenvironment is a common feature of many pulmonary diseases with congenital diaphragmatic hernia (CDH) and fetal tracheal occlusion (FETO, a therapy for CDH) being extreme examples with changes in lung structure, cell differentiation and function. To address limitations in cell culture and in vivo mechanotransductive models we developed two mouse lung organoid (mLO) mechanotransductive models using postnatal day 5 (PND5) mouse lung CD326-positive cells and fibroblasts subjected to increased, decreased, and cyclic strain. In the first model, mLOs were exposed to forskolin (FSK) and/or disrupted (DIS) and evaluated at 20 hours. mLO cross-sectional area changed by +59%, +24% and -68% in FSK, control, and DIS mLOs respectively. FSK-treated organoids had twice as many proliferating cells as other organoids. In the second model, 20 hours of 10.25% biaxial cyclic strain increased the mRNAs of lung mesenchymal cell lineages compared to static stretch and no stretch. Cyclic stretch increased TGF-β and integrin-mediated signaling with upstream analysis indicating roles for histone deacetylases, microRNAs, and long non-coding RNAs. Cyclic stretch mLOs increased αSMA- and αSMA-PDGFRα-double positive cells compared to no stretch and static stretch mLOs. In this PND5 mLO mechanotransductive model, cell proliferation is increased by static stretch, and cyclic stretch induces mesenchymal gene expression changes important in postnatal lung development.

Sign in / Sign up

Export Citation Format

Share Document