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Snake venom-defined fibrin architecture dictates fibroblast survival and differentiation.

ABSTRACT: Fibrin is the provisional matrix formed after injury, setting the trajectory for the subsequent stages of wound healing. It is commonly used as a wound sealant and a natural hydrogel for three-dimensional (3D) biophysical studies. However, the traditional thrombin-driven fibrin systems are poorly controlled. Therefore, the precise roles of fibrin's biophysical properties on fibroblast functions, which underlie healing outcomes, are unknown. Here, we establish a snake venom-controlled fibrin system with precisely and independently tuned architectural and mechanical properties. Employing this defined system, we show that fibrin architecture influences fibroblast survival, spreading phenotype, and differentiation. A fine fibrin architecture is a key prerequisite for fibroblast differentiation, while a coarse architecture induces cell loss and disengages fibroblast's sensitivity towards TGF-β1. Our results demonstrate that snake venom-controlled fibrin can precisely control fibroblast differentiation. Applying these biophysical principles to fibrin sealants has translational significance in regenerative medicine and tissue engineering.

SUBMITTER: Wang Z

PROVIDER: S-EPMC9950370 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Snake venom-defined fibrin architecture dictates fibroblast survival and differentiation.

Wang Zhao Z Lauko Jan J Kijas Amanda W AW Gilbert Elliot P EP Turunen Petri P Yegappan Ramanathan R Zou Dongxiu D Mata Jitendra J Rowan Alan E AE

Nature communications 20230223 1

Fibrin is the provisional matrix formed after injury, setting the trajectory for the subsequent stages of wound healing. It is commonly used as a wound sealant and a natural hydrogel for three-dimensional (3D) biophysical studies. However, the traditional thrombin-driven fibrin systems are poorly controlled. Therefore, the precise roles of fibrin's biophysical properties on fibroblast functions, which underlie healing outcomes, are unknown. Here, we establish a snake venom-controlled fibrin syst ...[more]

PMID: 36823141

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Project description:BackgroundVentral root avulsion is an experimental model of proximal axonal injury at the central/peripheral nervous system interface that results in paralysis and poor clinical outcome after restorative surgery. Root reimplantation may decrease neuronal degeneration in such cases. We describe the use of a snake venom-derived fibrin sealant during surgical reconnection of avulsed roots at the spinal cord surface. The present work investigates the effects of this fibrin sealant on functional recovery, neuronal survival, synaptic plasticity, and glial reaction in the spinal motoneuron microenvironment after ventral root reimplantation.Methodology/principal findingsFemale Lewis rats (7 weeks old) were subjected to VRA and root replantation. The animals were divided into two groups: 1) avulsion only and 2) replanted roots with fibrin sealant derived from snake venom. Post-surgical motor performance was evaluated using the CatWalk system twice a week for 12 weeks. The rats were sacrificed 12 weeks after surgery, and their lumbar intumescences were processed for motoneuron counting and immunohistochemistry (GFAP, Iba-1 and synaptophysin antisera). Array based qRT-PCR was used to evaluate gene regulation of several neurotrophic factors and receptors as well as inflammatory related molecules. The results indicated that the root reimplantation with fibrin sealant enhanced motor recovery, preserved the synaptic covering of the motoneurons and improved neuronal survival. The replanted group did not show significant changes in microglial response compared to VRA-only. However, the astroglial reaction was significantly reduced in this group.Conclusions/significanceIn conclusion, the present data suggest that the repair of avulsed roots with snake venom fibrin glue at the exact point of detachment results in neuroprotection and preservation of the synaptic network at the microenvironment of the lesioned motoneurons. Also such procedure reduced the astroglial reaction and increased mRNA levels to neurotrophins and anti-inflammatory cytokines that may in turn, contribute to improving recovery of motor function.

Project description:BackgroundThe explosive radiation and diversification of the advanced snakes (superfamily Colubroidea) was associated with changes in all aspects of the shared venom system. Morphological changes included the partitioning of the mixed ancestral glands into two discrete glands devoted for production of venom or mucous respectively, as well as changes in the location, size and structural elements of the venom-delivering teeth. Evidence also exists for homology among venom gland toxins expressed across the advanced snakes. However, despite the evolutionary novelty of snake venoms, in-depth toxin molecular evolutionary history reconstructions have been mostly limited to those types present in only two front-fanged snake families, Elapidae and Viperidae. To have a broader understanding of toxins shared among extant snakes, here we first sequenced the transcriptomes of eight taxonomically diverse rear-fanged species and four key viperid species and analysed major toxin types shared across the advanced snakes.ResultsTranscriptomes were constructed for the following families and species: Colubridae - Helicops leopardinus, Heterodon nasicus, Rhabdophis subminiatus; Homalopsidae - Homalopsis buccata; Lamprophiidae - Malpolon monspessulanus, Psammophis schokari, Psammophis subtaeniatus, Rhamphiophis oxyrhynchus; and Viperidae - Bitis atropos, Pseudocerastes urarachnoides, Tropidolaeumus subannulatus, Vipera transcaucasiana. These sequences were combined with those from available databases of other species in order to facilitate a robust reconstruction of the molecular evolutionary history of the key toxin classes present in the venom of the last common ancestor of the advanced snakes, and thus present across the full diversity of colubroid snake venoms. In addition to differential rates of evolution in toxin classes between the snake lineages, these analyses revealed multiple instances of previously unknown instances of structural and functional convergences. Structural convergences included: the evolution of new cysteines to form heteromeric complexes, such as within kunitz peptides (the beta-bungarotoxin trait evolving on at least two occasions) and within SVMP enzymes (the P-IIId trait evolving on at least three occasions); and the C-terminal tail evolving on two separate occasions within the C-type natriuretic peptides, to create structural and functional analogues of the ANP/BNP tailed condition. Also shown was that the de novo evolution of new post-translationally liberated toxin families within the natriuretic peptide gene propeptide region occurred on at least five occasions, with novel functions ranging from induction of hypotension to post-synaptic neurotoxicity. Functional convergences included the following: multiple occasions of SVMP neofunctionalised in procoagulant venoms into activators of the clotting factors prothrombin and Factor X; multiple instances in procoagulant venoms where kunitz peptides were neofunctionalised into inhibitors of the clot destroying enzyme plasmin, thereby prolonging the half-life of the clots formed by the clotting activating enzymatic toxins; and multiple occasions of kunitz peptides neofunctionalised into neurotoxins acting on presynaptic targets, including twice just within Bungarus venoms.ConclusionsWe found novel convergences in both structural and functional evolution of snake toxins. These results provide a detailed roadmap for future work to elucidate predator-prey evolutionary arms races, ascertain differential clinical pathologies, as well as documenting rich biodiscovery resources for lead compounds in the drug design and discovery pipeline.

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Snake venom-defined fibrin architecture dictates fibroblast survival and differentiation.

Publications

Snake venom-defined fibrin architecture dictates fibroblast survival and differentiation.

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