scholarly journals Toward Spatial Identities in Human Brain Organoids-on-Chip Induced by Morphogen-Soaked Beads

2020 ◽  
Vol 7 (4) ◽  
pp. 164
Author(s):  
Lihi Ben-Reuven ◽  
Orly Reiner
Keyword(s):  
Human Brain ◽  
Embryonic Stem ◽  
Self Organization ◽  
Spatial Patterning ◽  
Imaging Device ◽  
Factor Expression ◽  
On Chip ◽  
Key Aspects ◽  
Transcription Factor Expression

Recent advances in stem-cell technologies include the differentiation of human embryonic stem cells (hESCs) into organ-like structures (organoids). These organoids exhibit remarkable self-organization that resembles key aspects of in vivo organ development. However, organoids have an unpredictable anatomy, and poorly reflect the topography of the dorsoventral, mediolateral, and anteroposterior axes. In vivo the temporal and the spatial patterning of the developing tissue is orchestrated by signaling molecules called morphogens. Here, we used morphogen-soaked beads to influence the spatial identities within hESC-derived brain organoids. The morphogen- and synthetic molecules-soaked beads were interpreted as local organizers, and key transcription factor expression levels within the organoids were affected as a function of the distance from the bead. We used an on-chip imaging device that we have developed, that allows live imaging of the developing hESC-derived organoids. This platform enabled studying the effect of changes in WNT/BMP gradients on the expression of key landmark genes in the on-chip human brain organoids. Titration of CHIR99201 (WNT agonist) and BMP4 directed the expression of telencephalon and medial pallium genes; dorsal and ventral midbrain markers; and isthmus-related genes. Overall, our protocol provides an opportunity to study phenotypes of altered regional specification and defected connectivity, which are found in neurodevelopmental diseases.

scholarly journals Applications of brain organoids in neurodevelopment and neurological diseases

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Nan Sun ◽  
Xiangqi Meng ◽  
Yuxiang Liu ◽  
Dan Song ◽  
Chuanlu Jiang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Human Brain ◽  
Neurological Diseases ◽  
Three Dimensional ◽  
Embryonic Stem ◽  
Cell Types ◽  
Current State ◽  
Spatiotemporal Process ◽  
Brain Organoid

AbstractA brain organoid is a self-organizing three-dimensional tissue derived from human embryonic stem cells or pluripotent stem cells and is able to simulate the architecture and functionality of the human brain. Brain organoid generation methods are abundant and continue to improve, and now, an in vivo vascularized brain organoid has been encouragingly reported. The combination of brain organoids with immune-staining and single-cell sequencing technology facilitates our understanding of brain organoids, including the structural organization and the diversity of cell types. Recent publications have reported that brain organoids can mimic the dynamic spatiotemporal process of early brain development, model various human brain disorders, and serve as an effective preclinical platform to test and guide personalized treatment. In this review, we introduce the current state of brain organoid differentiation strategies, summarize current progress and applications in the medical domain, and discuss the challenges and prospects of this promising technology.

scholarly journals Embryonic organoids recapitulate early heart organogenesis

2019 ◽  
Author(s):  
Giuliana Rossi ◽  
Andrea Boni ◽  
Romain Guiet ◽  
Mehmet Girgin ◽  
Robert G. Kelly ◽  
...  
Keyword(s):  
Heart Development ◽  
Cardiac Tissue ◽  
Embryonic Stem ◽  
Coordinated Development ◽  
Cardiac Progenitors ◽  
Tissue Interactions ◽  
Heart Field ◽  
Morphogenetic Potential ◽  
Key Aspects

AbstractOrganoids are powerful models for studying tissue development, physiology, and disease. However, current culture systems disrupt the inductive tissue-tissue interactions needed for the complex morphogenetic processes of native organogenesis. Here we show that mouse embryonic stem cells (mESCs) can be coaxed to robustly undergo the fundamental steps of early heart organogenesis with an in vivo-like spatiotemporal fidelity. These axially patterned embryonic organoids support the generation of cardiovascular progenitors, as well as first and second heart field compartments. The cardiac progenitors self-organize into an anterior domain reminiscent of a cardiac crescent before forming a beating cardiac tissue near a putative primitive gut-like tube, from which it is separated by an endocardial-like layer. These findings unveil the surprising morphogenetic potential of mESCs to execute key aspects of organogenesis through the coordinated development of multiple tissues. This platform could be an excellent tool for studying heart development in unprecedented detail and throughput.

scholarly journals One-stop Microfluidic Assembly of Human Brain Organoids to Model Prenatal Cannabis Exposure

2020 ◽  
Author(s):  
Zheng Ao ◽  
Hongwei Cai ◽  
Daniel J Havert ◽  
Zhuhao Wu ◽  
Zhiyi Gong ◽  
...  
Keyword(s):  
Human Brain ◽  
Brain Development ◽  
Developmental Disorders ◽  
Embryonic Stem ◽  
Microfluidic Platform ◽  
Cell Culture Techniques ◽  
Human Brain Development ◽  
One Stop ◽  
On Chip ◽  
Early Human

AbstractPrenatal cannabis exposure (PCE) influences human brain development, but it is challenging to model PCE using animals and current cell culture techniques. Here, we developed a one-stop microfluidic platform to assemble and culture human cerebral organoids from human embryonic stem cells (hESC) to investigate the effect of PCE on early human brain development. By incorporating perfusable culture chambers, air-liquid interface, and one-stop protocol, this microfluidic platform can simplify the fabrication procedure, and produce a large number of organoids (169 organoids per 3.5 cm x 3.5 cm device area) without fusion, as compared with conventional fabrication methods. These one-stop microfluidic assembled cerebral organoids not only recapitulate early human brain structure, biology, and electrophysiology but also have minimal size variation and hypoxia. Under on-chip exposure to the psychoactive cannabinoid, delta-9-tetrahydrocannabinol (THC), cerebral organoids exhibited reduced neuronal maturation, downregulation of cannabinoid receptor type 1 (CB1) receptors, and impaired neurite outgrowth. Moreover, transient on-chip THC treatment also decreased spontaneous firing in microfluidic assembled brain organoids. This one-stop microfluidic technique enables a simple, scalable, and repeatable organoid culture method that can be used not only for human brain organoids, but also for many other human organoids including liver, kidney, retina, and tumor organoids. This technology could be widely used in modeling brain and other organ development, developmental disorders, developmental pharmacology and toxicology, and drug screening.

scholarly journals Transcriptional analysis defines TCR and cytokine-stimulated MAIT cells as rapid polyfunctional effector T cells that can coordinate the immune response

2019 ◽  
Author(s):  
Rajesh Lamichhane ◽  
Marion Schneider ◽  
Sara M. de la Harpe ◽  
Thomas W. R. Harrop ◽  
Rachel F. Hannaway ◽  
...  
Keyword(s):  
Immune Response ◽  
Transcription Factor ◽  
T Cell ◽  
Cell Receptor ◽  
Transcriptional Analysis ◽  
Mait Cells ◽  
Cytokines And Chemokines ◽  
Factor Expression ◽  
Transcription Factor Expression

AbstractMAIT cells are an abundant innate-like T cell population which can be activated via either their T cell receptor (TCR), which recognizes MR1-bound pyrimidine antigens derived from microbial riboflavin biosynthesis, or via cytokines, such as IL-12 and IL-18. In vivo, these two modes of activation may act in concert or independently depending upon the nature of the microbial or inflammatory stimuli. It is unknown, however, how the MAIT cell response differs to the different modes of activation. Here, we define the transcriptional and effector responses of human MAIT cells to TCR and cytokine stimulation. We report that MAIT cells rapidly respond to TCR stimulation through the production of multiple effector cytokines and chemokines, alteration of their cytotoxic granule content and transcription factor expression, and upregulation of co-stimulatory proteins CD40L and 4-1BB. In contrast, cytokine-mediated activation is slower and results in more limited production of cytokines, chemokines, and co-stimulatory proteins; differences in granule content and transcription factor expression are also evident. Therefore, we propose that in infections by riboflavin-synthesizing bacteria, MAIT cells play a key early role in effecting and coordinating the immune response, while in the absence of TCR stimulation (e.g. viral infection) their role is likely to differ.

scholarly journals Self-organization of stem cells into embryos: A window on early mammalian development

Science ◽  
2019 ◽  
Vol 364 (6444) ◽  
pp. 948-951 ◽  
Author(s):  
Marta N. Shahbazi ◽  
Eric D. Siggia ◽  
Magdalena Zernicka-Goetz
Keyword(s):  
Stem Cells ◽  
Three Dimensional ◽  
Embryonic Stem ◽  
Self Organization ◽  
In Vivo Studies ◽  
Mammalian Development ◽  
Intrinsic Capacity ◽  
Three Dimensional Models ◽  
Early Mammalian Development

Embryonic development is orchestrated by robust and complex regulatory mechanisms acting at different scales of organization. In vivo studies are particularly challenging for mammals after implantation, owing to the small size and inaccessibility of the embryo. The generation of stem cell models of the embryo represents a powerful system with which to dissect this complexity. Control of geometry, modulation of the physical environment, and priming with chemical signals reveal the intrinsic capacity of embryonic stem cells to make patterns. Adding the stem cells for the extraembryonic lineages generates three-dimensional models that are more autonomous from the environment and recapitulate many features of the pre- and postimplantation mouse embryo, including gastrulation. Here, we review the principles of self-organization and how they set cells in motion to create an embryo.

scholarly journals Hemodynamic-mediated endocardial signaling controls in vivo myocardial reprogramming

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Manuel Gálvez-Santisteban ◽  
Danni Chen ◽  
Ruilin Zhang ◽  
Ricardo Serrano ◽  
Cathleen Nguyen ◽  
...  
Keyword(s):  
Environmental Changes ◽  
Cardiac Injury ◽  
Bmp Signaling ◽  
Heart Regeneration ◽  
Lower Vertebrate ◽  
Hemodynamic Forces ◽  
Factor Expression ◽  
Transcription Factor Expression ◽  
Insight Into

Lower vertebrate and neonatal mammalian hearts exhibit the remarkable capacity to regenerate through the reprogramming of pre-existing cardiomyocytes. However, how cardiac injury initiates signaling pathways controlling this regenerative reprogramming remains to be defined. Here, we utilize in vivo biophysical and genetic fate mapping zebrafish studies to reveal that altered hemodynamic forces due to cardiac injury activate a sequential endocardial-myocardial signaling cascade to direct cardiomyocyte reprogramming and heart regeneration. Specifically, these altered forces are sensed by the endocardium through the mechanosensitive channel Trpv4 to control Klf2a transcription factor expression. Consequently, Klf2a then activates endocardial Notch signaling which results in the non-cell autonomous initiation of myocardial Erbb2 and BMP signaling to promote cardiomyocyte reprogramming and heart regeneration. Overall, these findings not only reveal how the heart senses and adaptively responds to environmental changes due to cardiac injury, but also provide insight into how flow-mediated mechanisms may regulate cardiomyocyte reprogramming and heart regeneration.

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