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Embryogenesis in Mechanical Womb

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biochemical pathways, Biological Engineering, Biological Networks, Biological Networks, Gene Regulation and Evolution, Cell Biology, Cell Biology, Signaling & Cell Circuits, Developmental biology, Embryology, Fetal Ultrasound, Gene Therapy & Gene Editing Development, Genome Biology, Medical Devices R&D and Inventions, Methods, Placenta, Pre-Clinical Animal Model Development, Preimplantation Genetic Diagnosis and Reproductive Genomics, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Reproductive Biology & Bio Instrumentation, Signaling & Cell Circuits, tagged development, embryo, gastrulation, mechanical womb, uterus on April 8, 2021| Leave a Comment »

Embryogenesis in Mechanical Womb

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

A highly effective platforms for the ex utero culture of post-implantation mouse embryos have been developed in the present study by scientists of the Weizmann Institute of Science in Israel. The study was published in the journal Nature. They have grown more than 1,000 embryos in this way. This study enables the appropriate development of embryos from before gastrulation (embryonic day (E) 5.5) until the hindlimb formation stage (E11). Late gastrulating embryos (E7.5) are grown in three-dimensional rotating bottles, whereas extended culture from pre-gastrulation stages (E5.5 or E6.5) requires a combination of static and rotating bottle culture platforms.

At Day 11 of development more than halfway through a mouse pregnancy the researchers compared them to those developing in the uteruses of living mice and were found to be identical. Histological, molecular and single-cell RNA sequencing analyses confirm that the ex utero cultured embryos recapitulate in utero development precisely. The mouse embryos looked perfectly normal. All their organs developed as expected, along with their limbs and circulatory and nervous systems. Their tiny hearts were beating at a normal 170 beats per minute. But, the lab-grown embryos becomes too large to survive without a blood supply. They had a placenta and a yolk sack, but the nutrient solution that fed them through diffusion was no longer sufficient. So, a suitable mechanism for blood supply is required to be developed.

Till date the only way to study the development of tissues and organs is to turn to species like worms, frogs and flies that do not need a uterus, or to remove embryos from the uteruses of experimental animals at varying times, providing glimpses of development more like in snapshots than in live videos. This research will help scientists understand how mammals develop and how gene mutations, nutrients and environmental conditions may affect the fetus. This will allow researchers to mechanistically interrogate post-implantation morphogenesis and artificial embryogenesis in mammals. In the future it may be possible to develop a human embryo from fertilization to birth entirely outside the uterus. But the work may one day raise profound questions about whether other animals, even humans, should or could be cultured outside a living womb.

References:

https://www.nature.com/articles/s41586-021-03416-3

https://www.sciencedirect.com/science/article/pii/S0092867414000750?via%3Dihub

https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1469-185X.1978.tb00993.x

https://www.nature.com/articles/199297a0

https://rep.bioscientifica.com/view/journals/rep/35/1/jrf_35_1_018.xml

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The function of the junk jumping gene (LINE1) uncovered

Posted in Biological Networks, Biological Networks, Gene Regulation and Evolution, Clinical Genomics, Developmental biology, Gene Regulation, Gene Regulation and Evolution, Genetics & Innovations in Treatment, Genome Biology, Population genetics, Population Health Management, Genetics & Pharmaceutical, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, tagged development, Dux, embryo, jumping gene, LINE1, transposons on July 21, 2018| Leave a Comment »

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Long interspersed nuclear elements 1 (LINE1) is repeated half a million times in the human genome, making up nearly a fifth of the DNA in every cell. But nobody cared to study it and may be the reason to call it junk DNA. LINE1, like other transposons (or “jumping genes”), has the unusual ability to copy and insert itself in random places in the genome. Many other research groups uncovered possible roles in early mouse embryos and in brain cells. But nobody quite established a proper report about the functions of LINE1.

Geneticists gave attention to LINE1 when it was found to cause cancer or genetic disorders like hemophilia. But researchers at University of California at San Francisco suspected there was more characteristics of LINE1. They suspected that if it can be most harmless then it can be worst harmful also.

Many reports showed that LINE1 is especially active inside developing embryos, which suggests that the segment actually plays a key role in coordinating the development of cells in an embryo. Researchers at University of California at San Francisco figured out how to turn LINE1 off in mouse embryos by blocking LINE1 RNA. As a result the embryos got stuck in the two-cell stage, right after a fertilized egg has first split. Without LINE1, embryos essentially stopped developing.

The researchers thought that LINE1 RNA particles act as molecular “glue,” bringing together a suite of molecules that switch off the two-cell stage and kick it into the next phase of development. In particular, it turns off a gene called Dux, which is active in the two-cell stage.

LINE1’s ability to copy itself, however, seems to have nothing to do with its role in embryonic development. When LINE1 was blocked from inserting itself into the genome, the embryonic stem cells remained unaffected. It’s possible that cells in embryos have a way of making LINE1 RNA while also preventing its potentially harmful “jumping” around in the genome. But it’s unlikely that every one of the thousands of copies of LINE1 is actually being used to regulate embryonic development.

LINE1 is abundant in the genomes of almost all mammals. Other transposons, also once considered junk DNA, have turned out to have critical roles in development in human cells too. There are differences between mice and humans, so, the next obvious step is to study LINE1 in human cells, where it makes up 17 percent of the genome.

References:

https://www-theatlantic-com.cdn.ampproject.org/c/s/www.theatlantic.com/amp/article/563354/

https://www.ncbi.nlm.nih.gov/pubmed/29937225

https://www.nature.com/scitable/topicpage/transposons-the-jumping-genes-518

https://www.sciencedaily.com/releases/2018/06/180621141038.htm

https://www.ncbi.nlm.nih.gov/pubmed/16015595

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Biologists create first predictive computational model of gene networks

Posted in Biological Networks, Gene Regulation and Evolution, Cell Biology, Signaling & Cell Circuits, Computational Biology/Systems and Bioinformatics, tagged Biologist, California Institute of Technology, Computational model, embryo, gene, Gene regulatory network, Proceedings of the National Academy of Sciences of the United States of America, Sea urchin on August 30, 2012| 1 Comment »

Reported by: Dr. Venkat S. Karra, Ph.D.

Biologists create first predictive computational model of gene networks

Biologists at the California Institute of Technology (Caltech) have spent the last decade or so detailing how these gene networks control development in sea-urchin embryos. Now, for the first time, they have built a computational model of one of these networks.

This model, the scientists say, does a remarkably good job of calculating what these networks do to control the fates of different cells in the early stages of sea-urchin development—confirming that the interactions among a few dozen genes suffice to tell an embryo how to start the development of different body parts in their respective spatial locations. The model is also a powerful tool for understanding gene regulatory networks in a way not previously possible, allowing scientists to better study the genetic bases of both development and evolution.

The researchers described their computer model in a paper in the Proceedings of the National Academy of Sciences.

The model encompasses the gene regulatory network that controls the first 30 hours of the development of endomesoderm cells, which eventually form the embryo’s gut, skeleton, muscles, and immune system. This network—so far the most extensively analyzed developmental gene regulatory network of any animal organism—consists of about 50 regulatory genes that turn one another on and off.

To create the model, the researchers distilled everything they knew about the network into a series of logical statements that a computer could understand.

By computing the results of each sequence hour by hour, the model determines when and where in the embryo each gene is on and off. Comparing the computed results with experiments, the researchers found that the model reproduced the data almost exactly. “It works surprisingly well,” the researchers say.

Endothelial Differentiation and Morphogenesis of Cardiac Precursors

Posted in Cardiovascular Pharmacogenomics, tagged congenital heart defects, development, embryo, embryogenesis, Endothelium, gene expression, heart development, transcription factors, vasculogenesis on July 17, 2012| 3 Comments »

Reporter: Sudipta Saha, Ph.D.

Beyond characterization of the fundamental anatomy of vascular development, the first investigators in this field participated in one of the classic debates in all of developmental biology: where and when do endothelial cells (and hence blood vessels) arise in the developing embryo? Because blood vessels are first observed in the yolk sac in avian and mammalian embryos. It was initially assumed that all blood vessels arise from extra-embryonic tissues. However, careful histological analysis subsequently indicated that isolated foci of endothelial cells can also be observed in the embryo proper, which suggested that blood vessels arise from an intraembryonic source (specifically, the mesoderm) rather than via colonization. The formation of new blood vessels in the adult organism not only contributed to the progression of diseases such as cancer and diabetic retinopathy but also can be promoted in therapeutic approaches to various ischemic pathologies. Because many of the signals important to blood vessel development during embryogenesis are recapitulated during adult blood vessel formation, much work has been performed to better-understand the molecular control of endothelial differentiation in the developing embryo. Activators and inhibitors of developmental pathways have been tested for their ability to modulate angiogenesis in early phase clinical trials, and in the case of anti-Flk1 antibodies clinical utility has been demonstrated for anti-tumor strategies. Analyses of circulating endothelial progenitor cells, which have angiogenic potential, do indeed suggest that there are similarities in the biology of these cells compared with developmental endothelial precursors. Stem cell therapeutics therefore represents another potential arena for translation of insights from vascular development to clinical practice. Even though our understanding of endothelial development is much richer than it was even a few years ago and despite the potential applications of this knowledge in clinical medicine, there are still a number of key issues on this topic that remain to be resolved. Precisely how early are endothelial precursors specified during development, and what is the nature of this progenitor cell pool? What are the relationships among signaling pathways that specify endothelial fates in a coordinated fashion? Is there a transcriptional hierarchy that regulates vascular development? The answers to these and other questions about endothelial development are likely to be forthcoming in the near future as experimental methods continue to evolve (http://atvb.ahajournals.org/content/25/11/2246.full).

The development of the vertebrate heart can be considered an additive process, in which additional layers of complexity have been added throughout the evolution of a simple structure (linear heart tube) in the form of modular elements (atria, ventricles, septa, and valves). Each modular element confers an added capacity to the vertebrate heart and can be identified as individual structures patterned in a precise manner. An understanding of the individual modular steps in cardiac morphogenesis is particularly relevant to congenital heart disease, which usually involves defects in specific structural components of the developing heart. Organ formation requires the precise integration of cell type-specific gene expression and morphological development; both are intertwined in their regulation by transcription factors. Although many transcription factors have been described as regulators of cardiac-specific gene expression, the transcriptional regulation of cardiac morphogenesis is still not well explored. For a transcription factor to be considered directly involved in heart development, it must be expressed in developing heart tissues and exert an influence on processes that impact the morphogenesis of the developing heart. Transcription factors can regulate the expression of other genes in a tissue-specific and quantitative manner and are thus major regulators of embryonic developmental processes. A number of complex transcriptional networks and interactions are involved in the morphogenesis of the developing vertebrate heart. The identities of crucial regulators involved in defined events in cardiogenesis are being uncovered at a rapid rate, but a number of critical questions remain. First and foremost, it is still not known which transcription factors are involved in the earliest differentiation of cardiac cells from the mesoderm. Second, the downstream pathways regulated by transcription factors responsible for key morphogenetic events are still largely unknown. Third, the concept of maintained function or redeployment of functions throughout various stages of development remains to be addressed in detail. The challenge for the future lies in defining pathways downstream from cardiac transcription factors and understanding the intersection of these pathways as the heart develops from a simple patterned structure into a complex multifunctional organ (http://circres.ahajournals.org/content/90/5/509.full).

Tissue development and regeneration involve tightly coordinated and integrated processes: selective proliferation of resident stem and precursor cells, differentiation into target somatic cell type, and spatial morphological organization. The role of the mechanical environment in the coordination of these processes is poorly understood. It has been reported that multipotent cells derived from native cardiac tissue continually monitored cell substratum rigidity and showed enhanced proliferation, endothelial differentiation, and morphogenesis when the cell substratum rigidity closely matched that of myocardium. Mechanoregulation of these diverse processes required p190RhoGAP, a guanosine triphosphatase-activating protein for RhoA, acting through RhoA-dependent and -independent mechanisms. Natural or induced decreases in the abundance of p190RhoGAP triggered a series of developmental events by coupling cell-cell and cell-substratum interactions to genetic circuits controlling differentiation (http://www.ncbi.nlm.nih.gov/pubmed/22669846).