CD49f Is a Novel Marker of Functional and Reactive Human iPSC-Derived Astrocytes

Barbar, Lilianne; Jain, Tanya; Zimmer, Matthew; Kruglikov, Illya; Sadick, Jessica S.; Wang, Minghui; Kalpana, Kriti; Rose, Indigo V.L.; Burstein, Suzanne R.; Rusielewicz, Tomasz; Nijsure, Madhura P.; Guttenplan, Kevin A.; Domenico, Angelique di; Croft, Gist F.; Zhang, Bin; Nobuta, Hiroko; Hébert, Jean M.; Liddelow, Shane A.; Fossati, Valentina

doi:10.1016/j.neuron.2020.05.014

Cited by 155 publications

(221 citation statements)

References 72 publications

Supporting

Mentioning

175

Contrasting

Unclassified

Order By: Relevance

“…We cannot exclude the possibility that adult astrocytes would respond differently, but we are unaware of a specific mechanism that would produce this result. We also note that a recent report demonstrates that hIPSC-derived astrocytes from adult donors can be converted to neurotoxic, A1 astrocytes with the same TNF-α+IL-1α+C1q cocktail used in our studies [49], and all of the gene/transcript changes we confirmed in our data (Figure 4) follow the same pattern in RNA-seq data from that study. Interestingly, in both our data and this recent publication, some A1 astrocyte genes in reported in mice (e.g., GFAP) are not increased with cytokine treatment; this may be an important area for future study (i.e., determining specific differences between murine and human reactive astrocytes).…”

Section: Discussionsupporting

confidence: 88%

“…Indeed, while fetal CNS cells are typically used in cell culture experiments (e.g., rat embryonic hippocampal cultures), we cannot exclude the possibility that adult astrocytes would respond differently, although we are unaware of a specific mechanism that would produce this result. We also note that a recent report demonstrates that hIPSCderived astrocytes from adult donors can be converted to neurotoxic, A1 astrocytes with the same TNF-α+IL-1α+C1q cocktail used in our studies [48], and all of the gene/transcript changes we confirmed in our data (Figure 4) follow the same pattern in RNA-seq data from that study.…”

Section: Discussionsupporting

confidence: 87%

See 1 more Smart Citation

Amyloid beta acts synergistically as a pro-inflammatory cytokine

LaRocca

Cavalier

Roberts

et al. 2020

Preprint

View full text Add to dashboard Cite

SUMMARYThe amyloid beta (Aβ) peptide is believed to play a central role in Alzheimer’s disease (AD), the most common age-related neurodegenerative disorder. However, the natural, evolutionarily-selected functions of Aβ are incompletely understood. Here, we report that nanomolar concentrations of Aβ act synergistically with known cytokines to promote pro-inflammatory activation in primary human astrocytes (a cell type increasingly implicated in brain aging and AD). Using transcriptomics (RNA-seq), we show that Aβ can directly substitute for the complement component C1q in a cytokine cocktail previously shown to induce astrocyte immune activation. Furthermore, we show that astrocytes synergistically activated by Aβ have a transcriptional signature similar to neurotoxic “A1” astrocytes known to accumulate with age and in AD. Interestingly, we find that this biological action of Aβ at low concentrations is distinct from the transcriptome changes induced by the high/supraphysiological doses of Aβ often used in in vitro studies. Collectively, our results suggest an important, cytokine-like function for Aβ and a novel mechanism by which it may directly contribute to the neuroinflammation associated with brain aging and AD.

show abstract

Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 87%

Amyloid beta acts synergistically as a pro-inflammatory cytokine

LaRocca

Cavalier

Roberts

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…A caveat of this approach is that most of these factors directly induce GFAP expression, making it critical to use orthogonal readouts like functionality and transcriptomic/proteomic profiles to validate the identity of human-stem cell derived astrocytes. Recently, a novel marker of human astrocytes, CD49f, has been identified to help enrich hiPSC-derived astrocytes (Barbar et al, 2020). CD49f can be used to purify primary and in vitro astrocytes and serves as a reactivity-independent marker.…”

Section: Astrocytesmentioning

confidence: 99%

Growing Glia: Cultivating Human Stem Cell Models of Gliogenesis in Health and Disease

Lanjewar

Sloan

2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Glia are present in all organisms with a central nervous system but considerably differ in their diversity, functions, and numbers. Coordinated efforts across many model systems have contributed to our understanding of glial-glial and neuron-glial interactions during nervous system development and disease, but human glia exhibit prominent species-specific attributes. Limited access to primary samples at critical developmental timepoints constrains our ability to assess glial contributions in human tissues. This challenge has been addressed throughout the past decade via advancements in human stem cell differentiation protocols that now offer the ability to model human astrocytes, oligodendrocytes, and microglia. Here, we review the use of novel 2D cell culture protocols, 3D organoid models, and bioengineered systems derived from human stem cells to study human glial development and the role of glia in neurodevelopmental disorders.

show abstract

“…Seminal studies revealed that astrocytes can respond in ways that exacerbate or help the brain return to homeostasis after an inflammatory process [60]. Astrocyte populations are very diverse [61] and newer markers to more faithfully detect astrocyte subtypes such as CD49f are available [62]. Conducting detailed analyses of astrocyte subtypes are central to our ongoing studies to fully understand the mechanistic interaction(s) between OPN and glial cell function in the healthy and virally infected brain.…”

Section: Discussionmentioning

confidence: 99%

Osteopontin/secreted phosphoprotein-1 behaves as a molecular brake regulating the neuroinflammatory response to chronic viral infection

Mahmud

Greif

et al. 2020

J Neuroinflammation

View full text Add to dashboard Cite

Background Osteopontin (OPN) as a secreted signaling protein is dramatically induced in response to cellular injury and neurodegeneration. Microglial inflammatory responses in the brain are tightly associated with the neuropathologic hallmarks of neurodegenerative disease, but understanding of the molecular mechanisms remains in several contexts poorly understood. Methods Micro-positron emission tomography (PET) neuroimaging using radioligands to detect increased expression of the translocator protein (TSPO) receptor in the brain is a non-invasive tool used to track neuroinflammation in living mammals. Results In humanized, chronically HIV-infected female mice in which OPN expression was knocked down with functional aptamers, uptake of TSPO radioligand DPA-713 was markedly upregulated in the cortex, olfactory bulb, basal forebrain, hypothalamus, and central grey matter compared to controls. Microglia immunoreactive for Iba-1 were more abundant in some HIV-infected mice, but overall, the differences were not significant between groups. TSPO+ microglia were readily detected by immunolabeling of post-mortem brain tissue and unexpectedly, two types of neurons also selectively stained positive for TSPO. The reactive cells were the specialized neurons of the cerebellum, Purkinje cells, and a subset of tyrosine hydroxylase-positive neurons of the substantia nigra. Conclusions In female mice with wild-type levels of osteopontin, increased levels of TSPO ligand uptake in the brain was seen in animals with the highest levels of persistent HIV replication. In contrast, in mice with lower levels of osteopontin, the highest levels of TSPO uptake was seen, in mice with relatively low levels of persistent infection. These findings suggest that osteopontin may act as a molecular brake regulating in the brain, the inflammatory response to HIV infection.

show abstract

CD49f Is a Novel Marker of Functional and Reactive Human iPSC-Derived Astrocytes

Cited by 155 publications

References 72 publications

Amyloid beta acts synergistically as a pro-inflammatory cytokine

Amyloid beta acts synergistically as a pro-inflammatory cytokine

Growing Glia: Cultivating Human Stem Cell Models of Gliogenesis in Health and Disease

Osteopontin/secreted phosphoprotein-1 behaves as a molecular brake regulating the neuroinflammatory response to chronic viral infection

Contact Info

Product

Resources

About