scholarly journals Reconstructing aspects of human embryogenesis with pluripotent stem cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Berna Sozen ◽  
Victoria Jorgensen ◽  
Bailey A. T. Weatherbee ◽  
Sisi Chen ◽  
Meng Zhu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Pluripotent Stem Cells ◽  
Clinical Importance ◽  
Early Embryo ◽  
Transcriptional Level ◽  
Cell Models ◽  
Human Embryogenesis ◽  
Cavitation Characteristic ◽  
Stem Cell Models

AbstractUnderstanding human development is of fundamental biological and clinical importance. Despite its significance, mechanisms behind human embryogenesis remain largely unknown. Here, we attempt to model human early embryo development with expanded pluripotent stem cells (EPSCs) in 3-dimensions. We define a protocol that allows us to generate self-organizing cystic structures from human EPSCs that display some hallmarks of human early embryogenesis. These structures mimic polarization and cavitation characteristic of pre-implantation development leading to blastocyst morphology formation and the transition to post-implantation-like organization upon extended culture. Single-cell RNA sequencing of these structures reveals subsets of cells bearing some resemblance to epiblast, hypoblast and trophectoderm lineages. Nevertheless, significant divergences from natural blastocysts persist in some key markers, and signalling pathways point towards ways in which morphology and transcriptional-level cell identities may diverge in stem cell models of the embryo. Thus, this stem cell platform provides insights into the design of stem cell models of embryogenesis.

Metformin suppresses self‐renewal and stemness of cancer stem cell models derived from pluripotent stem cells

2021 ◽  
Author(s):  
Maram H. Zahra ◽  
Said M. Afify ◽  
Ghmkin Hassan ◽  
Hend M. Nawara ◽  
Kazuki Kumon ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Pluripotent Stem Cells ◽  
Cell Models ◽  
Self Renewal ◽  
Stem Cell Models

scholarly journals Quinoline based mono- and bis-(thio)carbohydrazones: synthesis, anticancer activity in 2D and 3D cancer and cancer stem cell models

RSC Advances ◽  
2016 ◽  
Vol 6 (106) ◽  
pp. 104763-104781 ◽  
Author(s):  
Aleksandra Božić ◽  
Aleksandar Marinković ◽  
Snežana Bjelogrlić ◽  
Tamara R. Todorović ◽  
Ilija N. Cvijetić ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Antitumor Activity ◽  
Cancer Stem Cell ◽  
Cell Models ◽  
Target Profile ◽  
Apoptotic Activity ◽  
2D And 3D ◽  
Stem Cell Models

Study of antitumor activity of mono- and bis-quinoline based (thio)carbohydrazones on THP-1 and AsPC-1 cancer stem cells, revealed that thiocarbohydrazones had superior pro-apoptotic activity than carbohydrazones with multi-target profile activities.

scholarly journals Reconstructing human early embryogenesis in vitro with pluripotent stem cells

2021 ◽  
Author(s):  
Berna Sozen ◽  
Victoria Jorgensen ◽  
Meng Zhu ◽  
Tongtong Cui ◽  
Magdalena Zernicka-Goetz
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Human Development ◽  
Pluripotent Stem Cells ◽  
Molecular Mechanisms ◽  
Early Embryo ◽  
Human Stem Cells ◽  
Amniotic Cavity ◽  
Early Human

ABSTRACTUnderstanding human development is of fundamental biological and clinical importance. Yet despite its significance, insights into early developmental events in humans still remain largely unknown. While recent advances show that stem cells can mimic embryogenesis1–9 to unravel hidden developmental mechanisms, a stem cell-based model of early human embryogenesis is lacking. Here, we use human extended pluripotent stem cells10to reconstitute early human development in 3-dimensions and recapitulate early embryo-like events. We first perform a systematic characterisation to reveal unique signalling requirements for building the human pre-implantation blastocyst. Further, we show that these in vitro stem cell-derived blastocyst-like structures are able to undertake spatiotemporal self-organisation to mimic peri-implantation remodelling in which a polarised rosette opens up the amniotic cavity within a developing disc. The hallmarks of human early development displayed by this stem cell-based in vitro model mimics features of embryonic day 3 to day 9/10 of natural development. Thus, this platform represents a tractable model system to contribute to the basic understanding of cellular and molecular mechanisms governing early embryonic events in humans and to provide valuable insights into the design of differentiation protocols for human stem cells in clinical applications.

scholarly journals Heightened potency of human pluripotent stem cell lines created by transient BMP4 exposure

2015 ◽  
Vol 112 (18) ◽  
pp. E2337-E2346 ◽  
Author(s):  
Ying Yang ◽  
Katsuyuki Adachi ◽  
Megan A. Sheridan ◽  
Andrei P. Alexenko ◽  
Danny J. Schust ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Lines ◽  
Pluripotent Stem Cells ◽  
Es Cells ◽  
Early Embryo ◽  
Extravillous Trophoblast ◽  
Cell Phenotype ◽  
Small Areas

Human pluripotent stem cells (PSCs) show epiblast-type pluripotency that is maintained with ACTIVIN/FGF2 signaling. Here, we report the acquisition of a unique stem cell phenotype by both human ES cells (hESCs) and induced pluripotent stem cells (iPSCs) in response to transient (24–36 h) exposure to bone morphogenetic protein 4 (BMP4) plus inhibitors of ACTIVIN signaling (A83-01) and FGF2 (PD173074), followed by trypsin dissociation and recovery of colonies capable of growing on a gelatin substratum in standard medium for human PSCs at low but not high FGF2 concentrations. The self-renewing cell lines stain weakly for CDX2 and strongly for NANOG, can be propagated clonally on either Matrigel or gelatin, and are morphologically distinct from human PSC progenitors on either substratum but still meet standard in vitro criteria for pluripotency. They form well-differentiated teratomas in immune-compromised mice that secrete human chorionic gonadotropin (hCG) into the host mouse and include small areas of trophoblast-like cells. The cells have a distinct transcriptome profile from the human PSCs from which they were derived (including higher expression of NANOG, LEFTY1, and LEFTY2). In nonconditioned medium lacking FGF2, the colonies spontaneously differentiated along multiple lineages, including trophoblast. They responded to PD173074 in the absence of both FGF2 and BMP4 by conversion to trophoblast, and especially syncytiotrophoblast, whereas an A83-01/PD173074 combination favored increased expression of HLA-G, a marker of extravillous trophoblast. Together, these data suggest that the cell lines exhibit totipotent potential and that BMP4 can prime human PSCs to a self-renewing alternative state permissive for trophoblast development. The results may have implications for regulation of lineage decisions in the early embryo.

Stem Cell Research

2015 ◽  
Vol 34 (4) ◽  
pp. 349-351 ◽  
Author(s):  
Alan Trounson ◽  
Kyle Kolaja ◽  
Thomas Petersen ◽  
Klaus Weber ◽  
Maralee McVean ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Regenerative Medicine ◽  
Stem Cell Research ◽  
Basic Research ◽  
The State ◽  
Cell Models ◽  
Testing Strategies ◽  
Toxicological Research ◽  
Stem Cell Models

Stem cells have great potential in basic research and are being slowly integrated into toxicological research. This symposium provided an overview of the state of the field, stem cell models, described allogenic stem cell treatments and issues of immunogenicity associated with protein therapeutics, and tehn concentrated on stem cell uses in regenerative medicine focusing on lung and testing strategies on engineered tissues from a pathologist’s perspective.

Sulindac Sulfide Reverts the Activation of the WNT-Signaling and Aberrant Self Renewal Induced by the AML-Associated Fusion Proteins PML/RARα and PLZF/RARα.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 878-878
Author(s):  
Gunnar Steinert ◽  
Anita Seshire ◽  
Dieter Hoelzer ◽  
Martin Ruthardt ◽  
Elena Puccetti
Keyword(s):  
Stem Cell ◽  
Wnt Signaling ◽  
Fusion Proteins ◽  
The Self ◽  
Molecular Therapy ◽  
Transcriptional Level ◽  
Cell Models ◽  
Self Renewal ◽  
Nb4 Cells ◽  
Stem Cell Models

Abstract Leukemia-specific translocations - t(15;17), t(11;17), or t(8;21) - lead to the expression of leukemia associated fusion proteins (LAFP) such as PML/RAR, PLZF/RAR and AML-1/ETO. LAFP induce and maintain a leukemic phenotype by blocking terminal differentiation of hematopoietic progenitors and by increasing the self renewal potential of the leukemic stem cells (LSC). The key mechanims by which LAFP increase LSC self renewal is the activation of the Wnt-signaling pathway by up-regulating of γ-catenin and β-catenin at a transcriptional level. The aberrant activation of Wnt-signaling by the LAFP decisively contributes to the pathogenesis of AML. To disclose whether a “leukemic stem cell therapy” is effective we targeted the Wnt-signaling by Sulindac Sulfid (SuSu) in PML/RAR- or PLZF/RAR- (X-RAR) positive stem cell models. SuSu represents the active metabolite of Sulindac, a nonsteroidal anti-inflammatory drug (NSAID), known to inactivate the Wnt-signaling. SuSu was used at a clinically achievable concentration of 50–100 μM. As leukemia models we used U937 cells stably expressing the X-RAR and NB4 cells. As stem cell models we used i.) the aldehyde dehydrogenase positive/CD34+/CD38- fraction of the KG-1 cells stably expressing the X-RAR; ii.) Sca-1+/lin- murine HSC retrovirally transduced with the X-RAR in semi solid medium. The amount of total γ-catenin and β-catenin and activated β-catenin was determined by immunoblotting. We report that SuSu i.) down-regulated not only β-catenin but also γ-catenin in X-RAR expressing U937 and KG-1 cells; ii.) reduced the active form of β-catenin in the presence of X-RAR; iii.) induced a high apoptosis rate in PML/RAR-positive NB4 cells; iv.) reduced the “stem cell fraction” of KG-1 cells expressing X-RAR but not of mock transfected controls; iv.) reduced the self renewal potential of X-RAR-positive HSC as revealed by a significantly reduced replating efficiency. Here we provide evidence that the exposure to therapeutically achievable dosages of a NSAID revert the aberrant activation of the Wnt-signaling by LAFP. The significant reduction of the aberrant self renewal potential of HSC in the presence of X-RAR further support that the inhibition of the aberrantly activated Wnt signaling in AML might be a valid molecular therapy approach which has to further validated in in vivo leukemia models and in a more clinical setting.

scholarly journals Strategy to Establish Embryo-Derived Pluripotent Stem Cells in Cattle

2021 ◽  
Vol 22 (9) ◽  
pp. 5011
Author(s):  
Daehwan Kim ◽  
Sangho Roh
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Stem Cell Research ◽  
Pluripotent Stem Cells ◽  
Embryonic Stem ◽  
Culture Conditions ◽  
Human Diseases ◽  
Induced Pluripotent

Stem cell research is essential not only for the research and treatment of human diseases, but also for the genetic preservation and improvement of animals. Since embryonic stem cells (ESCs) were established in mice, substantial efforts have been made to establish true ESCs in many species. Although various culture conditions were used to establish ESCs in cattle, the capturing of true bovine ESCs (bESCs) has not been achieved. In this review, the difficulty of establishing bESCs with various culture conditions is described, and the characteristics of proprietary induced pluripotent stem cells and extended pluripotent stem cells are introduced. We conclude with a suggestion of a strategy for establishing true bESCs.

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

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

scholarly journals LIN28 coordinately promotes nucleolar/ribosomal functions and represses the 2C-like transcriptional program in pluripotent stem cells

2021 ◽  
Author(s):  
Zhen Sun ◽  
Hua Yu ◽  
Jing Zhao ◽  
Tianyu Tan ◽  
Hongru Pan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryo Development ◽  
Pluripotent Stem Cells ◽  
Rna Binding ◽  
Stem Cell Differentiation ◽  
Early Embryo ◽  
Transcriptional Program ◽  
Cell Stage ◽  
Early Embryo Development ◽  
Nucleolar Stress

AbstractLIN28 is an RNA binding protein with important roles in early embryo development, stem cell differentiation/reprogramming, tumorigenesis and metabolism. Previous studies have focused mainly on its role in the cytosol where it interacts with Let-7 microRNA precursors or mRNAs, and few have addressed LIN28’s role within the nucleus. Here, we show that LIN28 displays dynamic temporal and spatial expression during murine embryo development. Maternal LIN28 expression drops upon exit from the 2-cell stage, and zygotic LIN28 protein is induced at the forming nucleolus during 4-cell to blastocyst stage development, to become dominantly expressed in the cytosol after implantation. In cultured pluripotent stem cells (PSCs), loss of LIN28 led to nucleolar stress and activation of a 2-cell/4-cell-like transcriptional program characterized by the expression of endogenous retrovirus genes. Mechanistically, LIN28 binds to small nucleolar RNAs and rRNA to maintain nucleolar integrity, and its loss leads to nucleolar phase separation defects, ribosomal stress and activation of P53 which in turn binds to and activates 2C transcription factor Dux. LIN28 also resides in a complex containing the nucleolar factor Nucleolin (NCL) and the transcriptional repressor TRIM28, and LIN28 loss leads to reduced occupancy of the NCL/TRIM28 complex on the Dux and rDNA loci, and thus de-repressed Dux and reduced rRNA expression. Lin28 knockout cells with nucleolar stress are more likely to assume a slowly cycling, translationally inert and anabolically inactive state, which is a part of previously unappreciated 2C-like transcriptional program. These findings elucidate novel roles for nucleolar LIN28 in PSCs, and a new mechanism linking 2C program and nucleolar functions in PSCs and early embryo development.

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