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Abstract Bioengineers have designed numerous instructive brain extracellular matrix (ECM) environments with tailored and tunable protein compositions and biomechanical properties in vitro to study astrocyte reactivity during trauma and inflammation. However, a major limitation of both protein‐based and synthetic model microenvironments is that astrocytes within fail to retain their characteristic stellate morphology and quiescent state without becoming activated under “normal” culture conditions. Here, a synthetic hydrogel is introduced, which for the first time demonstrates maintenance of astrocyte quiescence and activation on demand. With this synthetic brain hydrogel, the brain‐specific integrin‐binding and matrix metalloprotease‐degradable domains of proteins are shown to control astrocyte star‐shaped morphologies, and an ECM condition that maintains astrocyte quiescence with minimal activation can be achieved. In addition, activation can be induced in a dose‐dependent manner via both defined cytokine cocktails and low molecular weight hyaluronic acid. This synthetic brain hydrogel is envisioned as a new tool to study the physiological role of astrocytes in health and disease.
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This content will become publicly available on October 1, 2026
Diverse Subpopulations of Reactive Astrocytes Following Chronic Toxoplasma Infection
ABSTRACT Astrocytes provide physical and metabolic support for neurons, regulate the blood–brain barrier, and react to injury, infection, and disease. When astrocytes become reactive, maintenance of the inflammatory state and its functional implications throughout chronic neuroinflammation are all poorly understood. Several models of acute inflammation have revealed astrocyte subpopulations that go beyond a two‐activation state model, instead encompassing distinct functional subsets. However, how reactive astrocyte (RA) subsets evolve over time during chronic inflammatory disease or infection has been difficult to address. Here we use a prolific human pathogen,Toxoplasma gondii, that causes lifelong infection in the brain alongside aLcn2CreERT2reporter mouse line to examine reactive astrocyte subsets during chronic neuroinflammation. Single‐cell RNA sequencing revealed diverse astrocyte populations including transcriptionally uniqueLcn2CreERT2+ RAs which change over the course of infection in a subset‐dependent manner. In addition to an immune‐regulatingLcn2CreERT2+ astrocyte population enriched with gene transcripts encoding chemokines CCL5, CXCL9, CXCL10, and receptors CCR7 and IL7R, a specific subset ofLcn2CreERT2+ astrocytes highly expressedtransthyretin(Ttr), a secreted carrier protein involved in glycolytic enzyme activation and potential vasculature regulation and angiogenesis. These findings provide novel information about the evolution and diversity of reactive astrocyte subtypes and functional signatures at different stages of infection, revealing an undocumented role for transthyretin‐expressing astrocytes in immune regulation at the central nervous system (CNS) vasculature.
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- Award ID(s):
- 2215705
- PAR ID:
- 10656667
- Publisher / Repository:
- Wiley
- Date Published:
- Journal Name:
- Glia
- Volume:
- 73
- Issue:
- 10
- ISSN:
- 0894-1491
- Page Range / eLocation ID:
- 2003 to 2024
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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