scholarly journals Induction of inverted morphology in brain organoids by vertical-mixing bioreactors

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Dang Ngoc Anh Suong ◽  
Keiko Imamura ◽  
Ikuyo Inoue ◽  
Ryotaro Kabai ◽  
Satoko Sakamoto ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Inner Core ◽  
Vertical Mixing ◽  
Stem Cell Differentiation ◽  
Turbulent Energy ◽  
Inverted Structure ◽  
Human Brain Development ◽  
Outer Periphery ◽  
Orbital Mixing ◽  
Brain Organoid

AbstractOrganoid technology provides an opportunity to generate brain-like structures by recapitulating developmental steps in the manner of self-organization. Here we examined the vertical-mixing effect on brain organoid structures using bioreactors and established inverted brain organoids. The organoids generated by vertical mixing showed neurons that migrated from the outer periphery to the inner core of organoids, in contrast to orbital mixing. Computational analysis of flow dynamics clarified that, by comparison with orbital mixing, vertical mixing maintained the high turbulent energy around organoids, and continuously kept inter-organoid distances by dispersing and adding uniform rheological force on organoids. To uncover the mechanisms of the inverted structure, we investigated the direction of primary cilia, a cellular mechanosensor. Primary cilia of neural progenitors by vertical mixing were aligned in a multidirectional manner, and those by orbital mixing in a bidirectional manner. Single-cell RNA sequencing revealed that neurons of inverted brain organoids presented a GABAergic character of the ventral forebrain. These results suggest that controlling fluid dynamics by biomechanical engineering can direct stem cell differentiation of brain organoids, and that inverted brain organoids will be applicable for studying human brain development and disorders in the future.

scholarly journals FBW7 couples structural integrity with functional output of primary cilia

2020 ◽  
Author(s):  
Eleni Petsouki ◽  
Vasileios Gerakopoulos ◽  
Nicholas Szeto ◽  
Wenhan Chang ◽  
Mary Beth Humphrey ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Structural Integrity ◽  
Stem Cell Differentiation ◽  
Bone Architecture ◽  
Structural Defects ◽  
Independent Manner ◽  
Mesenchymal Stem Cell Differentiation ◽  
Cilia Formation ◽  
Length Changes ◽  
Msc Differentiation

AbstractStructural defects in cilia have robust effects in diverse tissues and systems. However, how ciliary length changes influence signaling output are unknown. Here, we examined the functional role of a ciliary length control mechanism whereby FBW7-mediated destruction of NDE1 positively regulated ciliary length, in mesenchymal stem cell differentiation. We show that FBW7 functions as a master regulator of both negative (NDE1) and positive (TALPID3) regulators of ciliogenesis, with an overall positive net effect on cilia formation, MSC differentiation, and bone architecture. Deletion of Fbxw7 suppresses ciliation, Hedgehog activity, and differentiation, which are rescued in Fbxw7/Nde1-null cells. However, despite formation of abnormally long cilia in Nde1-null cells, MSC differentiation is suppressed. NDE1 promotes MSC differentiation by increasing the activity of the Hedgehog pathway by direct binding and enhancing GLI2 activity in a cilia-independent manner. We propose that ciliary structure-function coupling is determined by intricate interactions of structural and functional proteins.

scholarly journals Challenges in Modeling Human Neural Circuit Formation via Brain Organoid Technology

2020 ◽  
Vol 14 ◽  
Author(s):  
Takeshi K. Matsui ◽  
Yuichiro Tsuru ◽  
Ken-ichiro Kuwako
Keyword(s):  
Human Brain ◽  
Brain Development ◽  
Neural Circuit ◽  
Disease Modeling ◽  
Three Dimensional ◽  
Neural Lineage ◽  
Human Brain Development ◽  
Brain Organoid ◽  
Circuit Formation

Human brain organoids are three-dimensional self-organizing tissues induced from pluripotent cells that recapitulate some aspects of early development and some of the early structure of the human brain in vitro. Brain organoids consist of neural lineage cells, such as neural stem/precursor cells, neurons, astrocytes and oligodendrocytes. Additionally, brain organoids contain fluid-filled ventricle-like structures surrounded by a ventricular/subventricular (VZ/SVZ) zone-like layer of neural stem cells (NSCs). These NSCs give rise to neurons, which form multiple outer layers. Since these structures resemble some aspects of structural arrangements in the developing human brain, organoid technology has attracted great interest in the research fields of human brain development and disease modeling. Developmental brain disorders have been intensely studied through the use of human brain organoids. Relatively early steps in human brain development, such as differentiation and migration, have also been studied. However, research on neural circuit formation with brain organoids has just recently began. In this review, we summarize the current challenges in studying neural circuit formation with organoids and discuss future perspectives.

scholarly journals Unraveling Human Brain Development and Evolution Using Organoid Models

2021 ◽  
Vol 9 ◽  
Author(s):  
Sarah Fernandes ◽  
Davis Klein ◽  
Maria C. Marchetto
Keyword(s):  
Human Brain ◽  
Brain Development ◽  
Brain Region ◽  
Model Systems ◽  
Transcriptional Signature ◽  
Human Brain Development ◽  
Advanced Stages ◽  
Brain Organoid ◽  
Development And Evolution ◽  
Human Specific

Brain organoids are proving to be physiologically relevant models for studying human brain development in terms of temporal transcriptional signature recapitulation, dynamic cytoarchitectural development, and functional electrophysiological maturation. Several studies have employed brain organoid technologies to elucidate human-specific processes of brain development, gene expression, and cellular maturation by comparing human-derived brain organoids to those of non-human primates (NHPs). Brain organoids have been established from a variety of NHP pluripotent stem cell (PSC) lines and many protocols are now available for generating brain organoids capable of reproducibly representing specific brain region identities. Innumerous combinations of brain region specific organoids derived from different human and NHP PSCs, with CRISPR-Cas9 gene editing techniques and strategies to promote advanced stages of maturation, will successfully establish complex brain model systems for the accurate representation and elucidation of human brain development. Identified human-specific processes of brain development are likely vulnerable to dysregulation and could result in the identification of therapeutic targets or disease prevention strategies. Here, we discuss the potential of brain organoids to successfully model human-specific processes of brain development and explore current strategies for pinpointing these differences.

scholarly journals Primary Cilium Is Involved in Stem Cell Differentiation and Renewal through the Regulation of Multiple Signaling Pathways

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1428
Author(s):  
Sila Yanardag ◽  
Elena N. Pugacheva
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Signaling Pathways ◽  
Primary Cilium ◽  
Primary Cilia ◽  
Vision Loss ◽  
Stem Cell Differentiation ◽  
Future Research ◽  
Renal Anomalies

Signaling networks guide stem cells during their lineage specification and terminal differentiation. Primary cilium, an antenna-like protrusion, directly or indirectly plays a significant role in this guidance. All stem cells characterized so far have primary cilia. They serve as entry- or check-points for various signaling events by controlling the signal transduction and stability. Thus, defects in the primary cilia formation or dynamics cause developmental and health problems, including but not limited to obesity, cardiovascular and renal anomalies, hearing and vision loss, and even cancers. In this review, we focus on the recent findings of how primary cilium controls various signaling pathways during stem cell differentiation and identify potential gaps in the field for future research.

scholarly journals FBW7 couples structural integrity with functional output of primary cilia

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Eleni Petsouki ◽  
Vasileios Gerakopoulos ◽  
Nicholas Szeto ◽  
Wenhan Chang ◽  
Mary Beth Humphrey ◽  
...  
Keyword(s):  
Stem Cell ◽  
Primary Cilia ◽  
Structural Integrity ◽  
Interaction Network ◽  
Stem Cell Differentiation ◽  
Bone Architecture ◽  
Structural Defects ◽  
Independent Manner ◽  
And Function ◽  
Msc Differentiation

AbstractStructural defects in primary cilia have robust effects in diverse tissues and systems. However, how disorders of ciliary length lead to functional outcomes are unknown. We examined the functional role of a ciliary length control mechanism of FBW7-mediated destruction of NDE1, in mesenchymal stem cell (MSC) differentiation. We show that FBW7 functions as a master regulator of both negative (NDE1) and positive (TALPID3) regulators of ciliogenesis, with an overall positive net effect on primary cilia formation, MSC differentiation to osteoblasts, and bone architecture. Deletion of Fbxw7 suppresses ciliation, Hedgehog activity, and differentiation, which are partially rescued in Fbxw7/Nde1-null cells. We also show that NDE1, despite suppressing ciliogenesis, promotes MSC differentiation by increasing the activity of the Hedgehog pathway by direct binding and enhancing GLI2 activity in a cilia-independent manner. We propose that FBW7 controls a protein-protein interaction network coupling ciliary structure and function, which is essential for stem cell differentiation.

Expression of Primary Cilia on Liver Stem and Progenitor Cells: Potential Role for Mechanosensing in Liver Development

2013 ◽  
Author(s):  
Emma C. Moran ◽  
Pedro M. Baptista ◽  
Kenichiro Nishii ◽  
David Wasnick ◽  
Shay Soker ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Cell Types ◽  
The Body ◽  
Embryonic Stem Cell Differentiation ◽  
Mother Centriole ◽  
Stem And Progenitor Cells ◽  
Cycle Regulation

The primary cilium is a non-motile organelle that projects out from the plasma membrane of many cell types in the body. It consists of an axoneme with microtubules arranged in a 9+0 arrangement that extends from the mother centriole contained within the basal body. Once thought to be a non-essential organelle, it is now known that primary cilia have an important role in embryonic and post-natal development, as well as maintenance of adult tissues. Mutations affecting primary ciliary development result in a class of serious diseases known as ciliopathies [1, 2]. Recent research suggests that the primary cilia/ centrosomes might play a role in embryonic stem cell differentiation through cell cycle regulation and their association with the Hedgehog signaling pathway [3, 4].

scholarly journals Brain Organoids: Studying Human Brain Development and Diseases in a Dish

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Jie Xu ◽  
Zhexing Wen
Keyword(s):  
Stem Cell ◽  
High Throughput Screening ◽  
Disease Modeling ◽  
Rapid Development ◽  
Three Dimensional ◽  
Cell Types ◽  
Future Directions ◽  
Human Brain Development ◽  
Basic Biology ◽  
Brain Organoid

With the rapid development of stem cell technology, the advent of three-dimensional (3D) cultured brain organoids has opened a new avenue for studying human neurodevelopment and neurological disorders. Brain organoids are stem-cell-derived 3D suspension cultures that self-assemble into an organized structure with cell types and cytoarchitectures recapitulating the developing brain. In recent years, brain organoids have been utilized in various aspects, ranging from basic biology studies, to disease modeling, and high-throughput screening of pharmaceutical compounds. In this review, we overview the establishment and development of brain organoid technology, its recent progress, and translational applications, as well as existing limitations and future directions.

scholarly journals A novel approach to derive human midbrain-specific organoids from neuroepithelial stem cells

2016 ◽  
Author(s):  
Anna S. Monzel ◽  
Lisa M. Smits ◽  
Kathrin Hemmer ◽  
Siham Hachi ◽  
Edinson Lucumi Moreno ◽  
...  
Keyword(s):  
Stem Cells ◽  
Human Brain ◽  
Dopaminergic Neurons ◽  
Disease Modeling ◽  
Neurological Diseases ◽  
Oligodendrocyte Differentiation ◽  
Human Brain Development ◽  
Novel Approach ◽  
Brain Organoid

AbstractResearch on human brain development and neurological diseases is limited by the lack of advanced experimental in vitro models that truly recapitulate the complexity of the human brain. Furthermore, animal models of human neurodegenerative diseases have failed dramatically, and the success rate of clinical trials based on these models has been disappointing. Here, we describe a novel and robust human brain organoid system that is highly specific to the midbrain derived from regionally patterned neuroepithelial stem cells. These human midbrain organoids contain spatially organized groups of dopaminergic neurons, which make them an attractive model to study Parkinson’s disease. Midbrain organoids are characterized in detail for neuronal, astroglial and oligodendrocyte differentiation. Furthermore, we show the presence of synaptic connections and electrophysiological activity. The complexity of this model is further highlighted by the myelination of neurites. The present midbrain organoid system has the potential to be used for advanced in vitro disease modeling and therapy development.

Sign in / Sign up

Export Citation Format

Share Document