Biology subjects

Wei, Z.

Publications and source records attributed to Wei, Z..

At least 127 records · Page 7Linked to original sources

bioRxiv2023

OBIA: An Open Biomedical Imaging Archive

With the development of artificial intelligence (AI) technologies, biomedical imaging data play an important role in scientific research and clinical application, but the available resources are limited. Here we present Open Biomedical Imaging Archive (OBIA), a repository for archiving biomedical imaging and related clinical data. OBIA adopts five data objects (Collection, Individual, Study, Series, and Image) for data organization, accepts the submission of biomedical images of multiple modalities, organs, and diseases. In order to protect personal privacy, OBIA has formulated a unified de-identification and quality control process. In addition, OBIA provides friendly and intuitive web interface for data submission, browsing and retrieval, as well as image retrieval. As of September 2023, OBIA has housed data for a total of 937 individuals, 4136 studies, 24,701 series, and 1,938,309 images covering 9 modalities and 30 anatomical sites. Collectively, OBIA provides a reliable platform for biomedical imaging data management and offers free open access to all publicly available data to support research activities throughout the world. OBIA can be accessed at https://ngdc.cncb.ac.cn/obia.

bioinformatics↗

bioRxiv2023

SIDERITE: Unveiling Hidden Siderophore Diversity in the Chemical Space Through Digital Exploration

Siderophores, a highly diverse family of secondary metabolites, play a crucial role in facilitating the acquisition of the essential iron. However, the current discovery of siderophore relies largely on manual approaches. In this work, we introduced SIDERTE, a digitized siderophore information database containing 872 siderophore records with 649 unique structures. Leveraging this digitalized dataset, we gained a systematic overview of siderophores by their clustering patterns in the chemical space. Building upon this, we developed a functional group-based method for predicting new iron-binding molecules. Applying this method to 4,314 natural product molecules from TargetMols Natural Product Library for high throughput screening, we experimentally confirmed that 40 out of the 48 molecules predicted as siderophore candidates possessed iron-binding abilities. Expanding our approach to the COCONUT natural product database, we predicted a staggering 3,199 siderophore candidates, showcasing remarkable structure diversity that are largely unexplored. Our study provides a valuable resource for accelerating the discovery of novel iron-binding molecules and advancing our understanding towards siderophores.

biochemistry↗

bioRxiv2023

The spreading of facultative H3K9me3-heterochromatin drives congenital disease

Heterochromatin marked by trimethylated histone 3 at lysine 9 (H3K9me3) plays fundamental roles in reprogramming to direct cell fate determination in higher eukaryotes. However, the upstream factors that guide the establishment and spreading of H3K9me3-heterochromatin, leading to human developmental malformations, remain elusive. In this study, we found that Cdk13, a member of RNA polymerase II (RNAPII) kinase, suppresses congenital heart syndrome by preventing global facultative H3K9me3-heterochromatin spreading. Additionally, Cdk13 directs the phosphorylation of a large set of heterochromatin proteins at specific sites, which are required for the interaction between HP1 and histone H3K9 methyltransferases. Furthermore, we identified a compound, an inhibitor of heterochromatin regulators, that can alleviate syndromic heart defects in Cdk13-mutant mice through the inhibition of H3K9me3-heterochromatin spreading. In summary, this study reveals a novel role and mechanism of Cdk13-triggered facultative H3K9me3-heterochromatin spreading in human genetic disease and paves the way for the treatment of congenital heart syndrome.

genetics↗

bioRxiv2023

Biodecomposing Spirulina platensis by a de novo designed Bacillus subtilis-based method to develop a medium for the high cell-density cultivation of Escherichia coli in batch mode

High cell-density cultivation (HCDC) is fundamental to basic research and industrial applications, especially in batch mode. However, limited media are available for batch culture of HCDC, because the media for batch culture must contain extremely sufficient nutrients on the one hand and few or even no substrates to generate detrimental metabolite on the other hand to attain HCDC. Spirulina platensis (SP), a new media material, is considered ideal for the development of such media. Here, we develop a biolysis method for SP degradation based on the cultivation supernatant of Bacillus subtilis and extensively demonstrate its higher degradation (indicated by the production of more small peptides and free amino acids) and cultivation effectiveness with three other methods. Based on its SP hydrolysates, a modified SP-based broth (MSP) is then formulated. Tests on Escherichia coli K-12 show that MSP achieves HCDC with several benefits: (i) its maximum optical density at 600 nm is [~]16.67, significantly higher than that of Luria-Bertani (LB) broth (only [~]6.30); (ii) MSP requires only 36 h to reach peak growth, much faster than that of LB (48 h); (iii) its maximum growth (1.12 {+/-} 0.01 h-1) is significantly higher than that of LB (0.20 {+/-} 0.00 h-1); (v) MSP initiates growth immediately after inoculation (lag time <0), comparable to LB; (iv) the number of viable cells in MSP is high ([~]2.16 x 1011 ml-1), [~]10.19 times the amount in LB. Consequently, we envision MSP will become the first choice for E. coli HCDC batch culture in the future. ImportanceSo far, it is the first time to develop a high-efficiency method for transforming Spirulina platensis (SP) into medium ingredients. Based on its SP hydrolysates, a high cell-density cultivation (HCDC) medium for the batch culture of Escherichia coli is formulated for the first time, which is greatly beneficial for both basic research and industrial applications. In addition to HCDC, the SP hydrolysates can be extended to a wide range of applications, due to their rich nutrient content. Besides, this study demonstrates for the first time that SP is an ideal material to develop HCDC media. Furthermore, this study demonstrates that medium development and modification for batch culture can attain HCDC, without the development of new culture technologies. Therefore, this study highlights the importance of the rebirth of medium development and modification and supports the shift from developing new culture technologies to medium development and modification for HCDC in batch mode.

microbiology↗

bioRxiv2023

CCR9 overexpression promotes T-ALL progression by enhancing cholesterol biosynthesis

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of the lymphoid progenitor cells contributing to [~] 20% of the total ALL cases with higher prevalence in adults than the children. Despite the important role of human T-ALL cell lines in understanding the biology and treatment options, a detailed comparison of the tumorigenic potential of two commonly used T-ALL cell lines, MOLT4 and JURKAT cells is still lacking. In the present study, we compared the leukemogenic potentials of the two T-ALL cell lines (MOLT4 and JURKAT) in NOD-PrkdcscidIL2rgdull (NTG) mice and found that MOLT4 cells possessed a relatively higher aggressive phenotype characterized by their enhanced tissue infiltration as compared to the JURKAT cells. Gene expression profiling of the two cell lines revealed numerous differentially expressed genes (DEGs) including CC chemokine receptor 9 (CCR9), which augmented the invasion and metastasis of MOLT4 and JURKAT cells in vitro. The upregulation of CCR9 also promoted the tissue infiltration of JURKAT cells in the NTG mice. CCR9 overexpression increased cholesterol production by upregulating the expression of the core regulatory genes of the cholesterol biosynthesis pathway including MSMO1, MVD, and HMGCS1. Moreover, the upregulated expression of EGR1 was also found with CCR9 overexpression that modulated the expression of MSMO1, MVD, and HMGCS1. Notably, the treatment of the cells with simvastatin and siRNA-EGR1 decreased the aggressiveness of the CCR9 overexpressing JURKAT cells in vitro, suggesting the CCR9-EGR1 axis in T-ALL progression. This study highlights the distinct tumorigenic potentials of two T-ALL cell lines and reveals CCR9-regulated enhanced cholesterol biosynthesis in T-ALL. Simple summaryT-ALL is an aggressive cancer of the blood and bone marrow. In order to understand the biological mechanism of T-ALL, in vitro T-ALL cell lines are commonly employed. However, a comprehensive comparison of two common T-ALL cell lines, MOLT4 and JURKAT cells for T-ALL development is not yet available. We compared MOLT4 and JURKAT cells for T-ALL inducing potential and found that MOLT4 cells exhibited a relatively increased aggressiveness in mice as compared to JURKAT cells. We examined the molecular characteristics of two cell lines that could lead to differences in cancer development. Transcriptional profiling of MOLT4 and JURKAT cells revealed significant changes in the expression of several genes including CCR9. This aberrant expression of CCR9 impacted the migration and invasion of the T-ALL cell lines in vitro. In addition, higher expression levels of CCR9 also promoted T-ALL progression in vivo. Transcriptome analysis and gene ontology analysis of the DEGs of CCR9 over-expressing JURKAT cells indicated the enrichment of the genes in the cholesterol biosynthesis pathway, suggesting this metabolic rewiring mechanism as a strategy to cope with the increased energy demand of the malignant T-ALL cells.

cancer biology↗

bioRxiv2023

A novel virus-induced cyclic dinucleotide, 2'3'-c-di-GMP, mediates STING-dependent antiviral immunity in Drosophila

In mammals, the enzyme cGAS senses the presence of cytosolic DNA and synthesizes the cyclic dinucleotide (CDN) 2'3'-cGAMP. This CDN binds to and activates the protein STING to trigger immunity. We recently discovered in the model organism Drosophila melanogaster two cGAS-like receptors (cGLRs) that activate STING-dependent antiviral immunity and can produce 3'2'-cGAMP, in addition to 2'3'-cGAMP. Here we explore CDN-mediated immunity in 14 different Drosophila species covering 50 million years of evolution and report that 2'3'-cGAMP and 3'2'-cGAMP fail to control infection by Drosophila C virus in D. serrata, D. sechellia and D. mojavensis. Using an accurate and sensitive mass spectrometry method, we discover an unexpected diversity of CDNs produced in a cGLR-dependent manner in response to viral infection in D. melanogaster, including a novel CDN, 2'3'-c-di-GMP. We show that 2'3'-c-di-GMP is the most potent STING agonist identified so far in D. melanogaster and that this molecule also activates a strong antiviral transcriptional response in D. serrata. Our results shed light on the evolution of cGLRs in flies and provide a basis for the understanding of the function and regulation of this emerging family of PRRs in animal innate immunity.

immunology↗

bioRxiv2023

Effects of six pyrimidine analogs on the growth of Tetrahymena thermophila and their implications in pyrimidine metabolism

Tetrahymena are ciliated protists that have been used to study the effects of toxic chemicals, including anticancer drugs. In this study, we tested the inhibitory effects of six pyrimidine analogs (5-fluorouracil, floxuridine, 5-deoxy-5-fluorouridine, 5-fluorouridine, gemcitabine, cytarabine) on wild-type CU428 and conditional mutant NP1 Tetrahymena thermophila at room temperature and the restrictive temperature (37{degrees}C) where NP1 does not form the oral apparatus. We found that cytarabine was the only tested analog that did not inhibit growth, and phagocytosis was not required for pyrimidine analog entry. IC50 values did not significantly differ between strains for the same analog at either temperature. To investigate the mechanism of inhibition, we used two pyrimidine bases (uracil and thymine) and three nucleosides (uridine, thymidine, 5-methyluridine) to help determine whether the inhibitory effects from analogs were reversible. We found that the inhibitory effects from 5-fluorouracil could be reversed by uracil and thymine, from floxuridine could be reversed by thymidine, and from 5-deoxy-5-fluorouridine could be reversed by uracil. None of the tested nucleobases or nucleosides could reverse the inhibitory effects of gemcitabine or 5-fluorouridine. Our results suggest that the five pyrimidine analogs act on different sites to inhibit T. thermophila growth and that nucleobases and nucleosides are metabolized differently.

cell biology↗

bioRxiv2023

Targeting GDF15 as a potential therapy for low back pain originating from endplate

The overactivation of osteoclasts in the endplate is one of the most important causes of low back pain (LBP) originating from endplate. Transforming growth factor-{beta} family has been demonstrated to play an important role during osteoclast differentiation. GDF15 was reported to participate in several pathological states. In this study, we reported that the lumbar spine instability (LSI) induced the overactivation of osteoclasts and CD31hiEmcnhi endothelial vessels in the bony endplate. In addition, the expression of GDF15 in human disc samples and mice models were also increased. GDF15 could promote the fusion of preosteoclasts via Rac1/Cdc42/PAK/Cofilin axis, and facilitate the angiogenesis via the secretion of PDGF-BB. Furthermore, we proved that the GDF15 inhibitor, CTL-002 could reduce the expression of GDF15 in the endplate and alleviate the overactivation of osteoclasts and CD31hiEmcnhi endothelial vessels induced by LSI in vivo. In conclusion, we demonstrated that GDF15 could regulates the fusion of preosteoclasts and targeting GDF15 in the endplate served as a novel anabolic therapy for low back pain treatment.

cell biology↗

bioRxiv2023

Efficient megakaryopoiesis and platelet production require phospholipid remodeling and PUFA uptake through CD36

Lipids contribute to hematopoiesis and membrane properties and dynamics, however, little is known about the role of lipids in megakaryopoiesis. Here, a lipidomic analysis of megakaryocyte progenitors, megakaryocytes, and platelets revealed a unique lipidome progressively enriched in polyunsaturated fatty acid (PUFA)-containing phospholipids. In vitro, inhibition of both exogenous fatty acid functionalization and uptake and de novo lipogenesis impaired megakaryocyte differentiation and proplatelet production. In vivo, mice on a high saturated fatty acid diet had significantly lower platelet counts, which was prevented by eating a PUFA-enriched diet. Fatty acid uptake was largely dependent on CD36, and its deletion in mice resulted in thrombocytopenia. Moreover, patients with a CD36 loss-of-function mutation exhibited thrombocytopenia and increased bleeding. Our results suggest that fatty acid uptake and regulation is essential for megakaryocyte maturation and platelet production, and that changes in dietary fatty acids may be a novel and viable target to modulate platelet counts.

cell biology↗

bioRxiv2023

Structure-dependent spontaneous calcium dynamics in cultured neuronal networks on microcontact-printed substrates

Microcontact printing (CP) is widely used in neuroscience research. However, CP yields reduced cell-substrate adhesion compared with directly coating cell adhesion molecules. Here, we demonstrate that the reduced cell-substrate adhesion caused by CP, high seeding density, and the local restriction would separately contribute to more aggregated (neurons closer to each other in separate clusters) neuronal networks. Calcium recordings revealed that more aggregated networks presented fewer spontaneous calcium activity patterns, and were more likely dominated by synchronized network-wide calcium oscillation (network bursts). First, on a uniform microcontact-printed substrate, densely seeded neurons were reaggregated into a Petri dish-wide network consisting of small clusters, of which the calcium dynamics were dominated by network bursts. Next, further analysis revealed this dominance was maintained since its appearance, and the initiation and propagation of bursts in the small-cluster network shared a similar mechanism with that of homogeneous networks. Then, sparsely seeded neurons formed several networks with different aggregation degrees, in which the less clustered ones presented abundant time-varying subnetwork burst patterns. Finally, by printing locally restricted patterns, highly clustered networks formed, where dominant network bursts reappeared. These findings demonstrate the existence of structure-dependent spontaneous calcium dynamics in cultured networks on microcontact-printed substrates, which provide important insights into designing cultured networks by using CP, and into deciphering the onset and evolution of network bursts in developmental nerve systems.

neuroscience↗

bioRxiv2023

Temporal physiological, transcriptomic and metabolomic analyses revealed molecular mechanism of Canna indica's response to Cr stress

Chromium (Cr) can interfere with plant gene expression, change the content of metabolites and affect plant growth. However, the molecular response mechanism of wetland plants at different time sequences under Cr stress has yet to be fully understood.The results showed that Cr stress increased the activities of superoxide dismutase (SOD), ascorbate peroxidase (APX) and peroxidase (POD), the contents of glutathione (GSH), malondialdehyde (MDA), and oxygen free radical (ROS), and inhibited the biosynthesis of photosynthetic pigments, thus leading to changes in plant growth and biomass. that Cr stress mainly affected 12 metabolic pathways, involving 38 differentially expressed metabolites, including amino acids, phenylpropane, and flavonoids. A total of 16247 differentially expressed genes were identified, among which, at the early stage of stress, C. indica responds to Cr toxicity mainly through galactose, starch and sucrose metabolism. With the extension of stress time, plant hormone signal transduction and MAPK signaling pathway in C. indica in the treatment group were significantly affected. Finally, in the late stage of stress, C. indica co-defuses Cr toxicity by activating its Glutathione metabolism and Phenylpropanoid biosynthesis. In conclusion, this study revealed the molecular response mechanism of C. indica to Cr stress at different times through multi-omics methods. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/524062v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@c2fec6org.highwire.dtl.DTLVardef@1e47da8org.highwire.dtl.DTLVardef@1f5be49org.highwire.dtl.DTLVardef@9fcf87_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2023

The splicing isoform Foxpdelta2 releases the autoinhibitory conformation and differentially regulates tTregs and pTregs homeostasis

Foxp3 is the master transcription factor for the development and function of regulatory T cells (Tregs). So far, little is known about whether the conformation change in Foxp3 could impact the Tregs biology. Alternative splicing of human Foxp3 results in the expression of two major isoforms: the full-length protein or an exon 2-deleted protein (Foxp3{Delta}2). Here, AlphaFold2 structure predictions and in vitro experiments demonstrated that the N-terminal domain of Foxp3 inhibits DNA binding by moving toward the C-terminus and that this movement is mediated by exon 2. Consequently, we generated exon 2 deficient mice and found Foxp3{Delta}2-bearing Tregs in the peripheral lymphoid organ were less sensitive to TCR due to the enhanced binding of Foxp3{Delta}2 to the Batf promoter and were unsusceptible to IL-2. In contrast, among ROR{gamma}t+ Tregs in the large intestine, Foxp3{Delta}2 Tregs expressed much more ROR{gamma}t-related genes, and more strikingly, the deletion of exon 2 of Foxp3 conferred a competitive advantage over WT ROR{gamma}t+ Tregs. Together, our results reveal that alternative splicing of exon 2 generates a constitutively active form of Foxp3, which plays a differential role in regulating tTregs and pTregs homeostasis. HighlightsO_LIFoxp3{Delta}2 broke the inhibitory loop and generated constitutive DNA-binding activity. C_LIO_LIFoxp3 isoforms differentially regulate tTregs and pTregs homeostasis C_LIO_LIFoxp3{Delta}2-bearing Tregs in the peripheral lymphoid organ were less sensitive to TCR and were unsusceptible to IL-2 C_LIO_LIFoxp3{Delta}2 ROR{gamma}t+ pTregs benefited them for better adapting to the gut environmental conditions C_LI

immunology↗

bioRxiv2022

Identifying B-cell epitopes using AlphaFold2 predicted structures and pretrained language model

MotivationIdentifying the B-cell epitopes is an essential step for guiding rational vaccine development and immunotherapies. Due to experimental approaches being expensive and time-consuming, many computational methods have been designed to assist B-cell epitope prediction. However, existing sequence-based methods have limited performance since they only use contextual features of the sequential neighbors while neglecting structural information. ResultsBased on the recent breakthrough of AlphaFold2 in protein structure prediction, we propose GraphBepi, a novel graph-based model for accurate B-cell epitope prediction. GraphBepi first generates the effective information sequence representations and protein structures from antigen sequences through the pretrained language model and AlphaFold2, respectively. GraphBepi then applies the edge-enhanced deep graph neural network (EGNN) to capture the spatial information from predicted protein structures and leverages the bidirectional long short-term memory neural networks (BiLSTM) to capture long-range dependencies from sequences. The low-dimensional representation learned by EGNN and BiLSTM is then combined to predict B-cell epitopes through a multilayer perceptron. Through comprehensive tests on the curated epitope dataset, GraphBepi was shown to outperform the state-of-the-art methods by more than 5.5% and 44.0% in terms of AUC and AUPR, respectively. We also provide the GraphBepi web server that is freely available at https://biomed.nscc-gz.cn/apps/GraphBepi. AvailabilityThe datasets, pre-computed features, source codes, and the pretrained model of GraphBepi are available at https://github.com/biomed-AI/GraphBepi. Contactyangyd25@mail.sysu.edu.cn or gaojz@nankai.edu.cn

bioinformatics↗

bioRxiv2022

Small Molecule Inducers of Neuroprotective miR-132 Identified by HTS-HTS in Human iPSC-derived Neurons

MicroRNAs (miRNAs) are short RNAs that regulate fundamental biological processes. miR-132, a key miRNA with established functions in Tau homeostasis and neuroprotection, is consistently downregulated in Alzheimers disease (AD) and other tauopathies. miR-132 overexpression rescues neurodegenerative phenotypes in several AD models. To complement research on miRNA-mimicking oligonucleotides targeting the central nervous system, we developed a high-throughput-screen coupled high-throughput-sequencing (HTS-HTS) in human induced pluripotent stem cell (iPSC)-derived neurons to identify small molecule inducers of miR-132. We discovered that cardiac glycosides, which are canonical sodium-potassium ATPase inhibitors, selectively upregulated miR-132 in the sub-M range. Coordinately, cardiac glycoside treatment downregulated total and phosphorylated Tau in rodent and human neurons and protected against toxicity by glutamate, N-methyl-D-aspartate, rotenone, and A{beta} oligomers. In conclusion, we identified small-molecule drugs that upregulated the neuroprotective miR-132 and ameliorated neurodegenerative phenotypes. Our dataset also represents a comprehensive resource for discovering small molecules that modulate specific miRNAs for therapeutic purposes.

neuroscience↗

bioRxiv2022

Three-dimensional structured illumination microscopy with enhanced axial resolution

We present two distinct, complementary methods for improving axial resolution in three-dimensional structured illumination microscopy (3D SIM) with minimal or no modification to the optical system. First, we show that placing a mirror directly opposite the sample enables 4-beam interference with higher spatial frequency content than 3D SIM illumination, offering near-isotropic imaging with [~]120 nm lateral and 160 nm axial resolution. Second, we develop an improved deep learning method that can be directly applied to 3D SIM data, obviating the need for additional hardware. This procedure results in [~]120 nm isotropic resolution and can be combined with denoising to facilitate volumetric imaging spanning dozens of time points. We demonstrate the potential of these advances by imaging a variety of cellular samples, delineating the nanoscale distribution of vimentin and microtubule filaments, observing the relative positions of caveolar coat proteins and lysosomal markers, and visualizing rich cytoskeletal dynamics within T-cells in the early stages of immune synapse formation.

cell biology↗

bioRxiv2022

Molecular atlas reveals the tri-sectional spinning mechanism of spider dragline silk

We performed the first molecular atlas of natural spider dragline silk production using genome assembly for the golden orb-web spider Trichonephila clavata and multiomics defining for the segmented major ampullate (Ma) gland: Tail, Sac, and Duct. We uncovered a hierarchical biosynthesis of spidroins, organic acids, lipids, and chitin in the sectionalized Ma gland dedicated to fine silk constitution. The ordered secretion of spidroins was achieved by the synergetic regulation of epigenetic and ceRNA signatures for genomic group-distributed spidroin genes. Single-cellular and spatial RNA profiling identified ten cell types with partitioned functional division determining the tri-sectional organization of the Ma gland. Convergent evolution and genetic manipulation analyses further validated that this tri-sectional architecture of the silk gland was analogous in silk-spinning animals and inextricably linked with silk formation. Our study provided multiple levels of data that significantly expand the knowledge of spider dragline silk generation and may eventually benefit spider-inspired fiber innovations.

genomics↗

bioRxiv2022

Coexistence of Cue-specific and Cue-independent Spatial Representations for Landmarks and Self-motion Cues in Human Retrosplenial Cortex

Landmark-based and self-motion-based navigation are two fundamental forms of spatial navigation, which involve distinct cognitive mechanisms. A critical question is whether these two navigation modes invoke common or distinct spatial representations for a given environment in the brain. While a number of electrophysiological studies in non-human animals have investigated this question but yielded inconsistent results, it still awaits rigorous investigation in humans. In the current study, we combined ultra-high field fMRI at 7T and desktop virtual reality with state-of-the-art fMRI data analysis techniques. Using a novel linear track navigation task, we dissociated the use of landmarks and self-motion cues, so that participants used different spatial cues to encode and retrieve the same set of spatial locations. Focusing on the retrosplenial cortex (RSC) and the hippocampus, we observed that RSC contained both cue-specific and cue-independent spatial representations, which were driven by objective location (where the participant was actually located) and subjective location (the participants self-reported location), respectively. The hippocampus showed strong functional coupling with RSC and exhibited a similar spatial coding scheme, but with reduced effect sizes. Taken together, the current study demonstrated for the first time concurrent cue-specific and cue-independent spatial representations in RSC in the same spatial context, suggesting that this area might transform cue-specific spatial inputs into coherent cue-independent spatial representations to guide navigation behavior.

neuroscience↗

bioRxiv2022

A Self-Healing, Viscoelastic Hydrogel Promotes Healing of Brain Lesions

Brain lesions can arise from traumatic brain injury, infection, and craniotomy. Although injectable hydrogels show promise for promoting healing of lesions and health of surrounding tissue, enabling cellular ingrowth and restoring neural tissue continue to be challenging. We hypothesized that these challenges arise in part from viscoelastic mismatch between the hydrogel and the brain parenchyma, and tested this hypothesis by developing and evaluating a self-healing hydrogel that mimicked both the composition and viscoelasticity of native brain parenchyma. The hydrogel was crosslinked by dynamic boronate ester bonds between phenylboronic acid grafted hyaluronic acid (HA-PBA) and dopamine grafted gelatin (Gel-Dopa). This HA-PBA/Gel-Dopa hydrogel could be injected into a lesion cavity in a shear-thinning manner with rapid hemostasis, high tissue adhesion and efficient self-healing. We tested this in an in vivo mouse model of brain lesions and found the hydrogel to support neural cell infiltration, decrease astrogliosis and glial scars, and close the lesions. The results suggest a role for viscoelasticity in brain lesion healing, and motivate additional experimentation in larger animals as the technology progresses towards potential application in humans.

bioengineering↗