The piRNA pathway in planarian flatworms: new model, new insights

2020 ◽  
Vol 401 (10) ◽  
pp. 1123-1141
Author(s):  
Iana V. Kim ◽  
Sebastian Riedelbauch ◽  
Claus-D. Kuhn
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Adult Stem Cells ◽  
Germline Development ◽  
Molecular Feature ◽  
Protein Coding ◽  
Regulate Gene Expression ◽  
Small Regulatory Rnas ◽  
Stable Genome ◽  
Pirna Pathway

AbstractPIWI-interacting RNAs (piRNAs) are small regulatory RNAs that associate with members of the PIWI clade of the Argonaute superfamily of proteins. piRNAs are predominantly found in animal gonads. There they silence transposable elements (TEs), regulate gene expression and participate in DNA methylation, thus orchestrating proper germline development. Furthermore, PIWI proteins are also indispensable for the maintenance and differentiation capabilities of pluripotent stem cells in free-living invertebrate species with regenerative potential. Thus, PIWI proteins and piRNAs seem to constitute an essential molecular feature of somatic pluripotent stem cells and the germline. In keeping with this hypothesis, both PIWI proteins and piRNAs are enriched in neoblasts, the adult stem cells of planarian flatworms, and their presence is a prerequisite for the proper regeneration and perpetual tissue homeostasis of these animals. The piRNA pathway is required to maintain the unique biology of planarians because, in analogy to the animal germline, planarian piRNAs silence TEs and ensure stable genome inheritance. Moreover, planarian piRNAs also contribute to the degradation of numerous protein-coding transcripts, a function that may be critical for neoblast differentiation. This review gives an overview of the planarian piRNA pathway and of its crucial function in neoblast biology.

scholarly journals Genome Editing Human Pluripotent Stem Cells to Model β-Cell Disease and Unmask Novel Genetic Modifiers

2021 ◽  
Vol 12 ◽  
Author(s):  
Matthew N. George ◽  
Karla F. Leavens ◽  
Paul Gadue
Keyword(s):  
Stem Cells ◽  
Genome Editing ◽  
Pluripotent Stem Cells ◽  
Genetic Disease ◽  
Single Gene ◽  
Monogenic Diabetes ◽  
Human Pluripotent Stem Cells ◽  
Genetic Modifiers ◽  
Β Cell ◽  
Protein Coding

A mechanistic understanding of the genetic basis of complex diseases such as diabetes mellitus remain elusive due in large part to the activity of genetic disease modifiers that impact the penetrance and/or presentation of disease phenotypes. In the face of such complexity, rare forms of diabetes that result from single-gene mutations (monogenic diabetes) can be used to model the contribution of individual genetic factors to pancreatic β-cell dysfunction and the breakdown of glucose homeostasis. Here we review the contribution of protein coding and non-protein coding genetic disease modifiers to the pathogenesis of diabetes subtypes, as well as how recent technological advances in the generation, differentiation, and genome editing of human pluripotent stem cells (hPSC) enable the development of cell-based disease models. Finally, we describe a disease modifier discovery platform that utilizes these technologies to identify novel genetic modifiers using induced pluripotent stem cells (iPSC) derived from patients with monogenic diabetes caused by heterozygous mutations.

scholarly journals Cardiac Regeneration After Myocardial Infarction: an Approachable Goal

2020 ◽  
Vol 22 (10) ◽  
Author(s):  
Mauro Giacca
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Adult Stem Cells ◽  
Ex Vivo ◽  
Embryonic Stem ◽  
Cardiac Regeneration ◽  
Myocardial Tissue ◽  
Induced Pluripotent ◽  
Large Animals

Abstract Purpose of Review Until recently, cardiac regeneration after myocardial infarction has remained a holy grail in cardiology. Failure of clinical trials using adult stem cells and scepticism about the actual existence of such cells has reinforced the notion that the heart is an irreversibly post-mitotic organ. Recent evidence has drastically challenged this conclusion. Recent Findings Cardiac regeneration can successfully be obtained by at least two strategies. First, new cardiomyocytes can be generated from embryonic stem cells or induced pluripotent stem cells and administered to the heart either as cell suspensions or upon ex vivo generation of contractile myocardial tissue. Alternatively, the endogenous capacity of cardiomyocytes to proliferate can be stimulated by the delivery of individual genes or, more successfully, of selected microRNAs. Summary Recent experimental success in large animals by both strategies now fuels the notion that cardiac regeneration is indeed possible. Several technical hurdles, however, still need to be addressed and solved before broad and successful clinical application is achieved.

scholarly journals Reconstitution of prospermatogonial specification in vitro from human induced pluripotent stem cells

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Young Sun Hwang ◽  
Shinnosuke Suzuki ◽  
Yasunari Seita ◽  
Jumpei Ito ◽  
Yuka Sakata ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Primordial Germ Cell ◽  
Postnatal Period ◽  
Germline Development ◽  
Specific Regulation ◽  
Induced Pluripotent

Abstract Establishment of spermatogonia throughout the fetal and postnatal period is essential for production of spermatozoa and male fertility. Here, we establish a protocol for in vitro reconstitution of human prospermatogonial specification whereby human primordial germ cell (PGC)-like cells differentiated from human induced pluripotent stem cells are further induced into M-prospermatogonia-like cells and T1 prospermatogonia-like cells (T1LCs) using long-term cultured xenogeneic reconstituted testes. Single cell RNA-sequencing is used to delineate the lineage trajectory leading to T1LCs, which closely resemble human T1-prospermatogonia in vivo and exhibit gene expression related to spermatogenesis and diminished proliferation, a hallmark of quiescent T1 prospermatogonia. Notably, this system enables us to visualize the dynamic and stage-specific regulation of transposable elements during human prospermatogonial specification. Together, our findings pave the way for understanding and reconstructing human male germline development in vitro.

scholarly journals Effects on Wound Healing of Human-Induced Pluripotent Stem Cell-Derived Cells Similar to Endothelial Colony-Forming Cells

2020 ◽  
Vol 16 (1) ◽  
pp. 3-12 ◽  
Author(s):  
Sang Hun Kim ◽  
Jeoung Hyun Nam ◽  
Man Ryul Lee ◽  
Yongsung Hwang ◽  
Eun Soo Park
Keyword(s):  
Stem Cells ◽  
Wound Healing ◽  
Induced Pluripotent Stem Cells ◽  
Granulation Tissue ◽  
Pluripotent Stem Cells ◽  
Adult Stem Cells ◽  
Statistical Significance ◽  
Embryonic Stem ◽  
Endothelial Colony Forming Cells ◽  
Induced Pluripotent

Background: Human-induced pluripotent stem cells (hiPSCs) complement the disadvantages of conventional embryonic stem cells and adult stem cells, and have the advantages of simplicity of production and pluripotency. Some recent studies have applied hiPSC in cell therapy.Methods: In this study, we examined the effect of cells similar to cord blood endothelial colony-forming cells (CB-ECFCs), differentiated from induced pluripotent stem cells, on angiogenesis and granulation tissue formation in the proliferative phase of wound healing. For cell transfer, we used methacrylated gelatin (GelMA)-co-poly(styrene sulfonate) (PSS) cryogel, which has better bioactivity than conventional hydrogels and excellent mechanical properties and swelling capacity. Two full-thickness skin defects, 0.8 cm in diameter, were made in each of our 12 experimental mice. Wound splinting models were used to prevent contraction of the wounds. In each of the experimental animals, 5×10<sup>5</sup> cells were applied with GelMA-co-PSS cryogel in one of the two wounds, while only a culture medium with cryogel was applied to the other wound.Results: Wound reduction rates in the experimental side showed increases compared to the control side in 3 days, but there was no statistical significance. The histological score was significantly increased (P<0.05), and histologic examination showed that angiogenesis and granulation formation were also increased in the experiment side.Conclusion: In conclusion, CB-ECFCs-like cells differentiated from hiPSCs were effective in promoting formation of angiogenesis and granulation tissue in a mouse wound healing model.

scholarly journals Analysis of the expression of PIWI-interacting RNAs during cardiac differentiation of human pluripotent stem cells

2019 ◽  
Author(s):  
Alejandro La Greca ◽  
María Agustina Scarafía ◽  
María Clara Hernández Cañás ◽  
Nelba Pérez ◽  
Sheila Castañeda ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Muscle Development ◽  
Germ Line ◽  
Cardiac Cells ◽  
Cardiac Differentiation ◽  
Fine Tuning ◽  
Protein Coding ◽  
Sense Strand ◽  
And Function

SummaryPIWI-interacting RNAs (piRNAs) are a class of non-coding RNAs initially thought to be restricted almost exclusively to germ line cells. In recent years, accumulating evidence has demonstrated that piRNAs are actually expressed in somatic cells like pluripotent, neural, cardiac and even cancer cells. However, controversy still remains around the existence and function of somatic piRNAs. Using small RNA-seq samples from H9 pluripotent stem cells differentiated to mesoderm progenitors and cardiomyocytes we identified the expression of 447 piRNAs, of which 241 were detected in pluripotency, 218 in mesoderm and 171 in cardiac cells. The majority of them originated from the sense strand of protein coding and lncRNAs genes in all stages of differentiation, though no evidences for secondary piRNAs (ping-pong loop) were found. Genes hosting piRNAs in cardiac samples were related to critical biological processes in the heart, like contraction and cardiac muscle development. Our results indicate that somatic piRNAs might have a role in fine-tuning the expression of genes involved in the differentiation of pluripotent cells to cardiomyocytes.

scholarly journals Reconstitution of prospermatogonial specification in vitro from human induced pluripotent stem cells

2020 ◽  
Author(s):  
Young Sun Hwang ◽  
Shinnosuke Suzuki ◽  
Yasunari Seita ◽  
Jumpei Ito ◽  
Yuka Sakata ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Primordial Germ Cell ◽  
Postnatal Period ◽  
Germline Development ◽  
Specific Regulation ◽  
Induced Pluripotent

ABSTRACTEstablishment of spermatogonia throughout the fetal and postnatal period is essential for production of spermatozoa and male fertility. Here, we established a protocol for in vitro reconstitution of human prospermatogonial specification whereby human primordial germ cell (PGC)-like cells (hPGCLCs) differentiated from human induced pluripotent stem cells were further induced into M-prospermatogonia-like cells (MLCs) and T1 prospermatogonia-like cells (T1LCs) using long-term cultured xenogeneic reconstituted testes. Single cell RNA-sequencing was used to delineate the lineage trajectory leading to T1LCs, which closely resemble human T1-prospermatogonia in vivo and exhibited gene expression related to spermatogenesis and diminished proliferation, a hallmark of quiescent T1 prospermatogonia. Notably, this system enabled us to visualize the dynamic and stage-specific regulation of transposable elements during human prospermatogonial specification. Together, our findings pave the way for understanding and reconstructing human male germline development in vitro.

scholarly journals When Long Noncoding RNAs Meet Genome Editing in Pluripotent Stem Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-13
Author(s):  
Fuquan Chen ◽  
Jiaojiao Ji ◽  
Jian Shen ◽  
Xinyi Lu
Keyword(s):  
Stem Cells ◽  
Transcriptional Regulation ◽  
Genome Editing ◽  
Pluripotent Stem Cells ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Biological Processes ◽  
Protein Coding ◽  
Protein Coding Genes ◽  
The Past

Most of the human genome can be transcribed into RNAs, but only a minority of these regions produce protein-coding mRNAs whereas the remaining regions are transcribed into noncoding RNAs. Long noncoding RNAs (lncRNAs) were known for their influential regulatory roles in multiple biological processes such as imprinting, dosage compensation, transcriptional regulation, and splicing. The physiological functions of protein-coding genes have been extensively characterized through genome editing in pluripotent stem cells (PSCs) in the past 30 years; however, the study of lncRNAs with genome editing technologies only came into attentions in recent years. Here, we summarize recent advancements in dissecting the roles of lncRNAs with genome editing technologies in PSCs and highlight potential genome editing tools useful for examining the functions of lncRNAs in PSCs.

scholarly journals Generation and Applications of Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Chengzhu Zhao ◽  
Makoto Ikeya
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Regenerative Medicine ◽  
Pluripotent Stem Cells ◽  
Adult Stem Cells ◽  
Disease Modeling ◽  
Induced Pluripotent Stem Cell ◽  
Potential Applications ◽  
Induced Pluripotent ◽  
Number Of Publications

Mesenchymal stem cells (MSCs) are adult stem cells with fibroblast-like morphology and isolated from the bone marrow via plastic adhesion. Their multipotency and immunoregulatory properties make MSCs possible therapeutic agents, and an increasing number of publications and clinical trials have highlighted their potential in regenerative medicine. However, the finite proliferative capacity of MSCs limits their scalability and global dissemination as a standardized therapeutic product. Furthermore, adult tissue provenance could constrain accessibility, impinge on cellular potency, and incur greater exposure to disease-causing pathogens based on the donor. These issues could be circumvented by the derivation of MSCs from pluripotent stem cells. In this paper, we review methods that induce and characterize MSCs derived from induced pluripotent stem cells (iPSCs) and introduce MSC applications to disease modeling, pathogenic mechanisms, and drug discovery. We also discuss the potential applications of MSCs in regenerative medicine including cell-based therapies and issues that should be overcome before iPSC-derived MSC therapy will be applied in the clinic.

scholarly journals LncRNAs in Stem Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Shanshan Hu ◽  
Ge Shan
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Cell Biology ◽  
Adult Stem Cells ◽  
Embryonic Stem ◽  
Noncoding Rnas ◽  
Special Position ◽  
Future Studies ◽  
Induced Pluripotent ◽  
Functional Mechanisms

Noncoding RNAs are critical regulatory factors in essentially all forms of life. Stem cells occupy a special position in cell biology and Biomedicine, and emerging results show that multiple ncRNAs play essential roles in stem cells. We discuss some of the known ncRNAs in stem cells such as embryonic stem cells, induced pluripotent stem cells, mesenchymal stem cells, adult stem cells, and cancer stem cells with a focus on long ncRNAs. Roles and functional mechanisms of these lncRNAs are summarized, and insights into current and future studies are presented.

scholarly journals Conserved Small Nucleotidic Elements at the Origin of Concerted piRNA Biogenesis from Genes and lncRNAs

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1491
Author(s):  
Silke Jensen ◽  
Emilie Brasset ◽  
Elise Parey ◽  
Hugues Roest Crollius ◽  
Igor V. Sharakhov ◽  
...  
Keyword(s):  
Regulatory Pathway ◽  
Cellular Functions ◽  
Germline Development ◽  
Protein Coding ◽  
Ping Pong ◽  
Sequence Complementarity ◽  
New Type ◽  
Non Coding Rnas ◽  
Pirna Pathway ◽  
Genomic Repeats

PIWI-interacting RNAs (piRNAs) target transcripts by sequence complementarity serving as guides for RNA slicing in animal germ cells. The piRNA pathway is increasingly recognized as critical for essential cellular functions such as germline development and reproduction. In the Anopheles gambiae ovary, as much as 11% of piRNAs map to protein-coding genes. Here, we show that ovarian mRNAs and long non-coding RNAs (lncRNAs) are processed into piRNAs that can direct other transcripts into the piRNA biogenesis pathway. Targeting piRNAs fuel transcripts either into the ping-pong cycle of piRNA amplification or into the machinery of phased piRNA biogenesis, thereby creating networks of inter-regulating transcripts. RNAs of the same network share related genomic repeats. These repeats give rise to piRNAs, which target other transcripts and lead to a cascade of concerted RNA slicing. While ping-pong networks are based on repeats of several hundred nucleotides, networks that rely on phased piRNA biogenesis operate through short ~40-nucleotides long repeats, which we named snetDNAs. Interestingly, snetDNAs are recurring in evolution from insects to mammals. Our study brings to light a new type of conserved regulatory pathway, the snetDNA-pathway, by which short sequences can include independent genes and lncRNAs in the same biological pathway.

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