SARS-CoV-2 and Malayan pangolin coronavirus infect human endoderm, ectoderm and induced lung progenitor cells

AbstractSince the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in several somatic cells, little is known about the infection of SASRS-CoV-2 and its related pangolin coronavirus (GX_P2V). Here we present for the first time that SARS-CoV-2 pseudovirus and GX_P2V could infect lung progenitor and even anterior foregut endoderm cells causing these cells death, which differentiated from human embryonic stem cells (hESCs). The infection and replication of SARS-CoV-2 and GX_P2V were inhibited when treated with whey protein of breastmilk and Remdesivir, confirming that these two viruses could infect lung progenitor and even anterior foregut endoderm. Moreover, we found that SARS-CoV-2 pseudovirus could infect endoderm and ectoderm. We found that whey protein blocked SARS-CoV-2 infecting these cells. In line with the SARS-CoV-2 results, GX_P2V could also infected endoderm and ectoderm, and also was inhibited by Remdesivir treatment. Although expressing coronavirus related receptor such as ACE2 and TMPRSS2, mesoderm cells are not permissive for SARS-CoV-2 and GX_P2V infection, which needed further to study the mechanisms. Interestingly, we also found that hESCs, which also express ACE2 and TMPRSS2 markers, are permissive for GX_P2V but not SARS-CoV-2 pseudovirus infection and replication, indicating the widespread cell types for GX_P2V infection. Heparin treatment blocked efficiently viral infection. These results provided insight that these stem cells maybe provided a stable repository of coronavirus function or genome. The potential consequence of SARS-CoV-2 and animal coronavirus such as GX_P2V infection in hESCs, germ layer and induced progenitors should be closely monitored.

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Modeling lung cell development using human pluripotent stem cells

10.21203/rs.3.rs-753708/v1 ◽

2021 ◽

Author(s):

Amy Wong

Keyword(s):

Stem Cells ◽

Lung Development ◽

Disease Modeling ◽

Cell Lineage ◽

Fetal Lung ◽

Cell Types ◽

Cell Lineages ◽

Lung Progenitor ◽

Air Liquid Interface ◽

First Time

Abstract Human PSC (hPSC) differentiations can capture developmental phenotypes and processes and are useful for studying fundamental biological mechanisms driving tissue morphogenesis and cell lineage development. Here, we show for the first time the temporal development of lung cell lineages using hPSC that model developmental milestones observed in primary tissue, the generation of renewable fetal lung epithelial spheroids, and the functional utility of the lung models at different differentiation stages for Cystic fibrosis disease modeling. We first show the presence of hPSC-derived lung progenitor cells reminiscent of early trimester lung development and containing basal stem cells that generate renewable airway spheroids. Maturation and polarization in air liquid interface (ALI) generates additional epithelial cell lineages found in adult airways including pulmonary neuroendocrine, brush, mature basal, ciliated and secretory cell types. Finally, pseudotime and RNA velocity analyses of the integrated datasets from the fetal and ALI stages reveal previously identified and new cell lineage relationships. Overall, hPSC differentiation can capture aspects of human lung development and potentially provide important insight into congenital causes of diseases.

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Multiple Roles for Cholinergic Signaling from the Perspective of Stem Cell Function

International Journal of Molecular Sciences ◽

10.3390/ijms22020666 ◽

2021 ◽

Vol 22 (2) ◽

pp. 666

Author(s):

Toshio Takahashi

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Function ◽

Cell Activity ◽

Embryonic Stem ◽

Cholinergic Neurons ◽

Cell Types ◽

Proliferative Potential ◽

True Nature ◽

Cholinergic Signaling

Stem cells have extensive proliferative potential and the ability to differentiate into one or more mature cell types. The mechanisms by which stem cells accomplish self-renewal provide fundamental insight into the origin and design of multicellular organisms. These pathways allow the repair of damage and extend organismal life beyond that of component cells, and they probably preceded the evolution of complex metazoans. Understanding the true nature of stem cells can only come from discovering how they are regulated. The concept that stem cells are controlled by particular microenvironments, also known as niches, has been widely accepted. Technical advances now allow characterization of the zones that maintain and control stem cell activity in several organs, including the brain, skin, and gut. Cholinergic neurons release acetylcholine (ACh) that mediates chemical transmission via ACh receptors such as nicotinic and muscarinic receptors. Although the cholinergic system is composed of organized nerve cells, the system is also involved in mammalian non-neuronal cells, including stem cells, embryonic stem cells, epithelial cells, and endothelial cells. Thus, cholinergic signaling plays a pivotal role in controlling their behaviors. Studies regarding this signal are beginning to unify our understanding of stem cell regulation at the cellular and molecular levels, and they are expected to advance efforts to control stem cells therapeutically. The present article reviews recent findings about cholinergic signaling that is essential to control stem cell function in a cholinergic niche.

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MicroRNAs and Stem-like Properties: The Complex Regulation Underlying Stemness Maintenance and Cancer Development

Biomolecules ◽

10.3390/biom11081074 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1074

Author(s):

Giuseppina Divisato ◽

Silvia Piscitelli ◽

Mariantonietta Elia ◽

Emanuela Cascone ◽

Silvia Parisi

Keyword(s):

Stem Cells ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Embryonic Stem ◽

Cell Types ◽

Cancer Development ◽

Special Focus ◽

Self Renewal ◽

Mesenchymal Transition ◽

Different Cell Types

Embryonic stem cells (ESCs) have the extraordinary properties to indefinitely proliferate and self-renew in culture to produce different cell progeny through differentiation. This latter process recapitulates embryonic development and requires rounds of the epithelial–mesenchymal transition (EMT). EMT is characterized by the loss of the epithelial features and the acquisition of the typical phenotype of the mesenchymal cells. In pathological conditions, EMT can confer stemness or stem-like phenotypes, playing a role in the tumorigenic process. Cancer stem cells (CSCs) represent a subpopulation, found in the tumor tissues, with stem-like properties such as uncontrolled proliferation, self-renewal, and ability to differentiate into different cell types. ESCs and CSCs share numerous features (pluripotency, self-renewal, expression of stemness genes, and acquisition of epithelial–mesenchymal features), and most of them are under the control of microRNAs (miRNAs). These small molecules have relevant roles during both embryogenesis and cancer development. The aim of this review was to recapitulate molecular mechanisms shared by ESCs and CSCs, with a special focus on the recently identified classes of microRNAs (noncanonical miRNAs, mirtrons, isomiRs, and competitive endogenous miRNAs) and their complex functions during embryogenesis and cancer development.

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Induced Pluripotent Stem Cells (iPSCs) in Vascular Research: from Two- to Three-Dimensional Organoids

Stem Cell Reviews and Reports ◽

10.1007/s12015-021-10149-3 ◽

2021 ◽

Author(s):

Anja Trillhaase ◽

Marlon Maertens ◽

Zouhair Aherrahrou ◽

Jeanette Erdmann

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Induced Pluripotent Stem Cells ◽

Stem Cell Research ◽

Pluripotent Stem Cells ◽

Embryonic Stem ◽

Cell Types ◽

3D Models ◽

Induced Pluripotent

AbstractStem cell technology has been around for almost 30 years and in that time has grown into an enormous field. The stem cell technique progressed from the first successful isolation of mammalian embryonic stem cells (ESCs) in the 1990s, to the production of human induced-pluripotent stem cells (iPSCs) in the early 2000s, to finally culminate in the differentiation of pluripotent cells into highly specialized cell types, such as neurons, endothelial cells (ECs), cardiomyocytes, fibroblasts, and lung and intestinal cells, in the last decades. In recent times, we have attained a new height in stem cell research whereby we can produce 3D organoids derived from stem cells that more accurately mimic the in vivo environment. This review summarizes the development of stem cell research in the context of vascular research ranging from differentiation techniques of ECs and smooth muscle cells (SMCs) to the generation of vascularized 3D organoids. Furthermore, the different techniques are critically reviewed, and future applications of current 3D models are reported. Graphical abstract

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Epigenetic Regulation of Mesenchymal Stem Cells: A Focus on Osteogenic and Adipogenic Differentiation

Stem Cells International ◽

10.4061/2011/201371 ◽

2011 ◽

Vol 2011 ◽

pp. 1-18 ◽

Cited By ~ 57

Author(s):

Chad M. Teven ◽

Xing Liu ◽

Ning Hu ◽

Ni Tang ◽

Stephanie H. Kim ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Epigenetic Regulation ◽

Adult Stem Cells ◽

Es Cells ◽

Adipogenic Differentiation ◽

Embryonic Stem ◽

Cell Types ◽

Differentiation Potential ◽

Msc Differentiation

Stem cells are characterized by their capability to self-renew and terminally differentiate into multiple cell types. Somatic or adult stem cells have a finite self-renewal capacity and are lineage-restricted. The use of adult stem cells for therapeutic purposes has been a topic of recent interest given the ethical considerations associated with embryonic stem (ES) cells. Mesenchymal stem cells (MSCs) are adult stem cells that can differentiate into osteogenic, adipogenic, chondrogenic, or myogenic lineages. Owing to their ease of isolation and unique characteristics, MSCs have been widely regarded as potential candidates for tissue engineering and repair. While various signaling molecules important to MSC differentiation have been identified, our complete understanding of this process is lacking. Recent investigations focused on the role of epigenetic regulation in lineage-specific differentiation of MSCs have shown that unique patterns of DNA methylation and histone modifications play an important role in the induction of MSC differentiation toward specific lineages. Nevertheless, MSC epigenetic profiles reflect a more restricted differentiation potential as compared to ES cells. Here we review the effect of epigenetic modifications on MSC multipotency and differentiation, with a focus on osteogenic and adipogenic differentiation. We also highlight clinical applications of MSC epigenetics and nuclear reprogramming.

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From blastocyst to gastrula: gene regulatory networks of embryonic stem cells and early mouse embryogenesis

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2013.0542 ◽

2014 ◽

Vol 369 (1657) ◽

pp. 20130542 ◽

Cited By ~ 18

Author(s):

David-Emlyn Parfitt ◽

Michael M. Shen

Keyword(s):

Stem Cells ◽

Gene Networks ◽

Regulatory Networks ◽

Embryonic Stem ◽

Cell Lineage ◽

Network Models ◽

Cell Types ◽

Mammalian Development ◽

A Genome

To date, many regulatory genes and signalling events coordinating mammalian development from blastocyst to gastrulation stages have been identified by mutational analyses and reverse-genetic approaches, typically on a gene-by-gene basis. More recent studies have applied bioinformatic approaches to generate regulatory network models of gene interactions on a genome-wide scale. Such models have provided insights into the gene networks regulating pluripotency in embryonic and epiblast stem cells, as well as cell-lineage determination in vivo . Here, we review how regulatory networks constructed for different stem cell types relate to corresponding networks in vivo and provide insights into understanding the molecular regulation of the blastocyst–gastrula transition.

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Designer blood: creating hematopoietic lineages from embryonic stem cells

Blood ◽

10.1182/blood-2005-09-3621 ◽

2006 ◽

Vol 107 (4) ◽

pp. 1265-1275 ◽

Cited By ~ 51

Author(s):

Abby L. Olsen ◽

David L. Stachura ◽

Mitchell J. Weiss

Keyword(s):

Stem Cells ◽

Es Cells ◽

Embryonic Stem ◽

Basic Research ◽

Cell Types ◽

Patient Specific ◽

Es Cell ◽

Blood Disorders ◽

Hematopoietic Stem

Embryonic stem (ES) cells exhibit the remarkable capacity to become virtually any differentiated tissue upon appropriate manipulation in culture, a property that has been beneficial for studies of hematopoiesis. Until recently, the majority of this work used murine ES cells for basic research to elucidate fundamental properties of blood-cell development and establish methods to derive specific mature lineages. Now, the advent of human ES cells sets the stage for more applied pursuits to generate transplantable cells for treating blood disorders. Current efforts are directed toward adapting in vitro hematopoietic differentiation methods developed for murine ES cells to human lines, identifying the key interspecies differences in biologic properties of ES cells, and generating ES cell-derived hematopoietic stem cells that are competent to repopulate adult hosts. The ultimate medical goal is to create patient-specific and generic ES cell lines that can be expanded in vitro, genetically altered, and differentiated into cell types that can be used to treat hematopoietic diseases.

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The influence of scaffold elasticity on germ layer specification of human embryonic stem cells

Biomaterials ◽

10.1016/j.biomaterials.2011.09.012 ◽

2011 ◽

Vol 32 (36) ◽

pp. 9612-9621 ◽

Cited By ~ 103

Author(s):

Janet Zoldan ◽

Emmanouil D. Karagiannis ◽

Christopher Y. Lee ◽

Daniel G. Anderson ◽

Robert Langer ◽

...

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Human Embryonic Stem Cells ◽

Embryonic Stem ◽

Germ Layer

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Cellular Functions of OCT-3/4 Regulated by Ubiquitination in Proliferating Cells

Cancers ◽

10.3390/cancers12030663 ◽

2020 ◽

Vol 12 (3) ◽

pp. 663

Author(s):

Kwang-Hyun Baek ◽

Jihye Choi ◽

Chang-Zhu Pei

Keyword(s):

Stem Cells ◽

Cellular Proliferation ◽

Critical Role ◽

Embryonic Stem ◽

Cell Types ◽

Ubiquitin Proteasome System ◽

Specific Cell ◽

Cellular Mechanisms ◽

Proliferating Cells ◽

Proliferation And Differentiation

Octamer-binding transcription factor 3/4 (OCT-3/4), which is involved in the tumorigenesis of somatic cancers, has diverse functions during cancer development. Overexpression of OCT-3/4 has been detected in various human somatic tumors, indicating that OCT-3/4 activation may contribute to the development and progression of cancers. Stem cells can undergo self-renewal, pluripotency, and reprogramming with the help of at least four transcription factors, OCT-3/4, SRY box-containing gene 2 (SOX2), Krüppel-like factor 4 (KLF4), and c-MYC. Of these, OCT-3/4 plays a critical role in maintenance of undifferentiated state of embryonic stem cells (ESCs) and in production of induced pluripotent stem cells (iPSCs). Stem cells can undergo partitioning through mitosis and separate into specific cell types, three embryonic germ layers: the endoderm, the mesoderm, and the trophectoderm. It has been demonstrated that the stability of OCT-3/4 is mediated by the ubiquitin-proteasome system (UPS), which is one of the key cellular mechanisms for cellular homeostasis. The framework of the mechanism is simple, but the proteolytic machinery is complicated. Ubiquitination promotes protein degradation, and ubiquitination of OCT-3/4 leads to regulation of cellular proliferation and differentiation. Therefore, it is expected that OCT-3/4 may play a key role in proliferation and differentiation of proliferating cells.

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Lineages of embryonic stem cells show non-Markovian state transitions

10.1101/2020.11.23.372268 ◽

2020 ◽

Author(s):

Tee Udomlumleart ◽

Sofia Hu ◽

Salil Garg

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Embryonic Stem ◽

Cell Types ◽

Developmental State ◽

Markovian Process ◽

State Transitions ◽

Informational Entropy ◽

Kin Relations ◽

State Switching

AbstractPluripotent embryonic stem cells (ESCs) contain the ability to constitute the cell types of the adult vertebrate through a series of developmental state transitions. In culture, ESCs reversibly transition between states in a manner previously described as stochastic. However, whether ESCs retain memory of their previous states or transition in a memoryless (Markovian) process remains relatively unknown. Here we show lineages of ESCs do not exhibit the Markovian property: their previous states and kin relations influence future choices. In a subset of lineages, related ESCs remain likely to occupy the same state weeks after labeling. Unexpectedly, the distribution of lineages across states away from the equilibrium point predicted by a Markov model remains consistent over time, suggesting a conservation of informational entropy in this system. Additionally, some lineages appear highly dynamic in their ability to switch states but do not dominate the culture, suggesting that state switching is a separable property from growth. Together, these data suggest ESC state transitions are a proscribed process governed by additional variables.

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