Hydrogels with precisely controlled integrin activation dictate vascular patterning and permeability

Li, Shuoran; Nih, Lina R.; Bachman, Haylee; Peng, Fei; Li, Yilei; Nam, Eunwoo; Dimatteo, Robert; Carmichael, S. Thomas; Barker, Thomas H.; Segura, Tatiana

doi:10.1038/nmat4954

Cited by 172 publications

(135 citation statements)

References 61 publications

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“…We then encapsulated human primary astrocytes in hydrogels containing a single integrin‐binding peptide for 5 min prior to fixing and staining for the integrin heterodimers receptors expected to bind the peptide ligand, based on an assay developed by Li et al (Table S5, Supporting Information) . This assay only stains integrins at the cell membrane, and positive staining correlates with ECM binding.…”

Section: Resultsmentioning

confidence: 99%

Control of Astrocyte Quiescence and Activation in a Synthetic Brain Hydrogel

Galarza

Crosby

Pak

et al. 2020

Adv Healthcare Materials

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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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Section: Resultsmentioning

confidence: 99%

Control of Astrocyte Quiescence and Activation in a Synthetic Brain Hydrogel

Galarza

Crosby

Pak

et al. 2020

Adv Healthcare Materials

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“…To mimic native cell niches in vitro, 3D microenvironments with application-specific and systematically tailored properties are required [15]. These synthetic hydrogels are suited to mimic complex developmental processes in vitro, as excellently demonstrated for the promotion of neural tube formation, angiogenesis, epithelial cyst formation, and culture of small intestine organoids [19][20][21][22][23][24][25][26]. These synthetic hydrogels are suited to mimic complex developmental processes in vitro, as excellently demonstrated for the promotion of neural tube formation, angiogenesis, epithelial cyst formation, and culture of small intestine organoids [19][20][21][22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

“…Fully synthetic materials, such as poly (ethylene glycol) (PEG)-based or hyaluronic acid (HA)-based hydrogels [16][17][18], can be generated with defined physical and chemical properties and provide reproducible and tunable 3D platforms for the creation of defined cell microenvironments. These synthetic hydrogels are suited to mimic complex developmental processes in vitro, as excellently demonstrated for the promotion of neural tube formation, angiogenesis, epithelial cyst formation, and culture of small intestine organoids [19][20][21][22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Notch‐inducing hydrogels reveal a perivascular switch of mesenchymal stem cell fate

et al. 2018

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The fate of mesenchymal stem cells (MSCs) in the perivascular niche, as well as factors controlling their fate, is poorly understood. Here, we study MSCs in the perivascular microenvironment of endothelial capillaries by modifying a synthetic 3D biomimetic poly(ethylene glycol) (PEG)-hydrogel system We show that MSCs together with endothelial cells form micro-capillary networks specifically in soft PEG hydrogels. Transcriptome analysis of human MSCs isolated from engineered capillaries shows a prominent switch in extracellular matrix (ECM) production. We demonstrate that the ECM phenotypic switch of MSCs can be recapitulated in the absence of endothelial cells by functionalizing PEG hydrogels with the Notch-activator Jagged1. Moreover, transient culture of MSCs in Notch-inducing microenvironments reveals the reversibility of this ECM switch. These findings provide insight into the perivascular commitment of MSCs by use of engineered niche-mimicking synthetic hydrogels.

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“…Statistical analyses were performed as previously described 49 . For histology a minimum of n=5 was used.…”

Section: Discussionmentioning

confidence: 99%

“…One key difference between injection of HA-MAP into the stroke cavity compared to any other hydrogel that we have tested 25,[46][47][48][49] is that it elicits astrocyte infiltration into the stroke cavity.…”

Section: Astrocytes Continue To Infiltrate Lesion Over Timementioning

confidence: 99%

Hyaluronic acid particle hydrogels decrease cerebral atrophy and promote pro-reparative astrocyte/axonal infiltration in the core after ischemic stroke

Sideris

Chen

et al. 2019

Preprint

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The death rate due to stroke is decreasing, resulting in more individuals living with stroke related disabilities. Following stroke, dying cells contribute to the large influx of highly reactive astrocytes and pro-inflammatory microglia that release cytokines and lead to a cytotoxic environment that causes further brain damage and prevents endogenous repair. Paradoxically, these same cells also activate pro-repair mechanisms that contribute to endogenous repair and brain plasticity. Here, we show that the direct injection of a hyaluronic acid based microporous annealed particle (HA-MAP) hydrogel into the stroke core reduces the percent of highly reactive astrocytes and increases the percent of alternatively activated microglia in and around the lesion. Further, we show that HA-MAP hydrogel promotes reparative astrocyte infiltration into the lesion, which directly coincides with axonal penetration into the lesion. Additionally, HA-MAP injection decreases cerebral atrophy and preserves nigrostriatal bundles after stroke. This work shows that the injection of a porous scaffold into the stroke core can lead to clinically relevant decrease in cerebral atrophy and modulates the phenotype of astrocytes and microglia towards a pro-repair phenotype.

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Hydrogels with precisely controlled integrin activation dictate vascular patterning and permeability

Cited by 172 publications

References 61 publications

Control of Astrocyte Quiescence and Activation in a Synthetic Brain Hydrogel

Control of Astrocyte Quiescence and Activation in a Synthetic Brain Hydrogel

Notch‐inducing hydrogels reveal a perivascular switch of mesenchymal stem cell fate

Hyaluronic acid particle hydrogels decrease cerebral atrophy and promote pro-reparative astrocyte/axonal infiltration in the core after ischemic stroke

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