Oligodendrogliogenesis and axon remyelination after traumatic spinal cord injuries in animal studies: a systematic review

© 2019 IBRO Extensive oligodendrocyte death after acute traumatic spinal cord injuries (TSCI) leads to axon demyelination and subsequently may leave axons vulnerable to degeneration. Despite the present evidence showing spontaneous remyelination after TSCI the cellular origin of new myelin and the time course of the axon ensheathment/remyelination remained controversial issue. In this systematic review the trend of oligodendrocyte death after injury as well as the extent and the cellular origin of oligodendrogliogenesis were comprehensively evaluated. The study design was based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-guided systematic review. PubMed and EMBASE were searched with no temporal or linguistic restrictions. Also, hand-search was performed in the bibliographies of relevant articles. Non-interventional animal studies discussing different types of myelinating cells including oligodendrocytes, Schwann cells and oligodendrocyte progenitor cells (OPCs) were evaluated. The extent of oligodendrocyte death, oligodendrocyte differentiation and remyelination were the pathophysiological outcome measures. We found 12,359 studies, 34 of which met the inclusion criteria. The cumulative evidence shows extensive oligodendrocytes cell death during the first week post-injury (pi). OPCs and peripheral invading Schwann cells are the dominant cells contributing in myelin formation. The maximum OPC proliferation was observed at around 2 weeks pi and oligodendrogliogenesis continues at later stages until the number of oligodendrocytes return to normal tissue by one month pi. Taken together, the evidence in animals reveals the potential role for endogenous myelinating cells in the axon ensheathment/remyelination after TSCI and this can be the target of pharmacotherapy to induce oligodendrocyte differentiation and myelin formation post-injury

The fate of neurons after traumatic spinal cord injury in rats: a systematic review

Objective(s): To reach an evidence-based knowledge in the context of the temporal-spatial pattern of neuronal death and find appropriate time of intervention in order to preserve spared neurons and promote regeneration after traumatic spinal cord injury (TSCI). Materials and Methods: The study design was based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-guided systematic review. PubMed and EMBASE were searched (24 October, 2015) with no temporal or linguistic restrictions. Hand-search was performed in the bibliographies of relevant articles. Non-interventional animal studies evaluating time-dependent neuronal death following acute mechanical trauma to the spinal cord were included. We separately evaluated the fate of various populations of neurons including propriospinal neurons, ventral motor neurons, Clarke’s column neurons, and supraspinal neurons. Results: We found 11,557 non-duplicated studies. Screening through the titles and abstracts led to 549 articles, 49 of which met the inclusion criteria. Both necrotic and apoptotic neuronal deaths occur after TSCI, though necrosis is the prominent mechanism. There are differences in the responses of intrinsic neurons of the spinal cord to the TSCI. Also, the extent of neuronal death in the supraspinal neurons depends on the anatomical location of their axons. Conclusion: In order to develop new therapies, selection of the injury model and time of intervention has a crucial role in the efficacy of therapy. In addition, examining the safety and efficacy of an intervention by reliable methods not confounded by the injury-related changes would promote translation of therapies to the clinical application

Volume Changes After Traumatic Spinal Cord Injury in Animal Studies - A Systematic Review

There are limited data on the lesion volume changes following spinal cord injury (SCI). In this study, a meta-analysis was performed to evaluate the volume size changes of the injured spinal cord over time among animal studies in traumatic SCI. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a comprehensive electronic search of English literature of PubMed and EMBASE databases from 1946 to 2015 concerning the time-dependent changes in the volume of the spinal cord following mechanical traumatic SCI. A hand-search was also performed for non-interventional, non-molecular, and non-review studies. Quality appraisal, data extraction, qualitative and quantitative analyses were performed afterward. Of 11,561 articles yielded from electronic search, 49 articles were assessed for eligibility after reviewing of titles, abstracts, and references. Ultimately, 11 articles were eligible for quantitative synthesis. The ratio of lesion volume to spinal cord total volume increased over time. Avascularity appeared in spinal cord 4 hours after injury. During the first week, the spinal subarachnoid space decreased. The hemorrhagic lesion size peaked in 1 week and decreased thereafter. Significant loss of gray and white matter occurred from day 3 with a slower progression of white matter damage. Changes of lesion extent over time is critical in pathophysiologic processes after SCI. Early avascularity, rapid loss of gray matter, slow progression of white matter damage, and late cavitation are the pathophysiologic key points of SCI, which could be helpful in choosing the proper intervention on a timely basis

Improving ex-vivo expansion of mesenchymal stromal/stem cells using acellular fetal membranes

© 2019 Dr. Aida Shakouri-MotlaghMesenchymal stromal/stem cells (MSCs) have considerable potential in the fields of cell therapies, tissue engineering, and regenerative medicine. According to clinicaltrials.gov, MSCs are employed in more than 700 registered clinical trials as potential treatments. However, the clinical application of MSCs is limited by their low prevalence in the human body and inefficient methods for large-scale ex-vivo production. During ex-vivo expansion, MSCs experience a vastly different environment compared to their natural microenvironment (i.e. their niche), and these environmental differences are likely to be main drivers for the loss of key MSC properties. In this study, the general aim was to investigate the effect of two main components of the MSC niche on decidua-derived MSCs (DMSCs) from human placenta during ex-vivo expansion; the extracellular matrix (ECM) and extracellular vesicles (EVs). Coatings produced from ECM are promising surfaces for the improved ex-vivo expansion of MSCs. However, identifying a readily available source of ECM to generate these coatings is the bottleneck of this technology. In Chapter 2 of this thesis, ECM coatings derived from decellularised fetal membranes were assessed as suitable substrates for MSC expansion. The fetal membrane’s two main components, the amnion and the chorion, were separated, decellularised and processed further to produce solubilised forms of the decellularised amniotic membrane (s-dAM) and decellularised chorionic membrane (s-dCM). DMSCs were more proliferative, smaller in size (a measure of MSC potency, and exhibited greater adopogenic and osteogenic differentiation capacity when cultured on s-dAM compared to controls. Additionally, long-term culture studies revealed that late passage DMSCs (passage 8) cultured on s-dAM had decreased cell diameter over three passages. These data support the use of s-dAM as a substrate for improved MSC expansion. In addition to the ECM, extracellular vesicles are another important component of the MSC niche. However, the contribution of ECM and EVs has not been explored from an MSC expansion point of view. In Chapter 3, the effect of adding MSC-derived EVs to DMSCs cultured on the ECM coatings described in Chapter 2 was assessed. Addition of EVs to the DMSCs growing on Matrigel improved their attachment. However, regardless of the presence of EVs, DMSCs showed significantly better attachment on s-dAM. Furthermore, addition of EVs to DMSCs growing on s-dAM improved DMSC proliferation, migration and osteogenic capacity. The total antioxidant capacity of DMSCs growing on Matrigel, s-dAM and s-dCM increased, regardless of whether EVs were added to DMSCs or not. These data illustrate the relative contribution of ECM and EVs towards MSC expansion and show that supplementing the MSC culture with EVs can regulate certain MSC properties. In addition to issues of large-scale ex-vivo expansion of MSCs, their clinical application is limited due to their low survival rates and poor engraftment after delivery. A number of factors contribute to these issues including cell damage due to shear stress during injection, leakage of cells from the injection site, and lack of appropriate interactions with surrounding cells and extracellular matrix. In Chapter 4 of this thesis, s-dAM and s-dCM were investigated for their potential to form 3D thermoreversible and injectable hydrogels to be used as a cell delivery carrier for MSCs. At 37ºC, both s-dAM and s-dCM formed gels at concentrations of 4 and 8 mg/mL. DMSCs growing on s-dAM showed improved proliferation, adipogenesis and osteogenesis compared to TCP. Both s-dAM and s-dCM had shear thinning properties, and were therefore injectable. DMSCs embedded in both s-dAM and s-dCM had a viability of ~60% after injection and showed improved proliferation compared to Matrigel. These data support that the ECM from both s-dAM and s-dCM can be processed to produce thermoreversible and injectable hydrogels, and s-dAM hydrogels promote key properties of DMSCs

Triggered and Tunable Hydrogen Sulfide Release from Photogenerated Thiobenzaldehydes

International audienceHydrogen sulfide (H2 S) has been identified as an important cell-signaling mediator and has a number of biological functions, such as vascular smooth muscle relaxation, neurotransmission, and regulation of inflammation. A facile and versatile approach for H2 S production initiated by light irradiation and controlled by reaction with an amine or an amino acid was developed. The donor was synthesized in a one-pot reaction, and simple crystallization led to a yield of approximately 90 %. The synthetic strategy is scalable and versatile, and the H2 S donors can be expressed ina number of different molecular and macromolecular forms, including crystalline small-molecule compounds, water-soluble polymers, polystyrene films, and hydrogels. The H2 S donors based on polystyrene film and hydrogel were used as cell-culture scaffolds. The H2 S donor based on water-soluble polymer was applied in photocontrolled inhibition of P-selectin expression on human platelets and subsequent regulation of platelet aggregation. This study provides the simplest controllable H2 S source to study its biological functions. The developed materials are also new therapeutic platforms to deliver H2 S, as there is no accumulation of toxic byproducts, and the donor materials from polystyrene films and hydrogels can be readily removed after releasing H2 S