The neurogenic potential of astrocytes is regulated by inflammatory signals

Although the adult brain contains neural stem cells (NSCs) that generate new neurons throughout life, these astrocyte-like populations are restricted to two discrete niches. Despite their terminally differentiated phenotype, adult parenchymal astrocytes can re-acquire NSC-like characteristics following injury, and as such, these 'reactive' astrocytes offer an alternative source of cells for central nervous system (CNS) repair following injury or disease. At present, the mechanisms that regulate the potential of different types of astrocytes are poorly understood. We used in vitro and ex vivo astrocytes to identify candidate pathways important for regulation of astrocyte potential. Using in vitro neural progenitor cell (NPC)-derived astrocytes, we found that exposure of more lineage-restricted astrocytes to either tumor necrosis factor alpha (TNF-α) (via nuclear factor-κB (NFκB)) or the bone morphogenetic protein (BMP) inhibitor, noggin, led to re-acquisition of NPC properties accompanied by transcriptomic and epigenetic changes consistent with a more neurogenic, NPC-like state. Comparative analyses of microarray data from in vitro-derived and ex vivo postnatal parenchymal astrocytes identified several common pathways and upstream regulators associated with inflammation (including transforming growth factor (TGF)-β1 and peroxisome proliferator-activated receptor gamma (PPARγ)) and cell cycle control (including TP53) as candidate regulators of astrocyte phenotype and potential. We propose that inflammatory signalling may control the normal, progressive restriction in potential of differentiating astrocytes as well as under reactive conditions and represent future targets for therapies to harness the latent neurogenic capacity of parenchymal astrocytes

Genetic deletion of <em>Cdc42 r</em>eveals a crucial role for astrocyte recruitment to the injury site <em>in vitro</em> and <em>in vivo</em>.

It is generally suggested that astrocytes play important restorative functions after brain injury, yet little is known regarding their recruitment to sites of injury, despite numerous in vitro experiments investigating astrocyte polarity. Here, we genetically manipulated one of the proposed key signals, the small RhoGTPase Cdc42, selectively in mouse astrocytes in vitro and in vivo. We used an in vitro scratch assay as a minimal wounding model and found that astrocytes lacking Cdc42 (Cdc42&Delta;) were still able to form protrusions, although in a nonoriented way. Consequently, they failed to migrate in a directed manner toward the scratch. When animals were injured in vivo through a stab wound, Cdc42&Delta; astrocytes developed protrusions properly oriented toward the lesion, but the number of astrocytes recruited to the lesion site was significantly reduced. Surprisingly, however, lesions in Cdc42&Delta; animals, harboring fewer astrocytes contained significantly higher numbers of microglial cells than controls. These data suggest that impaired recruitment of astrocytes to sites of injury has a profound and unexpected effect on microglia recruitment

Der neue Länderindikatorensatz für die Gesundheitsberichterstattung

Im Mai 2003 wurde die dritte, neu bearbeitete Fassung des Indikatorensatzes für die Gesundheitsberichterstattung der Bundesländer von den Gesundheitsministerien aller Länder bestätigt. Die meisten Bundesländer haben damit begonnen, Daten nach dem neu systematisierten und mit Metadatenbeschreibungen versehenen Indikatorensatz für die landesspezifische Gesundheitsberichterstattung zu erfassen. Durch die Unterstützung von Datenhaltern auf Bundesebene und des Statistischen Bundesamtes ist es gelungen, die Datenbasis weiter auszubauen und den Datenzugang erstmalig auch über das Statistische Bundesamt zu gewährleisten. In dem Beitrag werden die methodischen und statistischen Grundlagen des Indikatorensatzes dargelegt. Der Nutzen des Indikatorensatzes für die Gesundheitsberichterstattung in den Ländern ist ein weiterer wichtiger Aspekt.In May 2003, the third revised version of the indicator set for health reporting activities was confirmed by the health ministries of all German States (Bundesländer). Modeled on the restructured indicator set which has been annotated with meta-data descriptions, most Bundesländer have now started to collect data for their specific health reporting activities. Thanks to the support provided by national data holders and the Federal Statistical Office, it has been possible to further enlarge the database and for the first time also ensure access via the Federal Statistical Office. In this contribution the authors describe the methodological and statistical principles of the indicator set. Another aspect is the benefit of the indicator set for the health reporting activities in the German States

A major Litomosoides carinii microfilarial sheath glycoprotein (gp22): amino terminal sequence and immunological studies with corresponding synthetic peptides

The major glycoprotein of the sheath of Litomosoides carinii microfilariae (gp22) was analysed for its amino acid and amino sugar composition. It is rich in proline, glutamine/glutamic acid and glycine and contains (N-acetyl)galactosamine. The N-terminal amino acid sequence was determined up to position 37. It consists of a group of 6 repeats of the pentapeptide sequence methionine-glycine-proline-glutamine-proline with two minor modifications in repeats 3-6, while the first two repeats follow the general pattern more loosely. Identical N-terminal amino acid sequences were found in at least two other sheath polypeptides (33 kDa, 39 kDa). Antisera prepared against 3 overlapping synthetic peptides corresponding to the amino terminus of gp22 recognized different epitopes. They all reacted with identical patterns of sheath polypeptides. The antisera failed to recognize antigens of 4th-stage larvae of L. carinii. In contrast, cross-reacting epitopes were detected in other parasite stages. Antisera reacted with material surrounding embryos and microfilariae in the uterus of females, and caused patchy fluorescence on the sheath of blood-derived and in vitro-released microfilariae

Live imaging of astrocyte responses to acute injury reveals selective juxtavascular proliferation

Astrocytes are thought to have important roles after brain injury, but their behavior has largely been inferred from postmortem analysis. To examine the mechanisms that recruit astrocytes to sites of injury, we used in vivo two-photon laser-scanning microscopy to follow the response of GFP-labeled astrocytes in the adult mouse cerebral cortex over several weeks after acute injury. Live imaging revealed a marked heterogeneity in the reaction of individual astrocytes, with one subset retaining their initial morphology, another directing their processes toward the lesion, and a distinct subset located at juxtavascular sites proliferating. Although no astrocytes actively migrated toward the injury site, selective proliferation of juxtavascular astrocytes was observed after the introduction of a lesion and was still the case, even though the extent was reduced, after astrocyte-specific deletion of the RhoGTPase Cdc42. Thus, astrocyte recruitment after injury relies solely on proliferation in a specific niche

Investigating age-related changes in proliferation and the cell division repertoire of parenchymal reactive astrocytes.

Reactive gliosis is a complicated process involving all types of glial cells and is the therapeutic target of efforts to treat several types of neuropathologies. Parenchymal astrocytes continuously survey their microenvironment to identify even tiny abnormalities in the central nervous system (CNS) homeostasis and react rapidly to brain damage, such as following ischemia, trauma, or neurodegenerative diseases, to prevent propagation of tissue damage. Aging can play causal roles in certain astroglial dysfunctions, however, still little is known to what extent the heterogeneous reaction of astrocytes at the injury site might be impaired over the course of aging. Based on our experience with both in vitro and in vivo experimental paradigms, we describe here in detail the analysis of age-related changes in (1) proliferative response of parenchymal astrocytes within the posttraumatic cerebral cortex grey matter (GM), and (2) repertoire of their cell divisions in adherent cell culture prepared from the injured GM of young and old double transgenic GFAP-mRFP1/(FUCCI)-S/G2/M-mAG-hGeminin mice by single cell time-lapse imaging