Showing papers by "In-Hyun Park published in 2022"
TL;DR: In this paper , the authors provide a basic framework for the nomenclature of human multicellular models of nervous system development and disease, including organoids, assembloids and transplants.
Abstract: Self-organizing three-dimensional cellular models derived from human pluripotent stem cells or primary tissue have great potential to provide insights into how the human nervous system develops, what makes it unique and how disorders of the nervous system arise, progress and could be treated. Here, to facilitate progress and improve communication with the scientific community and the public, we clarify and provide a basic framework for the nomenclature of human multicellular models of nervous system development and disease, including organoids, assembloids and transplants. The nomenclature for human multicellular models of nervous system development and disease, including organoids, assembloids and transplants, is discussed and a consensus framework is presented.
39 citations
TL;DR: In this paper , a method to generate functional microglia in human cortical organoids (hCOs) from human embryonic stem cells (hESCs) was developed, which can be used in fundamental and translational studies as a model to investigate the role of microglias in neurodevelopmental and neurodegenerative disorders.
Abstract: Abstract Microglia play a role in the emergence and preservation of a healthy brain microenvironment. Dysfunction of microglia has been associated with neurodevelopmental and neurodegenerative disorders. Investigating the function of human microglia in health and disease has been challenging due to the limited models of the human brain available. Here, we develop a method to generate functional microglia in human cortical organoids (hCOs) from human embryonic stem cells (hESCs). We apply this system to study the role of microglia during inflammation induced by amyloid-β (Aβ). The overexpression of the myeloid-specific transcription factor PU.1 generates microglia-like cells in hCOs, producing mhCOs (microglia-containing hCOs), that we engraft in the mouse brain. Single-cell transcriptomics reveals that mhCOs acquire a microglia cell cluster with an intact complement and chemokine system. Functionally, microglia in mhCOs protect parenchyma from cellular and molecular damage caused by Aβ. Furthermore, in mhCOs, we observed reduced expression of Aβ-induced expression of genes associated with apoptosis, ferroptosis, and Alzheimer’s disease (AD) stage III. Finally, we assess the function of AD-associated genes highly expressed in microglia in response to Aβ using pooled CRISPRi coupled with single-cell RNA sequencing in mhCOs. In summary, we provide a protocol to generate mhCOs that can be used in fundamental and translational studies as a model to investigate the role of microglia in neurodevelopmental and neurodegenerative disorders.
35 citations
TL;DR: In this paper , a method to generate functional microglia in human cortical organoids (hCOs) from human embryonic stem cells (hESCs) was developed, which can be used in fundamental and translational studies as a model to investigate the role of microglias in neurodevelopmental and neurodegenerative disorders.
Abstract: Abstract Microglia play a role in the emergence and preservation of a healthy brain microenvironment. Dysfunction of microglia has been associated with neurodevelopmental and neurodegenerative disorders. Investigating the function of human microglia in health and disease has been challenging due to the limited models of the human brain available. Here, we develop a method to generate functional microglia in human cortical organoids (hCOs) from human embryonic stem cells (hESCs). We apply this system to study the role of microglia during inflammation induced by amyloid-β (Aβ). The overexpression of the myeloid-specific transcription factor PU.1 generates microglia-like cells in hCOs, producing mhCOs (microglia-containing hCOs), that we engraft in the mouse brain. Single-cell transcriptomics reveals that mhCOs acquire a microglia cell cluster with an intact complement and chemokine system. Functionally, microglia in mhCOs protect parenchyma from cellular and molecular damage caused by Aβ. Furthermore, in mhCOs, we observed reduced expression of Aβ-induced expression of genes associated with apoptosis, ferroptosis, and Alzheimer’s disease (AD) stage III. Finally, we assess the function of AD-associated genes highly expressed in microglia in response to Aβ using pooled CRISPRi coupled with single-cell RNA sequencing in mhCOs. In summary, we provide a protocol to generate mhCOs that can be used in fundamental and translational studies as a model to investigate the role of microglia in neurodevelopmental and neurodegenerative disorders.
34 citations
TL;DR: The principles of neural axis formation by series of growth factors, such as SHH, WNT, BMP signalings, that are critical to generate various region-specific brain organoids are discussed.
Abstract: Region specific brain organoids are brain organoids derived by patterning protocols using extrinsic signals as opposed to cerebral organoids obtained by self-patterning. The main focus of this review is to discuss various region-specific brain organoids developed so far and their application in modeling neurodevelopmental disease. We first discuss the principles of neural axis formation by series of growth factors, such as SHH, WNT, BMP signalings, that are critical to generate various region-specific brain organoids. Then we discuss various neurodevelopmental disorders modeled so far with these region-specific brain organoids, and findings made on mechanism and treatment options for neurodevelopmental disorders (NDD).
9 citations
TL;DR: In this article , the authors found that intracellular glycogen led to specific reactivity to CDg4, a glycogen fluorescence sensor, in both human and mouse naïve embryonic stem cells.
2 citations
TL;DR: Jin et al. as discussed by the authors showed that inhibiting interferon signaling rescues both developmental and tau-associated phenotypes, rendering it a potential therapeutic target for Down syndrome.
1 citations
TL;DR: The neural developmental model of a human embryonic stem cell is applied and it is found that neuroepithelial cell differentiation is one of the first stages of hESC differentiation that are affected by KIAA0319 knocked down could affect radial migration and thus differentiation into diverse neural populations at the cortical layers.
Abstract: Dyslexia, also known as reading disability, is defined as difficulty processing written language in individuals with normal intellectual capacity and educational opportunity. The prevalence of dyslexia is between 5 and 17%, and the heritability ranges from 44 to 75%. Genetic linkage analysis and association studies have identified several genes and regulatory elements linked to dyslexia and reading ability. However, their functions and molecular mechanisms are not well understood. Prominent among these is KIAA0319, encoded in the DYX2 locus of human chromosome 6p22. The association of KIAA0319 with reading performance has been replicated in independent studies and different languages. Rodent models suggest that kiaa0319 is involved in neuronal migration, but its role throughout the cortical development is largely unknown. In order to define the function of KIAA0319 in human cortical development, we applied the neural developmental model of a human embryonic stem cell. We knocked down KIAA0319 expression in hESCs and performed the cortical neuroectodermal differentiation. We found that neuroepithelial cell differentiation is one of the first stages of hESC differentiation that are affected by KIAA0319 knocked down could affect radial migration and thus differentiation into diverse neural populations at the cortical layers.
1 citations
TL;DR: Knockdown of KIAA0319 expression is hypothesized to act by regulating neurogenesis in the reading related centers of the brain by targeting the cell cycle of proliferative cells, demonstrating how subtle changes in expression could affect an isolated trait such as reading without global brain effects.
Abstract: Reading Disability (RD), also known as dyslexia, is defined as difficulty processing written language in individuals with normal intellectual capacity and educational opportunity. The prevalence of RD is between 5% and 17%, and the heritability ranges from 44% to 75%. Genetic linkage analysis and genome-wide association studies (GWAS) have identified several genes and regulatory elements linked to RD and reading ability. However, their functions and molecular mechanisms are not well understood. Prominent among these is KIAA0319, encoded in the DYX2 locus of human chromosome 6p22. Association of KIAA0319 has been independently replicated in multiple independent studies and languages. Rodent models suggest that KIAA0319 is involved in neuronal migration, but its precise function is unknown. This studies aim to determine the mechanisms by which KIAA0319 affects reading and language performance. We hypothesize that KIAA0319 plays a critical role in neuronal development. RT-qPCR and quantitative immunofluorescence in the cortical neurons differentiated from H7 hESC show regulatory effects on proliferation and differentiation of neuronal progenitor cells. Knockdown of KIAA0319 expression promotes early exit from the neuroepithelial cell stage and drives cells into cell cycle arrested neuronal progenitor cell stage. This suggests that KIAA0319 act by regulating neurogenesis in the reading related centers of the brain by targeting the cell cycle of proliferative cells. This demonstrates how subtle changes in expression could affect an isolated trait such as reading without global brain effects.
TL;DR: In this paper , the authors show that mice with endothelial deficiency of any one of the three nuclear genes encoding for mitochondrial proteins, transcriptional factor (TFAM), respiratory complex IV component (COX10), or redox protein thioredoxin 2 (TRX2), exhibit retarded retinal vessel growth and arteriovenous malformations (AVM).
Abstract: Although mitochondrial activity is critical for angiogenesis, its mechanism is not entirely clear. Here we show that mice with endothelial deficiency of any one of the three nuclear genes encoding for mitochondrial proteins, transcriptional factor (TFAM), respiratory complex IV component (COX10), or redox protein thioredoxin 2 (TRX2), exhibit retarded retinal vessel growth and arteriovenous malformations (AVM). Single-cell RNA-seq analyses indicate that retinal ECs from the three mutant mice have increased TGFβ signaling and altered gene expressions associated with vascular maturation and extracellular matrix, correlating with vascular malformation and increased basement membrane thickening in microvesels of mutant retinas. Mechanistic studies suggest that mitochondrial dysfunction from Tfam, Cox10, or Trx2 depletion induces a mitochondrial localization and MAPKs-mediated phosphorylation of SMAD2, leading to enhanced ALK5-SMAD2 signaling. Importantly, pharmacological blockade of ALK5 signaling or genetic deficiency of SMAD2 prevented retinal vessel growth retardation and AVM in all three mutant mice. Our studies uncover a novel mechanism whereby mitochondrial dysfunction via the ALK5-SMAD2 signaling induces retinal vascular malformations, and have therapeutic values for the alleviation of angiogenesis-associated human retinal diseases.