Applications of brain organoids in neurodevelopment and neurological diseases

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.

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Induced Pluripotent Stem Cells (iPSCs) in Vascular Research: from Two- to Three-Dimensional Organoids

Stem Cell Reviews and Reports ◽

10.1007/s12015-021-10149-3 ◽

2021 ◽

Author(s):

Anja Trillhaase ◽

Marlon Maertens ◽

Zouhair Aherrahrou ◽

Jeanette Erdmann

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Induced Pluripotent Stem Cells ◽

Stem Cell Research ◽

Pluripotent Stem Cells ◽

Embryonic Stem ◽

Cell Types ◽

3D Models ◽

Induced Pluripotent

AbstractStem cell technology has been around for almost 30 years and in that time has grown into an enormous field. The stem cell technique progressed from the first successful isolation of mammalian embryonic stem cells (ESCs) in the 1990s, to the production of human induced-pluripotent stem cells (iPSCs) in the early 2000s, to finally culminate in the differentiation of pluripotent cells into highly specialized cell types, such as neurons, endothelial cells (ECs), cardiomyocytes, fibroblasts, and lung and intestinal cells, in the last decades. In recent times, we have attained a new height in stem cell research whereby we can produce 3D organoids derived from stem cells that more accurately mimic the in vivo environment. This review summarizes the development of stem cell research in the context of vascular research ranging from differentiation techniques of ECs and smooth muscle cells (SMCs) to the generation of vascularized 3D organoids. Furthermore, the different techniques are critically reviewed, and future applications of current 3D models are reported. Graphical abstract

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From blastocyst to gastrula: gene regulatory networks of embryonic stem cells and early mouse embryogenesis

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2013.0542 ◽

2014 ◽

Vol 369 (1657) ◽

pp. 20130542 ◽

Cited By ~ 18

Author(s):

David-Emlyn Parfitt ◽

Michael M. Shen

Keyword(s):

Stem Cells ◽

Gene Networks ◽

Regulatory Networks ◽

Embryonic Stem ◽

Cell Lineage ◽

Network Models ◽

Cell Types ◽

Mammalian Development ◽

A Genome

To date, many regulatory genes and signalling events coordinating mammalian development from blastocyst to gastrulation stages have been identified by mutational analyses and reverse-genetic approaches, typically on a gene-by-gene basis. More recent studies have applied bioinformatic approaches to generate regulatory network models of gene interactions on a genome-wide scale. Such models have provided insights into the gene networks regulating pluripotency in embryonic and epiblast stem cells, as well as cell-lineage determination in vivo . Here, we review how regulatory networks constructed for different stem cell types relate to corresponding networks in vivo and provide insights into understanding the molecular regulation of the blastocyst–gastrula transition.

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Tumorigenicity of pluripotent stem cells: biological insights from molecular imaging

Journal of The Royal Society Interface ◽

10.1098/rsif.2010.0353.focus ◽

2010 ◽

Vol 7 (suppl_6) ◽

Cited By ~ 54

Author(s):

Nigel G. Kooreman ◽

Joseph C. Wu

Keyword(s):

Stem Cells ◽

Molecular Imaging ◽

Pluripotent Stem Cells ◽

Embryonic Stem ◽

Cell Types ◽

Cell Replacement Therapy ◽

Cell Replacement ◽

Induced Pluripotent ◽

Teratoma Formation

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have the ability (i) to duplicate indefinitely while maintaining pluripotency and (ii) to differentiate into cell types of all three embryonic germ layers. These two properties of ESCs and iPSCs make them potentially suitable for tissue engineering and cell replacement therapy for many different diseases, including Parkinson's disease, diabetes and heart disease. However, one critical obstacle in the clinical application of ESCs or iPSCs is the risk of teratoma formation. The emerging field of molecular imaging is allowing researchers to track transplanted ESCs or iPSCs in vivo , enabling early detection of teratomas.

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Isolation of human testicular cells and co-culture with embryonic stem cells

Reproduction ◽

10.1530/rep-17-0346 ◽

2018 ◽

Vol 155 (2) ◽

pp. 151-164 ◽

Cited By ~ 3

Author(s):

Meenakshi Gaur ◽

Cyril Ramathal ◽

Renee A Reijo Pera ◽

Paul J Turek ◽

Constance M John

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Lucifer Yellow ◽

Colorimetric Detection ◽

Three Dimensional ◽

Embryonic Stem ◽

Cell Types ◽

Testicular Cells ◽

Polarized Secretion ◽

Cell Progression

Our overall goal is to create a three-dimensional human cell-based testicular model for toxicological and spermatogenesis studies. Methods to purify the major somatic testicular cells, namely Leydig cells (LCs), peritubular myoid cells (PCs) and Sertoli cells (SCs), from rats, mice and guinea pigs have been reported. In humans, the isolation of populations enriched for primary LCs, PCs or SCs also have described. One objective of this study was to determine if populations of cells enriched for all three of these cell types can be isolated from testes of single human donors, and we were successful in doing so from testes of three donors. Testes tissues were enzymatically digested, gravity sedimented and Percoll filtered to isolate populations enriched for LCs, PCs and SCs. LCs and PCs were identified by colorimetric detection of the expression of prototypical enzymes. Division of PCs and SCs in culture has been reported. We observed that primary human LCs could divide in culture by incorporation of 5-ethynyl-2′-deoxyuridine. SCs were identified and their functionality was demonstrated by the formation of tight junctions as shown by the expression of tight junction proteins, increased transepithelial electrical resistance, polarized secretion of biomolecules and inhibition of lucifer yellow penetration. Furthermore, we found that human SC feeder layers could facilitate germ cell progression of human embryonic stem cells (hESCs) by microarray analysis of gene expression.

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Defining totipotency using criteria of increasing stringency

10.1101/2020.03.02.972893 ◽

2020 ◽

Cited By ~ 7

Author(s):

Eszter Posfai ◽

John Paul Schell ◽

Adrian Janiszewski ◽

Isidora Rovic ◽

Alexander Murray ◽

...

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Single Cell ◽

Pluripotent Stem Cells ◽

Embryonic Stem ◽

Cell Types ◽

Differentiated Cells ◽

Totipotent Cell

AbstractTotipotency is the ability of a single cell to give rise to all the differentiated cells that build the conceptus, yet how to capture this property in vitro remains incompletely understood. Defining totipotency relies upon a variety of assays of variable stringency. Here we describe criteria to define totipotency. We illustrate how distinct criteria of increasing stringency can be used to judge totipotency by evaluating candidate totipotent cell types in the mouse, including early blastomeres and expanded or extended pluripotent stem cells. Our data challenge the notion that expanded or extended pluripotent states harbor increased totipotent potential relative to conventional embryonic stem cells under in vivo conditions.

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Modeling HIV-1 neuropathogenesis using three-dimensional human brain organoids (hBORGs) with HIV-1 infected microglia

Scientific Reports ◽

10.1038/s41598-020-72214-0 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Roberta S. dos Reis ◽

Shilpa Sant ◽

Hannah Keeney ◽

Marc C. E. Wagner ◽

Velpandi Ayyavoo

Keyword(s):

Human Brain ◽

Interleukin 1 ◽

Three Dimensional ◽

Cell Types ◽

Great Promise ◽

Experimental Systems ◽

Molecular Events ◽

Hiv Neuropathogenesis ◽

Brain Organoid ◽

Hiv 1

Abstract HIV-1 associated neurocognitive disorder (HAND) is characterized by neuroinflammation and glial activation that, together with the release of viral proteins, trigger a pathogenic cascade resulting in synaptodendritic damage and neurodegeneration that lead to cognitive impairment. However, the molecular events underlying HIV neuropathogenesis remain elusive, mainly due to lack of brain-representative experimental systems to study HIV-CNS pathology. To fill this gap, we developed a three-dimensional (3D) human brain organoid (hBORG) model containing major cell types important for HIV-1 neuropathogenesis; neurons and astrocytes along with incorporation of HIV-infected microglia. Both infected and uninfected microglia infiltrated into hBORGs resulting in a triculture system (MG-hBORG) that mirrors the multicellular network observed in HIV-infected human brain. Moreover, the MG-hBORG model supported productive viral infection and exhibited increased inflammatory response by HIV-infected MG-hBORGs, releasing tumor necrosis factor (TNF-α) and interleukin-1 (IL-1β) and thereby mimicking the chronic neuroinflammatory environment observed in HIV-infected individuals. This model offers great promise for basic understanding of how HIV-1 infection alters the CNS compartment and induces pathological changes, paving the way for discovery of biomarkers and new therapeutic targets.

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Reversine: A Synthetic Purine with a Dual Activity as a Cell Dedifferentiating Agent and a Selective Anticancer Drug

Current Medicinal Chemistry ◽

10.2174/0929867326666190103120725 ◽

2020 ◽

Vol 27 (21) ◽

pp. 3448-3462

Author(s):

Marco Piccoli ◽

Andrea Ghiroldi ◽

Michelle M. Monasky ◽

Federica Cirillo ◽

Giuseppe Ciconte ◽

...

Keyword(s):

Stem Cells ◽

Current Knowledge ◽

Embryonic Stem ◽

Cell Types ◽

Cancer Drug ◽

Anti Cancer ◽

Adult Cell ◽

Induced Pluripotent

The development of new therapeutic applications for adult and embryonic stem cells has dominated regenerative medicine and tissue engineering for several decades. However, since 2006, induced Pluripotent Stem Cells (iPSCs) have taken center stage in the field, as they promised to overcome several limitations of the other stem cell types. Nonetheless, other promising approaches for adult cell reprogramming have been attempted over the years, even before the generation of iPSCs. In particular, two years before the discovery of iPSCs, the possibility of synthesizing libraries of large organic compounds, as well as the development of high-throughput screenings to quickly test their biological activity, enabled the identification of a 2,6-disubstituted purine, named reversine, which was shown to be able to reprogram adult cells to a progenitor-like state. Since its discovery, the effect of reversine has been confirmed on different cell types, and several studies on its mechanism of action have revealed its central role in inhibitory activity on several kinases implicated in cell cycle regulation and cytokinesis. These key features, together with its chemical nature, suggested a possible use of the molecule as an anti-cancer drug. Remarkably, reversine exhibited potent cytotoxic activity against several tumor cell lines in vitro and a significant effect in decreasing tumor progression and metastatization in vivo. Thus, 15 years since its discovery, this review aims at critically summarizing the current knowledge to clarify the dual role of reversine as a dedifferentiating agent and anti-cancer drug.

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Exploring the role of stem cell therapy in treating neurodegenerative diseases: Challenges and current perspectives

Current Stem Cell Research & Therapy ◽

10.2174/1574888x16666210810103838 ◽

2021 ◽

Vol 16 ◽

Author(s):

Nidhi Puranik ◽

Ananta Prasad Arukha ◽

Shiv Kumar Yadav ◽

Dhananjay Yadav ◽

Jun O Jin

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Glial Cells ◽

Neurological Disorders ◽

Neurological Diseases ◽

Embryonic Stem ◽

Cell Types ◽

Cell Based Therapy ◽

Promising Therapeutic Approach ◽

Cord Injury

: Several human neurological disorders such as Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis; Huntington’s disease, spinal cord injury, multiple sclerosis, and brain stroke, are caused by the injury to neurons or glial cells. The recent years have witnessed the successful generation of neurons and glia cells driving efforts to develop stem-cell-based therapies for patients to combat a broad spectrum of human neurological diseases. The inadequacy of suitable cell types for cell replacement therapy in patients suffering from neurological disorders have hampered the development of this promising therapeutic approach. Attempts are thus being made to reconstruct viable neurons and glial cells from different stem cells such as the embryonic stem cells, mesenchymal stem cells, and neural stem cells. Dedicated research to cultivate stem cell-based brain transplantation therapies have been carried out. We aim at compiling the breakthroughs in the field of stem cell-based therapy for the treatment of neurodegenerative maladies, emphasizing on the shortcomings faced, victories achieved, and the future prospects of the therapy in clinical settings.

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