Dataset Information

Tuning Bulk Hydrogel Degradation by Simultaneous Control of Proteolytic Cleavage Kinetics and Hydrogel Network Architecture.

ABSTRACT: Degradation of three-dimensional hydrogels is known to regulate many cellular behaviors. Accordingly, several elegant approaches have been used to render hydrogels degradable by cell-secreted proteases. However, existing hydrogel systems are limited in their ability to simultaneously and quantitatively tune two aspects of hydrogel degradability: cleavage rate (the rate at which individual chemical bonds are cleaved) and degraded hydrogel architecture (the network structure during degradation). Using standard peptide engineering approaches, we alter the proteolytic kinetics of the polymer cleavage rate to tune gel degradation time from less than 12 h to greater than 9 days. Independently, we vary the cross-linker functionality to achieve network architectures that initially have identical molecular weight between cross-links but upon degradation are designed to release between 5% and 100% of the polymer. Confirming the biological relevance of both parameters, formation of vascular-like structures by endothelial cells is regulated both by bond cleavage rate and by degraded hydrogel architecture. This strategy to fine-tune different aspects of hydrogel degradability has applications in cell culture, regenerative medicine, and drug delivery.

SUBMITTER: Madl CM

PROVIDER: S-EPMC7286611 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Tuning Bulk Hydrogel Degradation by Simultaneous Control of Proteolytic Cleavage Kinetics and Hydrogel Network Architecture.

Madl Christopher M CM Katz Lily M LM Heilshorn Sarah C SC

ACS macro letters 20181011 11

Degradation of three-dimensional hydrogels is known to regulate many cellular behaviors. Accordingly, several elegant approaches have been used to render hydrogels degradable by cell-secreted proteases. However, existing hydrogel systems are limited in their ability to simultaneously and quantitatively tune two aspects of hydrogel degradability: cleavage rate (the rate at which individual chemical bonds are cleaved) and degraded hydrogel architecture (the network structure during degradation). U ...[more]

PMID: 32523799

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Project description:BACKGROUND:Neuronal cell loss contributes to the pathology of acute and chronic neurodegenerative diseases, including Alzheimer's disease (AD). It remains crucial to identify molecular mechanisms sensitizing neurons to various insults and cell death. To date, the multifunctional, autophagy-related protein Beclin 1 has been shown to be both necessary and sufficient for neuronal integrity in neurodegenerative models associated with protein aggregation. Interestingly, besides its role in cellular homeostasis, Beclin 1 has also been ascribed a role in apoptosis. This makes it critical to elucidate whether Beclin 1 regulates neuronal death and survival across neurodegenerative conditions independent of protein clearance. Here, we provide experimental evidence for a direct functional link between proteolytic cleavage of Beclin 1 and apoptotic neuronal cell loss in two independent models of neurodegeneration in vivo. METHODS:Proteolytic cleavage of Beclin 1 was characterized in lysates of human AD brain samples. We developed viral tools allowing for the selective neuronal expression of the various Beclin 1 forms, including Beclin 1 cleavage products as well as a cleavage-resistant form. The effect of these Beclin 1 forms on survival and integrity of neurons was examined in models of acute and chronic neurodegeneration in vitro and in vivo. Markers of neuronal integrity, neurodegeneration and inflammation were further assessed in a Kainic acid-based mouse model of acute excitotoxic neurodegeneration and in a hAPP-transgenic mouse model of AD following perturbation of Beclin 1 in the susceptible CA1 region of the hippocampus. RESULTS:We find a significant increase in caspase-mediated Beclin 1 cleavage fragments in brain lysates of human AD patients and mimic this phenotype in vivo using both an excitotoxic and hAPP-transgenic mouse model of neurodegeneration. Surprisingly, overexpression of the C-terminal cleavage-fragment exacerbated neurodegeneration in two distinct models of degeneration. Local inhibition of caspase activity ameliorated neurodegeneration after excitotoxic insult and prevented Beclin 1 cleavage. Furthermore, overexpression of a cleavage-resistant form of Beclin 1 in hippocampal neurons conferred neuroprotection against excitotoxic and Amyloid beta-associated insults in vivo. CONCLUSIONS:Together, these findings indicate that the cleavage state of Beclin 1 determines its functional involvement in both neurodegeneration and neuroprotection. Hence, manipulating the cleavage state of Beclin 1 may represent a therapeutic strategy for preventing neuronal cell loss across multiple forms of neurodegeneration.

Dataset Information

Tuning Bulk Hydrogel Degradation by Simultaneous Control of Proteolytic Cleavage Kinetics and Hydrogel Network Architecture.

Publications

Tuning Bulk Hydrogel Degradation by Simultaneous Control of Proteolytic Cleavage Kinetics and Hydrogel Network Architecture.

Similar Datasets

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