by Keyword: spinal-cord

Álvarez Z, Ortega JA, Sato K, Sasselli IR, Kolberg-Edelbrock AN, Qiu R, Marshall KA, Nguyen TP, Smith CS, Quinlan KA, Papakis V, Syrgiannis Z, Sather NA, Musumeci C, Engel E, Stupp SI, Kiskinis E, (2023). Artificial extracellular matrix scaffolds of mobile molecules enhance maturation of human stem cell-derived neurons Cell Stem Cell 30, 219-238

Human induced pluripotent stem cell (hiPSC) technologies offer a unique resource for modeling neurological diseases. However, iPSC models are fraught with technical limitations including abnormal aggregation and inefficient maturation of differentiated neurons. These problems are in part due to the absence of synergistic cues of the native extracellular matrix (ECM). We report on the use of three artificial ECMs based on peptide amphiphile (PA) supramolecular nanofibers. All nanofibers display the laminin-derived IKVAV signal on their surface but differ in the nature of their non-bioactive domains. We find that nanofibers with greater intensity of internal supramolecular motion have enhanced bioactivity toward hiPSC-derived motor and cortical neurons. Proteomic, biochemical, and functional assays reveal that highly mobile PA scaffolds caused enhanced β1-integrin pathway activation, reduced aggregation, increased arborization, and matured electrophysiological activity of neurons. Our work highlights the importance of designing biomimetic ECMs to study the development, function, and dysfunction of human neurons.Copyright © 2022 Elsevier Inc. All rights reserved.

JTD Keywords: differentiation, force-field, laminin, migration, nanostructures, peptide amphiphiles, spinal-cord, statistical-model, supramolecular materials, Coarse-grained model, Dynamics, Extracellular matrix, Ikvav, Ipsc-derived neurons, Laminin, Neuronal maturation, Peptide amphiphiles, Supramolecular motion, Supramolecular nanofibers

Mesquida-Veny, Francina, Martínez-Torres, Sara, Del Río, José Antonio, Hervera, Arnau, (2022). Genetic control of neuronal activity enhances axonal growth only on permissive substrates Molecular Medicine 28, 97

Abstract Background Neural tissue has limited regenerative ability. To cope with that, in recent years a diverse set of novel tools has been used to tailor neurostimulation therapies and promote functional regeneration after axonal injuries. Method In this report, we explore cell-specific methods to modulate neuronal activity, including opto- and chemogenetics to assess the effect of specific neuronal stimulation in the promotion of axonal regeneration after injury. Results Opto- and chemogenetic stimulations of neuronal activity elicited increased in vitro neurite outgrowth in both sensory and cortical neurons, as well as in vivo regeneration in the sciatic nerve, but not after spinal cord injury. Mechanistically, inhibitory substrates such as chondroitin sulfate proteoglycans block the activity induced increase in axonal growth. Conclusions We found that genetic modulations of neuronal activity on both dorsal root ganglia and corticospinal motor neurons increase their axonal growth capacity but only on permissive environments.

JTD Keywords: activation, chemogenetics, electrical-stimulation, expression, functional recovery, increases, injury, motor cortex, neuronal activity, optogenetics, permissive substrate, promotes recovery, regeneration, Optogenetics, Regeneration, Spinal-cord

Bohner, Marc, Maazouz, Yassine, Ginebra, Maria-Pau, Habibovic, Pamela, Schoenecker, Jonathan G., Seeherman, Howard, van den Beucken, Jeroen, Witte, Frank, (2022). Sustained local ionic homeostatic imbalance caused by calcification modulates inflammation to trigger heterotopic ossification Acta Biomaterialia 145, 1-24

Heterotopic ossification (HO) is a condition triggered by an injury leading to the formation of mature lamellar bone in extraskeletal soft tissues. Despite being a frequent complication of orthopedic and trauma surgery, brain and spinal injury, the etiology of HO is poorly understood. The aim of this study is to evaluate the hypothesis that a sustained local ionic homeostatic imbalance (SLIHI) created by mineral formation during tissue calcification modulates inflammation to trigger HO. This evaluation also considers the role SLIHI could play for the design of cell-free, drug-free osteoinductive bone graft substitutes. The evaluation contains five main sections. The first section defines relevant concepts in the context of HO and provides a summary of proposed causes of HO. The second section starts with a detailed analysis of the occurrence and involvement of calcification in HO. It is followed by an explanation of the causes of calcification and its consequences. This allows to speculate on the potential chemical modulators of inflammation and triggers of HO. The end of this second section is devoted to in vitro mineralization tests used to predict the ectopic potential of materials. The third section reviews the biological cascade of events occurring during pathological and material-induced HO, and attempts to propose a quantitative timeline of HO formation. The fourth section looks at potential ways to control HO formation, either acting on SLIHI or on inflammation. Chemical, physical, and drug-based approaches are considered. Finally, the evaluation finishes with a critical assessment of the definition of osteoinduction.

JTD Keywords: apatite, beta-tricalcium phosphate, bone, bone graft, bone morphogenetic protein, demineralized bone-matrix, experimental myositis-ossificans, extracellular calcium, heterotopic ossification, in-vitro, inflammation, multinucleated giant-cells, osteoinduction, spinal-cord-injury, total hip-arthroplasty, traumatic brain-injury, Apatite, Calcium-sensing receptor, Osteoinduction