Anti-inflammatory treatment induced regenerative oligodendrogenesis in parkinsonian mice

Introduction: The adult mammalian brain retains niches for neural stem cells (NSCs), which can generate glial and neuronal components of the brain tissue. However, it is barely established how chronic neuroinflammation, as it occurs in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, affects adult neurogenesis and, therefore, modulates the brain’s potential for self-regeneration. Methods: Neural stem cell culture techniques, intraventricular tumor necrosis factor (TNF)-a infusion and the 6-hydroxydopamine mouse model were used to investigate the influence of neuroinflammation on adult neurogenesis in the Parkinson’s disease background. Microscopic methods and behavioral tests were used to analyze samples. Results: Here, we demonstrate that differences in the chronicity of TNF-a application to cultured NSCs result in opposed effects on their proliferation. However, chronic TNF-a treatment, mimicking Parkinson’s disease associated neuroinflammation, shows detrimental effects on neural progenitor cell activity. Inversely, pharmacological inhibition of neuroinflammation in a 6-hydroxydopamine mouse model led to increased neural progenitor cell proliferation in the subventricular zone and neuroblast migration into the lesioned striatum. Four months after surgery, we measured improved Parkinson’s disease-associated behavior, which was correlated with long-term antiinflammatory treatment. But surprisingly, instead of newly generated striatal neurons, oligodendrogenesis in the striatum of treated mice was enhanced. Conclusions: We conclude that anti-inflammatory treatment, in a 6-hydroxydopamine mouse model for Parkinson’s disease, leads to activation of adult neural stem cells. These adult neural stem cells generate striatal oligodendrocytes. The higher numbers of newborn oligodendrocytes possibly contribute to axonal stability and function in this mouse model of Parkinson’s disease and thereby attenuate dysfunctions of basalganglian motorcontrol

Reduction of Matrix Metallopeptidase 13 and Promotion of Chondrogenesis by Zeel T in Primary Human Osteoarthritic Chondrocytes

Objectives: Zeel T (Ze14) is a multicomponent medicinal product. Initial preclinical data suggested a preventive effect on cartilage degradation. Clinical observational studies demonstrated that Ze14 reduced symptoms of osteoarthritis (OA), including stiffness and pain. This study aimed to explore these effects further to better understand the mode of action of Ze14 on human OA chondrocytes in vitro. Methods: Primary chondrocytes were obtained from the knees of 19 OA patients and cultured either as monolayers or in alginate beads. The cultures were treated with 20% or 10% (v/v) Ze14 or placebo. For RNA-seq, reads were generated with Illumina NextSeq5000 sequencer and aligned to the human reference genome (UCSC hg19). Differential expression analysis between Ze14 and placebo was performed in R using the DESeq2 package. Protein quantification by ELISA was performed on selected genes from the culture medium and/or the cellular fractions of primary human OA chondrocyte cultures. Results: In monolayer cultures, Ze14 20% (v/v) significantly modified the expression of 13 genes in OA chondrocytes by at least 10% with an adjusted p-value < 0.05: EGR1, FOS, NR4A1, DUSP1, ZFP36, ZFP36L1, NFKBIZ, and CCN1 were upregulated and ATF7IP, TXNIP, DEPP1, CLEC3A, and MMP13 were downregulated after 24 h Ze14 treatment. Ze14 significantly increased (mean 2.3-fold after 24 h, p = 0.0444 and 72 h, p = 0.0239) the CCN1 protein production in human OA chondrocytes. After 72 h, Ze14 significantly increased type II collagen pro-peptide production by mean 27% (p = 0.0147). For both time points CCN1 production by OA chondrocytes was correlated with aggrecan (r = 0.66, p = 0.0004) and type II collagen pro-peptide (r = 0.64, p = 0.0008) production. In alginate beads cultures, pro-MMP-13 was decreased by Ze14 from day 7–14 (from −16 to −25%, p < 0.05) and from day 17–21 (−22%, p = 0.0331) in comparison to controls. Conclusion: Ze14 significantly modified the expression of DUSP1, DEPP1, ZFP36/ZFP36L1, and CLEC3A, which may reduce MMP13 expression and activation. Protein analysis confirmed that Ze14 significantly reduced the production of pro-MMP-13. As MMP-13 is involved in type II collagen degradation, Ze14 may limit cartilage degradation. Ze14 also promoted extracellular matrix formation arguably through CCN1 production, a growth factor well correlated with type II collagen and aggrecan production

Bioisosteric analogs of MDMA: improving the pharmacological profile?

3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') is re-emerging in clinical settings as a candidate for the treatment of specific neuropsychiatric disorders (e.g. post-traumatic stress disorder) in combination with psychotherapy. MDMA is a psychoactive drug, typically regarded as an empathogen or entactogen, which leads to transporter-mediated monoamine release. Despite its therapeutic potential, MDMA can induce dose-, individual-, and context-dependent untoward effects outside safe settings. In this study, we investigated whether three new methylenedioxy bioisosteres of MDMA improve its off-target profile. In&nbsp;vitro methods included radiotracer assays, transporter electrophysiology, bioluminescence resonance energy transfer and fluorescence-based assays, pooled human liver microsome/S9 fraction incubations, metabolic stability studies, isozyme mapping, and liquid chromatography coupled to high-resolution mass spectrometry. In silico methods included molecular docking. Compared with MDMA, all three MDMA bioisosteres (ODMA, TDMA, and SeDMA) showed similar pharmacological activity at human serotonin, dopamine, and norepinephrine transporters (hSERT, hDAT, and hNET, respectively) but decreased agonist activity at 5-HT2A/2B/2C receptors. Regarding their hepatic metabolism, they differed from MDMA, with N-demethylation being the only metabolic route shared, and without forming phase II metabolites. In addition, TDMA showed an enhanced intrinsic clearance in comparison to its congeners. Additional screening for their interaction with human organic cation transporters (hOCTs) and plasma membrane monoamine transporter (hPMAT) revealed a weaker interaction of the MDMA analogs with hOCT1, hOCT2, and hPMAT. Our findings suggest that these new MDMA bioisosteres might constitute appealing therapeutic alternatives to MDMA, sparing the primary pharmacological activity at hSERT, hDAT, and hNET, but displaying a reduced activity at 5-HT2A/2B/2C receptors and alternative hepatic metabolism. Whether these MDMA bioisosteres may pose lower risk alternatives to the clinically re-emerging MDMA warrants further studies

Impaired serine metabolism complements LRRK2-G2019S pathogenicity in PD patients

Parkinson's disease (PD) is a multifactorial disorder with complex etiology. The most prevalent PD associated mutation, LRRK2-G2019S is linked to familial and sporadic cases. Based on the multitude of genetic predispositions in PD and the incomplete penetrance of LRRK2-G2019S, we hypothesize that modifiers in the patients' genetic background act as susceptibility factors for developing PD. To assess LRRK2-G2019S modifiers, we used human induced pluripotent stem cell-derived neuroepithelial stem cells (NESCs). Isogenic controls distinguish between LRRK2-G2019S dependent and independent cellular phenotypes. LRRK2-G2019S patient and healthy mutagenized lines showed altered NESC self-renewal and viability, as well as impaired serine metabolism. In patient cells, phenotypes were only partly LRRK2-G2019S dependent, suggesting a significant contribution of the genetic background. In this context we identified the gene serine racemase (SRR) as a novel patient-specific, developmental, genetic modifier contributing to the aberrant phenotypes. Its enzymatic product, n-serine, rescued altered cellular phenotypes. Susceptibility factors in the genetic background, such as SRR, could be new targets for early PD diagnosis and treatment.Analytical BioScience

Influence of female sex and fertile age on neuromyelitis optica spectrum disorders

Background: Gender and age at onset are important epidemiological factors influencing prevalence, clinical presentation, and treatment response in autoimmune diseases. Objective: To evaluate the impact of female sex and fertile age on aquaporin-4-antibody (AQP4-ab) status, attack localization, and response to attack treatment in patients with neuromyelitis optica (NMO) and its spectrum disorders (neuromyelitis optica spectrum disorder (NMOSD)). Methods: Female-to-male ratios, diagnosis at last visit (NMO vs NMOSD), attack localization, attack treatment, and outcome were compared according to sex and age at disease or attack onset. Results: A total of 186 NMO/SD patients (82% female) were included. In AQP4-ab-positive patients, female predominance was most pronounced during fertile age (female-to-male ratio 23:1). Female patients were more likely to be positive for AQP4-abs (92% vs 55%; p 40 years. Conclusion: Our data suggest an influence of sex and age on susceptibility to AQP4-ab-positive NMO/SD. Genetic and hormonal factors might contribute to pathophysiology of NMO/SD

IN VIVO ANALYSIS OF STEM CELLS AS A PREREQUISITE FOR AUTOLOGOUS CELL REPLACEMENT THERAPIES

The seminal discovery that somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) opens new horizons for future personalised cell replacement therapies. This is particularly interesting for neurological disorders since the central nervous system (CNS) possesses only limited regenerative potential and conventional therapies are inefficient. However, the unique feature of pluripotency bears a high risk of tumour formation and therefore restricts the direct utilisation of iPSCs for clinical applications. More recently, direct reprogramming from a somatic lineage into another e.g. into neurons, without passing through the pluripotent state, was achieved, thus circumventing the pluripotency-associated tumorigenic risk. The inability of neurons to self-renew and their restricted lineage potential, however, renders this technique inadequate for routine usage. Conversely, cardinal features of neural stem cells (NSCs) include the ability of self-renewal and trilineage differentiation potential, while their higher degree of differentiation compared to PSCs poses a lower tumorigenic risk. Thus, NSCs possess ideal requirements for neural cell based therapies. However, the features of NSCs under physiological conditions can deviate from their in vitro properties. Therefore, the in vivo features of two novel NSC lines were analysed in the present work in order to assess their relevance for therapeutic applications. The first line analysed, induced NSCs (iNSCs), were directly reprogrammed from mouse embryonic fibroblasts, without passing through the pluripotent state, by using a combination of 4 or 5 transcription factors. These iNSCs closely resemble wild-type NSCs in terms of morphology, gene expression profile, self-renewing capacity, epigenetic status, differentiation potential and functionality. Moreover, in vivo analysis revealed survival ability and multipotent differentiation capacity of the iNSCs. Thus, we proved that differentiated cells can be directly converted to acquire a true NSC identity. Remarkably, the iNSC technique overcomes some of the hurdles associated with PSCs or with induced neurons (iNs), e.g. high tumorigenic potential and inability to self-renew, respectively. In a follow-up study, we analysed the long-term in vivo properties of iNSCs and showed substantial long-term survival rates of grafted iNSCs without graft overgrowth. We further demonstrated neural multilineage differentiation potential of the iNSCs with a clear bias towards astrocytes as well as a permanent downregulation of progenitor and cell cycle markers. These data suggest that iNSCs are not predisposed to tumour formation, making them a safe source for long-term transplantations. Moreover, iNSC-derived progenies fulfil basic requirements to reconstruct damaged tissue i.e. migration, functional integration and interaction with the existing neural circuit, evidenced by the generation of synaptic connections and electrophysiological features. In addition to the murine iNSCs, we also examined multipotent neural precursor cells (NPCs) derived from human PSCs during this thesis. Noteworthy, the generation and propagation of a fully homogeneous neural culture is achieved by using only low-cost small molecules (smNPCs), without tedious manual manipulation and by robust and easy culture conditions. By this means, convenient and affordable large-scale approaches like cell replacement therapies are facilitated. Strikingly, smNPCs uniquely exhibit stable expandability while retaining a broad differentiation potential i.e. the competence to clonally and efficiently differentiate into neural tube-derived CNS lineages as well as neural crest-derived lineages. These features are, so far, only matched by PSCs. The extraordinary features of smNPCs were complemented by their in vivo capabilities: smNPCs possess the competence to survive, to differentiate into mature neurons and astrocytes and to integrate within a physiological neural network without any tumorigenic predisposition. Moreover, smNPCs did not only display a neurogenic differentiation propensity in vivo, but they were also capable of differentiating towards the midbrain dopaminergic (mDA) neuronal subtype in vivo when predifferentiated before transplantation. mDA neurons are of special interest for regenerative approaches to treat Parkinson’s disease (PD). Furthermore, we generated smNPCs from neuroectoderm- and mesoderm-derived iPSCs in order to determine if and to what extend the in vitro as well as in vivo capabilities of smNPCs are influenced by their somatic cell of origin. We found that robust and successful derivation of smNPCs as well as their differentiation potential are not affected by the donor cell type. However, transcriptomic analysis revealed that origin-dependent neural cell identies exist, to a certain degree, in smNPCs in vitro and in vivo though but only to a small extent. Remarkably, these neural cell identities provided certain advantageous features in a physiological neural environment i.e. a better survival rate and neurite outgrowth. Nevertheless, the major in vivo features that are required for the feasibility of successful cell replacement therapies are not restricted by the starting population i.e. robust neuronal differentiation efficiency as well as synapse formation. Overall, this work revealed that iNSCs and smNPCs exhibit important in vivo features that are decisive requirements for the success of future personalised cell replacement therapies. We conclude that not only the iNSC technique itself but also the long-term in vivo features of iNSC progenies render them as a highly desirable tool for glial regenerative therapies, while the multifaceted properties of smNPCs classify them as an extremely qualified tool for neuronal, and in particular mDA neuronal, cell replacement approaches

Sustainability Concept (Whole-Institution Approach) of the Catholic University of Eichstätt-Ingolstadt (Germany)

German universities today face major and diverse challenges in meeting the current and future expectations of society (Barlett and Chase 2013).On the one hand, students have to fulfill the requirements of current labor markets, on the other hand, the university itself as an educational institution and company should act as a role model. The concept of sustainable development and education for sustainable development currently represents an approach that universities around the world and especially in Germany are increasingly adopting. In Germany, some universities have already made progress in the process of adopting the whole-institution approach and can serve as a model for other universities on their way to becoming more sustainable. The aim of this article is to present the KU as a positive example of a German university that has been on the path towards becoming a more sustainable university for ten years and thus, according to Leal Filho (2009), belongs to the group of universities that have made a long-term commitment to sustainability. It should be emphasized that, in addition to research and teaching, the focus is on four furtherfields of action in connection with sustainability (governance, student initiatives andcommitment, campus management and operations, and transfer) for implementation of a whole-institution approach. This stringent approach is still too rare in Germany in this scope and complexity (HRK2017)

Auf dem Weg zu einer nachhaltigeren Universität : das Nachhaltigkeitskonzept (Whole Institution Approach) der Katholischen Universität Eichstätt-Ingolstadt

Die deutschen Hochschulen stehen heute vor grossen und vielfältigen Herausforderungen, um den aktuellen und zu-künftigen Erwartungen der Gesellschaft gerecht zu werden (Barlett & Chase, 2013). Studierende sollten einerseits die Anforderungen der aktuellen Arbeitsmärkte erfüllen, andererseits sollte die Universität selbst als Bildungseinrichtung und Unternehmen eine Vorbildfunktion einnehmen. Das Konzept der „Nachhaltigen Entwicklung“ und der Bildung für nachhaltige Entwicklung ist derzeit ein Ansatz, den Hochschulen weltweit und insbesondere in Deutschland zunehmend aufgreifen. In Deutschland haben einige Hochschulen bereits Fortschritte bei der Umsetzung des gesamtinstitutionellen Ansatzes erreicht und können als Modell für andere Hochschulen auf dem Weg zu mehr Nachhaltigkeit dienen. Ziel dieses Artikels ist es, die Katholische Universität Eichstätt-Ingolstadt (KU) als positives Beispiel für eine deutsche Universität vorzustellen, die sich seit zwölf Jahren auf dem Weg zu einer nachhaltigeren Universität befindet und damit nach Filho (2009) zur Gruppe der Universitäten gehört, die sich langfristig der Nachhaltigkeit verpflichtet haben (Hemmer & Lindau, 2021). Es ist hervorzuheben, dass neben Forschung und Lehre vier weitere Handlungsfelder (Governance, Studentische Initiativen und Engagement, Campusmanagement und -betrieb sowie Transfer) im Zusammenhang mit Nachhaltigkeit zur Umsetzung eines gesamtinstitutionellen Ansatzes wesentliche Aspekte darstellen. Dieser stringente und systemische Ansatz ist in Deutschland noch zu selten in diesem Umfang und dieser Komplexität zu beobachten (HRK, 2017). Mit diesen Ausführungen kann anderen Hochschulen einerseits eine Vorstellung von einer nachhaltigen Hochschule vermittelt und anderseits ermutigt werden, mit der Umsetzung von Bildung für nachhaltige Entwicklung (BNE) zu beginnen, ihre Bemühungen fortzusetzen und die gesamte Universität nachhaltiger zu gestalten. Die Ausführungen beziehen sich zum grossen Teil auf die Dokumentation der jährlich veröffentlichten Nachhaltigkeitsberichte der KU ( https://www.ku.de/unileben/nachhaltige-ku/nachhaltigkeitsbericht )