Rapid and Efficient Induction of Functional Astrocytes from Human Pluripotent Stem Cells

Canals, Isaac; Ginisty, Aurélie; Quist, Ella; Timmerman, Raissa; Fritze, Jonas; Miskinyte, Giedre; Monni, Emanuela; Hansen, Marita Grønning; Hidalgo, Isabel; Bryder, David; Bengzon, Johan; Ahlenius, Henrik

doi:10.1038/protex.2018.088

Cited by 25 publications

(36 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SOX10 has been associated with multiple brain conditions, including demyelination disorders (52), and NFIX, a factor unexplored in oligodendrocytes, has been linked to agenesis of the corpus callosum (53). Lastly, we found motifs for transcription factors potentially important for astrocyte identity, such as SOX9 (54,55).…”

Section: Inference Of Cell Type-specific Lineage-determining Transcrmentioning

confidence: 65%

Cell type-specific enhancer-promoter connectivity maps in the human brain and disease risk association

Nott¹,

Holtman²,

Coufal

et al. 2019

Preprint

View full text Add to dashboard Cite

Identification of cell type-specific regulatory elements in the human brain enables interpretation of non-coding GWAS risk variants. AbstractUnique cell type-specific patterns of activated enhancers can be leveraged to interpret non-coding genetic variation associated with complex traits and diseases such as neurological and psychiatric disorders. Here, we have defined active promoters and enhancers for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with regulatory regions in neurons, idiopathic Alzheimer's disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting GWAS variants in cell type-specific enhancers to gene promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring ADrisk variants ablated BIN1 expression in microglia but not in neurons or astrocytes. These findings revise and expand the genes likely to be influenced by non-coding variants in AD and suggest the probable brain cell types in which they function. of neurons, microglia, astrocytes, oligodendrocytes and other cell types that reside within the brain (1-4). In contrast, transcriptional mechanisms that control their developmental and functional properties in health and disease remain less well understood. Studies in animal models have provided deep insights into conserved processes, but significant differences between species often limit the translatability of findings in model systems to humans (5).Genome-wide association studies (GWASs) provide a genetic approach to identifying molecular pathways involved in complex traits and diseases by defining associations between genetic variants and phenotypes of interest (6, 7). Large-scale GWASs have discovered hundreds of single nucleotide polymorphisms (SNPs) that are associated with the risk of neurological and psychiatric disorders. The vast majority of disease-risk genetic variants are located in non-coding regions of the genome (7) and the specific cell type (s) in which the disease-risk variants are active is often unclear. Furthermore, linkagedisequilibrium between disease-risk variants at GWAS significant loci complicates the identification of causal variants. Collectively, these limitations have hindered the assignment and interpretation of disease-risk genes.GWAS-identified risk variants that are located in non-coding regions of the genome can exert phenotypic effects through several mechanisms, including perturbation of transcriptional enhancers and promoters (6). While promoters provide the essential sites of transcriptional initiation of mRNAs, they are frequently not sufficient to direct appropriate developmental and signal-dependent levels of gene expression (8,9). This additional information is provided by enhancers, short regions of DNA that, when bound by transcription factors, enhance mRNA expression from target promoters. Enhancers can reside hundreds of thousands of base pairs away from their target gene and their function is generally consid...

show abstract

Section: Inference Of Cell Type-specific Lineage-determining Transcrmentioning

confidence: 65%

Cell type-specific enhancer-promoter connectivity maps in the human brain and disease risk association

Nott¹,

Holtman²,

Coufal

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…The most conventional approach, 3D generation and maintenance, has become the standard method on which the majority of subsequent protocols have been based, including significant portions of direct conversion methods (Juopperi et al, ; Krencik & Zhang, ; Mormone, D'Sousa, Alexeeva, Bederson, & Germano, ). Finally, direct conversion through TF expression significantly decreases the induction protocols length but stands as a relatively new and unexplored approach (Caiazzo et al, ; Canals et al, ; Li, Tao, et al, ; Li, Tian, et al, ; Tchieu et al, ).…”

Section: Human Ipsc‐astrocyte Generationmentioning

confidence: 99%

“…Direct conversion methods utilize the expression of TFs to rapidly generate human astrocytes from iPSCs or NPCs (Canals et al, ; Caiazzo et al, 2015; Li, Tao, et al, ; Li, Tian, et al, ; Tchieu et al, ). The majority of these protocols follow the 3D generation outline, initiating neural induction while incorporating the use of doxycycline induced coexpression of the TFs NFIA and Sox9.…”

Section: Human Ipsc‐astrocyte Generationmentioning

confidence: 99%

An update on human astrocytes and their role in development and disease

Majo

Koontz

Rowitch

et al. 2020

Glia

View full text Add to dashboard Cite

Human astrocytes provide trophic as well as structural support to the surrounding brain cells. Furthermore, they have been implicated in many physiological processes important for central nervous system function. Traditionally astrocytes have been considered to be a homogeneous class of cells, however, it has increasingly become more evident that astrocytes can have very different characteristics in different regions of the brain, or even within the same region. In this review we will discuss the features of human astrocytes, their heterogeneity, and their generation during neurodevelopment and the extraordinary progress that has been made to model these fascinating cells in vitro, mainly from induced pluripotent stem cells. Astrocytes' role in disease will also be discussed with a particular focus on their role in neurodegenerative disorders. As outlined here, astrocytes are important for the homeostasis of the central nervous system and understanding their regional specificity is a priority to elucidate the complexity of the human brain.

show abstract

“…In highly heterogeneous cell populations, such as astrocytes in the rodent brain or primary human fibroblasts, the subtype of the starting cell type was shown to determine subtype outcomes of the iNs [73]. To meet this need to model the human neuron-glia cross talk in vitro with patient-specific cells, astrocytes and oligodendrocytes are currently generated via direct conversion from human iPSCs, but direct conversion protocols from fibroblasts into induced astrocytes and oligodendrocytes have yet only been established for rodent cells [85][86][87][88][89]. 1A,B).…”

Section: Subtype-specific In Conversionmentioning

confidence: 99%

“…While these advances clearly offer novel tools to better understand neurological diseases, there is very strong evidence that classical neuronal diseases do not only affect neurons, but involve many cell types represented in the human brain [84]. To meet this need to model the human neuron-glia cross talk in vitro with patient-specific cells, astrocytes and oligodendrocytes are currently generated via direct conversion from human iPSCs, but direct conversion protocols from fibroblasts into induced astrocytes and oligodendrocytes have yet only been established for rodent cells [85][86][87][88][89]. As an alternative route, direct conversion into induced neural stem cells, which then are amenable to directed 'development-mimicking' differentiation, represents another way to generate glial cell types from human fibroblasts [reviewed in Erharter et al].…”

Section: Subtype-specific In Conversionmentioning

confidence: 99%

Next‐generation disease modeling with direct conversion: a new path to old neurons

2019

View full text Add to dashboard Cite

Within just over a decade, human reprogramming-based disease modeling has developed from a rather outlandish idea into an essential part of disease research. While iPSCs are a valuable tool for modeling developmental and monogenetic disorders, their rejuvenated identity poses limitations for modeling age-associated diseases. Direct cell-type conversion of fibroblasts into induced neurons (iNs) circumvents rejuvenation and preserves hallmarks of cellular aging. iNs are thus advantageous for modeling diseases that possess strong age-related and epigenetic contributions and can complement iPSCbased strategies for disease modeling. In this review, we provide an overview of the state of the art of direct iN conversion and describe the key epigenetic, transcriptomic, and metabolic changes that occur in converting fibroblasts. Furthermore, we summarize new insights into this fascinating process, particularly focusing on the rapidly changing criteria used to define and characterize in vitro-born human neurons. Finally, we discuss the unique features that distinguish iNs from other reprogramming-based neuronal cell models and how iNs are relevant to disease modeling.

show abstract

Rapid and Efficient Induction of Functional Astrocytes from Human Pluripotent Stem Cells

Cited by 25 publications

References 0 publications

Cell type-specific enhancer-promoter connectivity maps in the human brain and disease risk association

Cell type-specific enhancer-promoter connectivity maps in the human brain and disease risk association

An update on human astrocytes and their role in development and disease

Next‐generation disease modeling with direct conversion: a new path to old neurons

Contact Info

Product

Resources

About