human stem cells
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2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Katherine G. Zyner ◽  
Angela Simeone ◽  
Sean M. Flynn ◽  
Colm Doyle ◽  
Giovanni Marsico ◽  
...  

AbstractThe establishment of cell identity during embryonic development involves the activation of specific gene expression programmes and is underpinned by epigenetic factors including DNA methylation and histone post-translational modifications. G-quadruplexes are four-stranded DNA secondary structures (G4s) that have been implicated in transcriptional regulation and cancer. Here, we show that G4s are key genomic structural features linked to cellular differentiation. We find that G4s are highly abundant in human embryonic stem cells and are lost during lineage specification. G4s are prevalent in enhancers and promoters. G4s that are found in common between embryonic and downstream lineages are tightly linked to transcriptional stabilisation of genes involved in essential cellular functions as well as transitions in the histone post-translational modification landscape. Furthermore, the application of small molecules that stabilise G4s causes a delay in stem cell differentiation, keeping cells in a more pluripotent-like state. Collectively, our data highlight G4s as important epigenetic features that are coupled to stem cell pluripotency and differentiation.


2021 ◽  
Author(s):  
Thomas Cech ◽  
Arthur Zaug

Abstract Telomeres, the natural ends of linear chromosomes, are comprised of repeat-sequence DNA and associated proteins1. Replication of telomeres allows continued proliferation of human stem cells and immortality of cancer cells2. Replication begins with telomerase3 extending the single-stranded DNA (ssDNA) of the telomeric G-strand [(TTAGGG)n]; the synthesis of the complementary C-strand [(CCCTAA)n] is much less well characterized. The CST (CTC1-STN1-TEN1) protein complex, a DNA Polymerase α-primase accessory factor4,5, is known to be required for telomere replication in vivo6,7,8,9, and the molecular analysis presented here reveals key features of its mechanism. We find that CST uses its ssDNA-binding activity to specify the origins for telomeric C-strand synthesis by bound Polα-primase. CST-organized DNA polymerization can copy a telomeric DNA template that folds into G-quadruplex structures, but the suboptimality of this template likely contributes to telomere replication problems observed in vivo. Combining telomerase, a short telomeric ssDNA primer, and CST-Polα-primase gives complete telomeric DNA replication, resulting in the same sort of ssDNA 3’-overhang found naturally on human telomeres. We conclude that the CST complex not only terminates telomerase extension10,11 and recruits Polα-primase to telomeric ssDNA4,12,13, but it also orchestrates C-strand synthesis. Because replication of the telomere has features distinct from replication of the rest of the genome, targeting telomere-replication components including CST holds promise for cancer therapeutics.


Author(s):  
Yasir Farooq

The advancement of technology in medical science has just changed human lives, as well as biomedical innovations are making human lives better but lesser harmful. In past, scientifically and religiously approved techniques such as testtube baby & human stem cells therapy have served humanity especially infertile and connubial parents. Nowadays, the advancement in CRISPER/cas9 technology which is about human germline gene editing, just rekindled the religious and ethical concerns, especially in Islamic perspectives. Although, human germline genome editing and modification have been started decades ago claims about disease prevention strategies have raised many religious concerns such as tampering with God’s creation, human dignity, safety and efficacy of the technology, and human genetic enhancement. This kind of editing might result in inheritable changes in the human genome. So, questions about its status whether it should be allowed or not, need deep & serious study from religious and ethical perspectives. This study will encompass Islamic perspectives on these concerns in the light of ethical principles of Islam while considering and assessing the permissibility or lawful status of CRISPR/Cas9 mediated human germline gene editing. This research study also aims to address the controversial discussions among Muslim jurists regarding human germline gene editing as well as to comprise the related ethical regulations and concerns.


2021 ◽  
Vol 79 (1) ◽  
Author(s):  
Lea Daverkausen-Fischer ◽  
Felicitas Pröls

AbstractAccumulation of misfolded proteins in the endoplasmic reticulum (ER) induces a well-orchestrated cellular response to reduce the protein burden within the ER. This unfolded protein response (UPR) is controlled primarily by three transmembrane proteins, IRE1α, ATF6, and PERK, the activity of which is controlled by BiP, the ER-resident Hsp70 protein. Binding of BiP to co-chaperones via their highly conserved J-domains stimulates the intrinsic ATPase activity of BiP, thereby providing the energy necessary for (re-)folding of proteins, or for targeting of misfolded proteins to the degradation pathway, processes specified and controlled by the respective co-chaperone. In this review, our aim is to elucidate the function of the co-chaperone ERDJ4, also known as MDG1, MDJ7, or DNAJB9. Knockout and knockin experiments clearly point to the central role of ERDJ4 in controlling lipogenesis and protein synthesis by promoting degradation of SREBP1c and the assembly of the protein complex mTORC2. Accumulating data reveal that ERDJ4 controls epithelial-to-mesenchymal transition, a central process during embryogenesis, in wound healing, and tumor development. Overexpression of ERdj4 has been shown to improve engraftment of transplanted human stem cells, possibly due to its ability to promote cellular survival in stressed cells. High ERDJ4-plasma levels are specific for fibrillary glomerulonephritis and serve as a diagnostic marker. As outlined in this review, the functions of ERDJ4 are manifold, depending on the cellular (patho-) physiological state, the cellular protein repertoire, and the subcellular localization of ERDJ4.


2021 ◽  
Author(s):  
William C Skarnes ◽  
Gang Ning ◽  
Sofia Giansiracusa ◽  
Alexander S Cruz ◽  
Cornelis Blauwendraat ◽  
...  

Modeling human disease in human stem cells requires precise, scarless editing of single nucleotide variants (SNV) on one or both chromosomes. Here we describe improved conditions for Cas9 RNP editing of SNVs that yield high rates of biallelic homology-directed repair. To recover both heterozygous and homozygous SNV clones, catalytically inactive dCas9 was added to moderate high activity Cas9 RNPs. dCas9 can also block re-cutting and damage to SNV alleles engineered with non-overlapping guide RNAs.


Author(s):  
A. A. Galiakberova ◽  
A. M. Surin ◽  
Z. V. Bakaeva ◽  
R. R. Sharipov ◽  
Dongxing Zhang ◽  
...  

AbstractThe study of human neurons and their interaction with neurochemicals is difficult due to the inability to collect primary biomaterial. However, recent advances in the cultivation of human stem cells, methods for their neuronal differentiation and chimeric fluorescent calcium indicators have allowed the creation of model systems in vitro. In this paper we report on the development of a method to obtain human neurons with the GCaMP6s calcium indicator, based on a human iPSC line with the TetON–NGN2 transgene complex. The protocol we developed allows us quickly, conveniently and efficiently obtain significant amounts of human neurons suitable for the study of various neurochemicals and their effects on specific neurophysiological activity, which can be easily registered using fluorescence microscopy. In the neurons we obtained, glutamate (Glu) induces rises in [Ca2+]i which are caused by ionotropic receptors for Glu, predominantly of the NMDA-type. Taken together, these facts allow us to consider the model we have created to be a useful and successful development of this technology.


2021 ◽  
Vol 28 (12) ◽  
pp. 2180
Author(s):  
Masaki Kinoshita ◽  
Michael Barber ◽  
William Mansfield ◽  
Yingzhi Cui ◽  
Daniel Spindlow ◽  
...  
Keyword(s):  

Author(s):  
Vanshika Jain ◽  
Deborah Sybil ◽  
Shubhangi Premchandani ◽  
Meenakshi Krishna ◽  
Sanjay Singh

The choice of an appropriate autogenous source of stem cells has not been adequately addressed especially for intraoral bone regeneration. The current review aims to assess the clinical success of various human stem cells in oral bone regeneration. Articles studying the potential of various stem cells utilized for reconstruction of intraoral bone defects in humans were included in this review. Relevant articles were electronically searched in MEDLINE-PubMed database using keywords with different combinations. Only the articles published in English between 2006 and 2020 were included in this review. It was concluded that intra and extraoral stem cells can be successfully used for bone regeneration of various jaw defects. Depending on the origin, quantity, and quality, each cell type has its own advantages and disadvantages. Also, it brings to the fore the need for more clinical studies to validate and adopt the use of stem cells in regular clinical practice.


2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Tatsuaki Kurosaki ◽  
Hitomi Sakano ◽  
Christoph Pröschel ◽  
Jason Wheeler ◽  
Alexander Hewko ◽  
...  

Abstract Background Fragile X syndrome (FXS) is an intellectual disability attributable to loss of fragile X protein (FMRP). We previously demonstrated that FMRP binds mRNAs targeted for nonsense-mediated mRNA decay (NMD) and that FMRP loss results in hyperactivated NMD and inhibition of neuronal differentiation in human stem cells. Results We show here that NMD is hyperactivated during the development of the cerebral cortex, hippocampus, and cerebellum in the Fmr1-knockout (KO) mouse during embryonic and early postnatal periods. Our findings demonstrate that NMD regulates many neuronal mRNAs that are important for mouse brain development. Conclusions We reveal the abnormal regulation of these mRNAs in the Fmr1-KO mouse, a model of FXS, and highlight the importance of early intervention.


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