Multiple sclerosis, remyelination and the role of fibronectin

Our central nervous system functions, among others, thanks to myelin. Myelin is a fatty layer of insulation among nervous cells, which is produced by specific cells, namely oligodendrocytes. Multiple sclerosis (MS) is a disease that damages myelin. These myelin injuries (lesions) seem largely responsible for the disease burden of MS. Often, these myelin injuries are permanent in MS, but sometimes myelin recovers spontaneously. This suggests that oligodendrocytes are capable of producing new myelin, but usually do not succeed. What signals prevent oligodendrocytes from producing new myelin in MS lesions? In this thesis, it was investigated how the signal molecule fibronectin influences oligodendrocytes. In these studies, it was discovered that, after myelin injury, fibronectin is ‘automatically’ produced by neighbor cells, including cells named astrocytes. This fibronectin normally promotes recovery of myelin by attracting young progenitor cells of oligodendrocytes. When these progenitors mature to become oligodendrocytes, fibronectin is degraded. However, in MS, fibronectin is not degraded, but accumulates en binds to form aggregates. These fibronectin aggregates were found to impair myelin regeneration by oligodendrocytes. In line with this, fibronectin aggregates are not present in recovered MS lesions. Finally, fibronectin aggregates may stimulate inflammatory reactions of inflammatory cells, named microglia and macrophages. Hence, the observations presented in this thesis suggest that interfering with fibronectin aggregation could contribute to promoting myelin regeneration in MS

Involvement, topics, and roles of nurses in shared decision-making with patients with dementia in acute hospitals:An integrative review

Aim: To describe nurses' roles, involvement, and topics in shared decision-making with older patients with dementia in acute hospitals. Design: An integrative review. Methods: A systematic search was performed until April 2022 in PubMed, PsychInfo, CINAHL, and Cochrane, followed by a manual search on the reference lists of relevant systematic reviews. Studies were independently screened, appraised using the Joanna Briggs Institute (JBI) methodology, and extracted by two reviewers. Results: Nine studies were included. Nurses were involved as treatment team members, intermediates, or patient supporters. Nurses' roles were most explicit in the preparatory phase of shared decision-making. The step of ‘developing tailor-made options’ was limitedly identified. ‘Deliberating and trying options to reach a decision’ were described from an outsider's perspective in which nurses attempted to influence the decision. In conclusion, nurses primarily have a role in decision-making by supplementing patient information. Patient and Public Contribution No Patient or Public Contribution.</p

Involvement, topics, and roles of nurses in shared decision-making with patients with dementia in acute hospitals:An integrative review

Aim: To describe nurses' roles, involvement, and topics in shared decision-making with older patients with dementia in acute hospitals. Design: An integrative review. Methods: A systematic search was performed until April 2022 in PubMed, PsychInfo, CINAHL, and Cochrane, followed by a manual search on the reference lists of relevant systematic reviews. Studies were independently screened, appraised using the Joanna Briggs Institute (JBI) methodology, and extracted by two reviewers. Results: Nine studies were included. Nurses were involved as treatment team members, intermediates, or patient supporters. Nurses' roles were most explicit in the preparatory phase of shared decision-making. The step of ‘developing tailor-made options’ was limitedly identified. ‘Deliberating and trying options to reach a decision’ were described from an outsider's perspective in which nurses attempted to influence the decision. In conclusion, nurses primarily have a role in decision-making by supplementing patient information. Patient and Public Contribution No Patient or Public Contribution.</p

Involvement, topics, and roles of nurses in shared decision-making with patients with dementia in acute hospitals:An integrative review

Aim: To describe nurses' roles, involvement, and topics in shared decision-making with older patients with dementia in acute hospitals. Design: An integrative review. Methods: A systematic search was performed until April 2022 in PubMed, PsychInfo, CINAHL, and Cochrane, followed by a manual search on the reference lists of relevant systematic reviews. Studies were independently screened, appraised using the Joanna Briggs Institute (JBI) methodology, and extracted by two reviewers. Results: Nine studies were included. Nurses were involved as treatment team members, intermediates, or patient supporters. Nurses' roles were most explicit in the preparatory phase of shared decision-making. The step of ‘developing tailor-made options’ was limitedly identified. ‘Deliberating and trying options to reach a decision’ were described from an outsider's perspective in which nurses attempted to influence the decision. In conclusion, nurses primarily have a role in decision-making by supplementing patient information. Patient and Public Contribution No Patient or Public Contribution.</p

Involvement, topics, and roles of nurses in shared decision-making with patients with dementia in acute hospitals:An integrative review

Aim: To describe nurses' roles, involvement, and topics in shared decision-making with older patients with dementia in acute hospitals. Design: An integrative review. Methods: A systematic search was performed until April 2022 in PubMed, PsychInfo, CINAHL, and Cochrane, followed by a manual search on the reference lists of relevant systematic reviews. Studies were independently screened, appraised using the Joanna Briggs Institute (JBI) methodology, and extracted by two reviewers. Results: Nine studies were included. Nurses were involved as treatment team members, intermediates, or patient supporters. Nurses' roles were most explicit in the preparatory phase of shared decision-making. The step of ‘developing tailor-made options’ was limitedly identified. ‘Deliberating and trying options to reach a decision’ were described from an outsider's perspective in which nurses attempted to influence the decision. In conclusion, nurses primarily have a role in decision-making by supplementing patient information. Patient and Public Contribution No Patient or Public Contribution.</p

Involvement, topics, and roles of nurses in shared decision-making with patients with dementia in acute hospitals:An integrative review

Aim: To describe nurses' roles, involvement, and topics in shared decision-making with older patients with dementia in acute hospitals. Design: An integrative review. Methods: A systematic search was performed until April 2022 in PubMed, PsychInfo, CINAHL, and Cochrane, followed by a manual search on the reference lists of relevant systematic reviews. Studies were independently screened, appraised using the Joanna Briggs Institute (JBI) methodology, and extracted by two reviewers. Results: Nine studies were included. Nurses were involved as treatment team members, intermediates, or patient supporters. Nurses' roles were most explicit in the preparatory phase of shared decision-making. The step of ‘developing tailor-made options’ was limitedly identified. ‘Deliberating and trying options to reach a decision’ were described from an outsider's perspective in which nurses attempted to influence the decision. In conclusion, nurses primarily have a role in decision-making by supplementing patient information. Patient and Public Contribution No Patient or Public Contribution.</p

Fibronectin in tissue regeneration:timely disassembly of the scaffold is necessary to complete the build

<p>Tissue injury initiates extracellular matrix molecule expression, including fibronectin production by local cells and fibronectin leakage from plasma. To benefit tissue regeneration, fibronectin promotes opsonization of tissue debris, migration, proliferation, and contraction of cells involved in the healing process, as well as angiogenesis. When regeneration proceeds, the fibronectin matrix is fully degraded. However, in a diseased environment, fibronectin clearance is often disturbed, allowing structural variants to persist and contribute to disease progression and failure of regeneration. Here, we discuss first how fibronectin helps tissue regeneration, with a focus on normal cutaneous wound healing as an example of complete tissue recovery. Then, we continue to argue that, although the fibronectin matrix generated following cartilage and central nervous system white matter (myelin) injury initially benefits regeneration, fibronectin clearance is incomplete in chronic wounds (skin), osteoarthritis (cartilage), and multiple sclerosis (myelin). Fibronectin fragments or aggregates persist, which impair tissue regeneration. The similarities in fibronectin-mediated mechanisms of frustrated regeneration indicate that complete fibronectin clearance is a prerequisite for recovery in any tissue. Also, they provide common targets for developing therapeutic strategies in regenerative medicine.</p>

The EIIIA domain from astrocyte-derived fibronectin mediates proliferation of oligodendrocyte progenitor cells following CNS demyelination

Central nervous system remyelination by oligodendrocyte progenitor cells (OPCs) ultimately fails in the majority of multiple sclerosis (MS) lesions. Remyelination benefits from transient expression of factors that promote migration and proliferation of OPCs, which may include fibronectin (Fn). Fn is present in demyelinated lesions in two major forms; plasma Fn (pFn), deposited following blood-brain barrier disruption, and cellular Fn, synthesized by resident glial cells and containing alternatively spliced domains EIIIA and EIIIB. Here, we investigated the distinctive roles that astrocyte-derived Fn (aFn) and pFn play in remyelination. We used an inducible Cre-lox recombination strategy to selectively remove pFn, aFn or both from mice, and examined the impact on remyelination of toxin-induced demyelinated lesions of spinal cord white matter. This approach revealed that astrocytes are a major source of Fn in demyelinated lesions. Furthermore, following aFn conditional knockout, the number of OPCs recruited to the demyelinated lesion decreased significantly, whereas OPC numbers were unaltered following pFn conditional knockout. However, remyelination completed normally following conditional knockout of aFn and pFn. Both the EIIIA and EIIIB domains of aFn were expressed following demyelination, and in vitro assays demonstrated that the EIIIA domain of aFn mediates proliferation of OPCs, but not migration. Therefore, although the EIIIA domain from aFn mediates OPC proliferation, aFn is not essential for successful remyelination. Since previous findings indicated that astrocyte-derived Fn aggregates in chronic MS lesions inhibit remyelination, aFn removal may benefit therapeutic strategies to promote remyelination in MS

The EIIIA domain from astrocyte-derived fibronectin mediates proliferation of oligodendrocyte progenitor cells following CNS demyelination

This is the final version of the article. It was first published by Wiley at http://dx.doi.org/10.1002/glia.22748Central nervous system remyelination by oligodendrocyte progenitor cells (OPCs) ultimately fails in the majority of multiple sclerosis (MS) lesions. Remyelination benefits from transient expression of factors that promote migration and proliferation of OPCs, which may include fibronectin (Fn). Fn is present in demyelinated lesions in two major forms; plasma Fn (pFn), deposited following blood-brain barrier disruption, and cellular Fn, synthesized by resident glial cells and containing alternatively spliced domains EIIIA and EIIIB. Here, we investigated the distinctive roles that astrocyte-derived Fn (aFn) and pFn play in remyelination. We used an inducible Cre-lox recombination strategy to selectively remove pFn, aFn or both from mice, and examined the impact on remyelination of toxin-induced demyelinated lesions of spinal cord white matter. This approach revealed that astrocytes are a major source of Fn in demyelinated lesions. Furthermore, following aFn conditional knockout, the number of OPCs recruited to the demyelinated lesion decreased significantly, whereas OPC numbers were unaltered following pFn conditional knockout. However, remyelination completed normally following conditional knockout of aFn and pFn. Both the EIIIA and EIIIB domains of aFn were expressed following demyelination, and in vitro assays demonstrated that the EIIIA domain of aFn mediates proliferation of OPCs, but not migration. Therefore, although the EIIIA domain from aFn mediates OPC proliferation, aFn is not essential for successful remyelination. Since previous findings indicated that astrocyte-derived Fn aggregates in chronic MS lesions inhibit remyelination, aFn removal may benefit therapeutic strategies to promote remyelination in MS.JMJS is recipient of a Junior Scientific Masterclass MD/PhD fellowship from the University Medical Center Groningen. This work was supported by grants from the Netherlands Organization of Scientific Research (NWO, WB, VIDI and Aspasia), the Dutch MS Research\ud Foundation (?Stichting MS Research?, WB, JMJS, DH), the UK MS Society (CZ, RJMF), and the Research School of Behavioral and Cognitive Neurosciences (BCN, JMJS). Parts of this study were performed at the UMCG Microscopy and Imaging Center (UMIC), which is supported by NWO grants 40-00506-98-9021 and 175-010-2009-023