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Article The ApoA-I mimetic peptide 5A enhances remyelination by promoting clearance and degradation of myelin debris Graphical abstract Highlights d ApoA-I mimetic peptide 5A enhances remyelination in a phagocyte-dependent manner d In addition to promoting lipid efflux, peptide 5A enhances clearance of myelin debris d Peptide 5A drives clearance of myelin debris via the fatty acid translocase CD36 We thank M.P. Tulleners for excellent technical assistance. The work was financially supported by the Research Foundation of Flanders (FWO Vlaanderen; 1S15519N, G099618FWO, and 12J9119N) and the Interreg V-A EMR program (EURLIPIDS, EMR23). The funding agencies had no role in the design, analysis, or writing of the article.

The apical papilla is a stem cell rich tissue located at the base of the developing dental root and is responsible for the progressive elongation and maturation of the root. The multipotent stem cells of the apical papilla (SCAP) are extensively studied in cell culture since they demonstrate a high capacity for osteogenic, adipogenic, and chondrogenic differentiation and are thus an attractive stem cell source for stem cell-based therapies. Currently, only few studies are dedicated to determining the role of the apical papilla in dental root development. In this review, we will focus on the architecture of the apical papilla and describe the specific SCAP signaling pathways involved in root maturation. Furthermore, we will explore the heterogeneity of the SCAP phenotype within the tissue and determine their micro-environmental interaction. Understanding the mechanism of postnatal dental root growth could further aid in developing novel strategies in dental root regeneration.

Stem cell-based regenerative therapies hold great promises to treat a wide spectrum of diseases. However, stem cell engraftment and survival are still challenging due to an unfavorable transplantation environment. Advanced glycation end-products (AGEs) can contribute to the generation of these harmful conditions. AGEs are a heterogeneous group of glycated products, nonenzymatically formed when proteins and/or lipids become glycated and oxidized. Our typical Western diet as well as cigarettes contain high AGEs content. AGEs are also endogenously formed in our body and accumulate with senescence and in pathological situations. Whether AGEs have an impact on stem cell viability in regenerative medicine remains unclear, and research on the effect of AGEs on stem cell proliferation and apoptosis is still ongoing. Therefore, this systematic review provides a clear overview of the effects of glycated proteins on cell viability in various types of primary isolated stem cells used in regenerative medicine. Figures were created using images from Servier Medical Art Commons Attribution 3.0 Unported License (http://smart.servier.com). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License. This work was supported by a Bijzonder onderzoeksfonds (BOF) grant from Hasselt University (grant number: 16NI05BOF). HB benefits from an aspirant PhD mandate (grant number: 1154120N) of the `Research Foundation-Flanders' (fonds voor wetenschappelijk onderzoek (FWO)). PG is also supported by the FWO (grant numbers: 12U7718N and 1502120N). Bito, V (corresponding author), Hasselt Univ, Biomed BIOMED Res Inst, Agoralaan Bldg C, B-3590 Diepenbeek, Belgium. virginie.bito@uhasselt.be

Additional file 1. The additional data includes information regarding the TEM protocol, TEM images of the PS NPs and HPCs, data on NP characterization and cell viability assessment. Furthermore, flow cytometry gating strategies are included.

Due to the restricted intrinsic capacity of resident chondrocytes to regenerate the lost cartilage postinjury, stem cell-based therapies have been proposed as a novel therapeutic approach for cartilage repair. Moreover, stem cell-based therapies using mesenchymal stem cells (MSCs) or induced pluripotent stem cells (iPSCs) have been used successfully in preclinical and clinical settings. Despite these promising reports, the exact mechanisms underlying stem cell-mediated cartilage repair remain uncertain. Stem cells can contribute to cartilage repair via chondrogenic differentiation, via immunomodulation, or by the production of paracrine factors and extracellular vesicles. But before novel cell-based therapies for cartilage repair can be introduced into the clinic, rigorous testing in preclinical animal models is required. Preclinical models used in regenerative cartilage studies include murine, lapine, caprine, ovine, porcine, canine, and equine models, each associated with its specific advantages and limitations. This review presents a summary of recent in vitro data and from in vivo preclinical studies justifying the use of MSCs and iPSCs in cartilage tissue engineering. Moreover, the advantages and disadvantages of utilizing small and large animals will be discussed, while also describing suitable outcome measures for evaluating cartilage repair. The study was performed within the framework of the cooperation between the University of Namur and Hasselt University. Melissa Lo Monaco is funded by “Bijzonder Onderzoeksfonds” and “Fonds Spécial de Recherche” (BOF16DOCNA02-FSR-confin UHasselt-UNamur). Jessica Ratajczak, Pascal Gervois, Petra Hilkens, and Annelies Bronckaers are funded by “Fonds Wetenschappelijk Onderzoek.” Greet Merckx is funded by “Bijzonder Onderzoeksfonds.”

Within the field of tissue engineering, natural tissues are reconstructed by combining growth factors, stem cells, and different biomaterials to serve as a scaffold for novel tissue growth. As adequate vascularization and innervation are essential components for the viability of regenerated tissues, there is a high need for easily accessible stem cells that are capable of supporting these functions. Within the human tooth and its surrounding tissues, different stem cell populations can be distinguished, such as dental pulp stem cells, stem cells from human deciduous teeth, stem cells from the apical papilla, dental follicle stem cells, and periodontal ligament stem cells. Given their straightforward and relatively easy isolation from extracted third molars, dental stem cells (DSCs) have become an attractive source of mesenchymal-like stem cells. Over the past decade, there have been numerous studies supporting the angiogenic, neuroprotective, and neurotrophic effects of the DSC secretome. Together with their ability to differentiate into endothelial cells and neural cell types, this makes DSCs suitable candidates for dental tissue engineering and nerve injury repair.

Stroke is the second most common cause of death and is a major cause of permanent disability. Given the current demographic trend of an ageing population and associated increased risk, the prevalence of and socioeconomic burden caused by stroke will continue to rise. Current therapies are unable to sufficiently ameliorate the disease outcome and are not applicable to all patients. Therefore, strategies such as cell-based therapies with mesenchymal stem cell (MSC) or induced pluripotent stem cell (iPSC) pave the way for new treatment options for stroke. These cells showed great preclinical promise despite the fact that the precise mechanism of action and the optimal administration route are unknown. To gain dynamic insights into the underlying repair processes after stem cell engraftment, noninvasive imaging modalities were developed to provide detailed spatial and functional information on the donor cell fate and host microenvironment. This review will focus on MSCs and iPSCs as types of widely used stem cell sources in current (bio)medical research and compare their efficacy and potential to ameliorate the disease outcome in animal stroke models. In addition, novel noninvasive imaging strategies allowing temporospatial in vivo tracking of transplanted cells and coinciding evaluation of neuronal repair following stroke will be discussed. Esther Wolfs, Jessica Ratajczak, Tim Vangansewinkel, Petra Hilkens, and Annelies Bronckaers are funded by Fonds Wetenschappelijk Onderzoek by grants G0A7514N, G089213N, G029112N, 12D8516N, and 1508015N, respectively. Yorg Dillen is funded by Bijzonder On- ¨ derzoeksfonds by grant BOF15DOC04.

In conclusion, we state that curiosity-driven research after normal synovial folds within the PIP-joint of the finger confirms their actual location. Neurovascular bundles in the normal PIP-joint’s capsule, and neurons in lamellated corpuscles within the Proper Collateral Ligament, may shed new light on the pathogenesis of rheumatoid arthritis in human finger joints.

Objective: Current available therapies are unable to adequately promote functional recovery in patients suffering from neurological disorders such as stroke, which are a major cause of death and permanent disability. As an alternative treatment, cell-based therapies are now emerging. Human neural stem cells are the most promising candidates to induce neuronal repair, but due to ethical and practical considerations, alternative sources of progenitor cells with neuronal differentiation potential are needed. The aim of the present study was to differentiate stem cells that were isolated from the human dental pulp (hDPSCs) towards functionally active neuronal cells in vitro. Methods: hDPSCs were subjected to a two-step protocol. First, neurosphere-formation was used to acquire neuronal induction. Secondly, neuronal maturation was induced, based on cAMP and NT-3 signaling. The ultrastructural characteristics of intra-neurospheral hDPSCs and their microenvironment were determined by means of transmission electron microscopy (TEM). Neurogenic maturated hDPSCs (d-hDPSCs) were subjected to immunocytochemical, PCR, ultrastructural and electrophysiological analysis. An Enzyme-Linked Immunosorbent Assay (ELISA) was performed for VEGF, NGF, BDNF and GDNF in order to evaluate the secretome of hDPSCs before and after neurogenic differentiation. Results: Based on the ultrastructural analysis it was shown that within the neurospheres, intercellular communication was promoted. Moreover, hDPSCs grew out of the neurospheres in vitro and established a neurogenic differentiated hDPSC culture (d-hDPSCs) which was characterized by the increased expression of the neuronal markers NeuN, MAP-2 and NCAM compared to the nondifferentiated counterpart. Moreover, the secretion of BDNF, VEGF and NGF differed between dhDPSCs and hDPSCSs. Ultrastructurally, d-hDPSCs acquired neuronal features including multiple intercommunicating cytoplasmic extensions and increased vesicular transport. Finally, patch clamp analysis demonstrated the functional activity of d-hDPSCs by the presence of TTX-sensitive voltagegated sodium and TEA-sensitive potassium channels. A subset of d-hDPSCs was able to fire a single action potential. Conclusions: Although promising results were achieved, establishing a completely functional dhDPSC culture remains a challenge. The results in this study demonstrate that hDPSCs are capable of neuronal commitment with distinct features of neuronal cells.

Dental pulp stem cells (DPSC), mesenchymal stem cells (MSC) from the tooth, share phenotypical and multilineage characteristics with bone marrow derived MSCs (BMMSCs). Since DPSCs are much easier to harvest in comparison to BMMSCs they are considered as a useful alternative MSC source in stem cell research. As MSCs retain some plasticity, the neural differentiation potential of DPSCs will be evaluated. DPSCs will be labelled with the commercially available ferumoxide Endorem® to allow visualization with MRI following engraftment. This study shows expression of NeuN in neurogenic differentiated DPSCs. Future studies should include quantitative and electrophysiological experiments. This study also shows that the optimal concentration for labelling DPSCs is 0,75µg/ml PLL with 15µg/ml Endorem®. The influence of Endorem® labelling on cellular processes of DPSCs needs to be determined before these cells can be considered as a clinical applicable intracellular contrast agent for MRI analysi

Comparative observations in the hind limb of the opossum, a primate predecessor, reveal essential differences regarding lower leg coupling mechanisms. Especially the primate ankle shows cardan joint properties, causing inversion of the foot before toe-off. Inversion is turning the footsole inwards, eversion is turning it outwards. By bony landmarks, features of longitudinal rotation of bones from 3-D frames were matched to available radiocinematographs of walking stages in (a) early stance, (b) mid-stance, (c) toe-off, and (d) swing. Flemish Interuniversity Council - University Development Cooperation (VLIR-UOS), Institutional University Cooperation, ADEKUS Suriname, Project 6: Education and research programme on physical therapy, Coordinators: Yves Vanlandewijck & Tony Chang

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by focal inflammatory lesions and prominent demyelination. Even though the currently available therapies are effective in treating the initial stages of disease, they are unable to halt or reverse disease progression into the chronic progressive stage. Thus far, no repair-inducing treatments are available for progressive MS patients. Hence, there is an urgent need for the development of new therapeutic strategies either targeting the destructive immunological demyelination or boosting endogenous repair mechanisms. Using in vitro, ex vivo, and in vivo models, we demonstrate that selective inhibition of phosphodiesterase 4 (PDE4), a family of enzymes that hydrolyzes and inactivates cyclic adenosine monophosphate (cAMP), reduces inflammation and promotes myelin repair. More specifically, we segregated the myelination-promoting and anti-inflammatory effects into a PDE4Dand PDE4B-dependent process respectively. We show that inhibition of PDE4D boosts oligodendrocyte progenitor cells (OPC) differentiation and enhances (re)myelination of both murine OPCs and human iPSC-derived OPCs. In addition, PDE4D inhibition promotes in vivo remyelination in the cuprizone model, which is accompanied by improved spatial memory and reduced visual evoked potential latency times. We further identified that PDE4B-specific inhibition exerts anti-inflammatory effects since it lowers in vitro monocytic nitric oxide (NO) production and improves in vivo neurological scores during the early phase of experimental autoimmune encephalomyelitis (EAE). In contrast to the pan PDE4 inhibitor roflumilast, the therapeutic dose of both the PDE4B-specific inhibitor A33 and the PDE4D-specific inhibitor Gebr32a did not trigger emesis-like side effects in rodents. Finally, we report distinct PDE4D isoform expression patterns in human area postrema neurons and human oligodendroglia lineage cells. Using the CRISPR-Cas9 system, we confirmed that pde4d1/2 and pde4d6 are the key targets to induce OPC differentiation. Collectively, these data demonstrate that gene specific PDE4 inhibitors have potential as novel therapeutic agents for targeting the distinct disease processes of MS. This work has been supported by FWO (12G0817N, 1S57521N, G041421N, and 12G0817N), Fondation Charctot Stichting (ID2020- 0019), Nationale Belgische Multiple Sclerose Liga (Charco18VT), MS Liga Vlaanderen and Stichting MS Research (18-1016 MS). MS, EP, JP and TV have a proprietary interest in selective PDE4D inhibitors for the treatment of demyelinating disorders and neurodegenerative disorders. JP has a proprietary interest in the PDE4 inhibitor roflumilast for the treatment of cognitive impairment as well as PDE4D inhibitors for the treatment of Alzheimer’s disease. We thank Prof. Dr. O.N. Viacheslav (University Medical Center Hamburg-Eppendorf, German Center for Cardiovascular Research) and Prof. Dr. M. Conti (University of California), for providing the PDE4B KO animals. Furthermore, we thank Rewind Therapeutics for providing the visual evoked potential equipment.