Biomedical subjects

Sigrid C Schwarz

Publications and source records attributed to Sigrid C Schwarz.

7 recordsLinked to original sources

PubMed2006

Transplantation of human neural precursor cells in the 6-OHDA lesioned rats: effect of immunosuppression with cyclosporine A.

Neural precursor cells (NPC) may provide a source for restaurative therapy. We wanted to study the immunogenic potential of human NPC. We transplanted human NPCs with or without cyclosporine A (10 mg/kg) expanded in serum-free conditions into the striatum of rats unilaterally lesioned with 6-hydroxydopamine. Four months after transplantation, there was significant improvement of amphetamine-induced rotational behavior 9 non-immunosuppressed (13.1+/-4.9 pre vs 8.5+/-4.0 after grafting) but nor for 11 animals immunosuppressed with CyA (12.3+/-1.7 vs 11.3+/-2.8). The number of TH-IR cells was comparable in both groups (1,580+/-700 vs 1,274+/-295). All grafted animals only showed mild activation of astrocytes and macrophages within the graft. There was no evidence for tumor formation. Immunosuppression of rats, xenotransplanted with human NPC did not improve graft survival or function.

Amphetamine↗

PubMed2006

Enhanced expression of hypersensitive alpha4* nAChR in adult mice increases the loss of midbrain dopaminergic neurons.

We describe an inducible genetic model for degeneration of midbrain dopaminergic neurons in adults. In previous studies, knock-in mice expressing hypersensitive M2 domain Leu9'Ser (L9'S) alpha4 nicotinic receptors (nAChR) at near-normal levels displayed dominant neonatal lethality and dopaminergic deficits in embryonic midbrain, because the hypersensitive nAChR is excitotoxic. However, heterozygous L9'S mice that retain the neomycin resistance cassette (neo) in a neighboring intron express low levels of the mutant allele (approximately 25% of normal levels), and these neo-intact mice are therefore viable and fertile. The neo cassette is flanked by loxP sites. In adult animals, we locally injected helper-dependent adenovirus (HDA) expressing cre recombinase. Local excision of the neo cassette, via cre-mediated recombination, was verified by genomic analysis. In L9'S HDA-cre injected animals, locomotion was reduced both under baseline conditions and after amphetamine application. There was no effect in L9'S HDA-control treated animals or in wild-type (WT) littermates injected with either virus. Immunocytochemical analyses revealed marked losses (> 70%) of dopaminergic neurons in L9'S HDA-cre injected mice compared to controls. At 20-33 days postinjection in control animals, the coexpressed marker gene, yellow fluorescent protein (YFP), was expressed in many neurons and few glial cells near the injection, emphasizing the neurotropic utility of the HDA. Thus, HDA-mediated gene transfer into adult midbrain induced sufficient functional expression of cre in dopaminergic neurons to allow for postnatal deletion of neo. This produced increased L9'S mutant nAChR expression, which in turn led to nicotinic cholinergic excitotoxicity in dopaminergic neurons.

Adenoviridae↗

PubMed2006

Uracil nucleotides stimulate human neural precursor cell proliferation and dopaminergic differentiation: involvement of MEK/ERK signalling.

Isolation and propagation of neural stem cells derived from human brain tissue uniquely enables the study of human neurogenesis in vitro. In addition, ex vivo-expanded human neural stem/precursor cells (NPCs) may offer novel therapeutic strategies. We investigated the effects of extracellular nucleotides on the proliferation and differentiation of human mesencephalic neural stem/precursor cells (hmNPCs). When combined with the mitogens epidermal growth factor and fibroblast growth factor 2, UTP (1 microm) boosted proliferation of hmNPCs as shown by increased expression of the proliferation marker proliferating cell nuclear antigen (330%). UTP-induced proliferation was abrogated by the preferential P2Y receptor blocker pyridoxal phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS). UTP also stimulated dopaminergic differentiation. Treatment with UTP (100 microm) increased the number of tyrosine hydroxylase (TH)-positive cells and TH protein by 267 and 319% respectively. UTP-stimulated dopaminergic differentiation of hmNPCs was blocked by the P2 receptor antagonists suramin (10 microm) and PPADS (100 microm). In addition, UDP (1 microm) enhanced TH protein expression by 194%. During differentiation, treatment with UTP stimulated the extracellular signal-regulated kinase (ERK) pathway. Both ERK1/2 phosphorylation and dopaminergic differentiation were inhibited by U0126, a selective ERK kinase inhibitor, as well as by suramin. When other P2 receptor agonists (ATP, ADP and adenosine 5'-O-(2-thiophosphate) (ADPbetaS); all 100 microm) were applied, both proliferation and dopaminergic differentiation of NPCs were compromised. We conclude that uracil nucleotides exert specific P2 receptor-mediated effects on midbrain-derived human NPCs, and may be used to enhance both proliferation and dopaminergic differentiation.

Adenine Nucleotides↗

PubMed2006

Developmental perspectives on human midbrain-derived neural stem cells.

Regeneration or restoration of lost or damaged neurons is very likely to profoundly alter the disability and needs of many patients. The replacement of dopaminergic (DA) neurons in patients with Parkinson's disease via implantation of embryonic midbrain tissue was taken from animal experiments to clinical applications. Ethical concerns related to the use of fetal tissue derived from abortions further argue for the search for alternative tissue sources. Today, it seems possible to generate functional DA neurons from a variety of stem cells, including embryonic and neural stem cells. Bone marrow stromal cells are another source for cell replacement. Neural stem cells derived from human fetal midbrain tissue maintain a considerable capacity to self-renew and to differentiate into DA neurons. Therefore, these cells may be a promising source to generate functional human DA neurons.

Humans↗

PubMed2005

Low atmospheric oxygen avoids maturation, senescence and cell death of murine mesencephalic neural precursors.

The efficient generation of specific brain cells in vitro may serve as a source of cells for brain repair in several devastating neurological diseases. Production of dopaminergic neurons from precursor cells for transplantation in Parkinson's disease has become a major research goal. We found that murine mesencephalic neurospheres were viable and proliferated, preserved telomerase activity, pluripotency and dopaminergic commitment for many weeks when cultured in 3% O2, whereas exposing these cells to 21% oxygen prohibited long-term expansion. Microarray data suggest that a variety of genes related to the cell cycle, cell maturation and apoptosis are differentially regulated in midbrain-derived precursors cultured in 3 versus 21% oxygen after 1-2 months. Taken together, we hypothesize that sustained high oxygen has deleterious effects on the self-renewal capacity of mesencephalic neural precursors, possibly accelerating maturation and senescence resulting in overall cell loss. Gene regulation governed by low oxygen tension may be relevant to the normal development and survival of midbrain neurons.

Animals↗

PubMed2004

Midbrain-derived neural stem cells: from basic science to therapeutic approaches.

Neural stem cells (NSCs) are a subtype of tissue-specific progenitor cells capable of extended self-renewal and the ability to generate all major cell types of nervous tissue, such as neurons, astroglia and oligodendroglial cells. Recent studies suggest that salient patterning in anterior-posterior and dorsal-ventral axes occurs early, concomitantly with neural induction and therefore stem cells and restricted precursors exhibit regionalization. Fetal mesencephalic NSCs can be isolated and expanded in vitro for many months while retaining their potential to differentiate into glia and neurons, with a subset of neurons displaying all the major properties of mature functional dopaminergic neurons. Since Parkinson's disease (PD) is characterized by the loss of a specific type of dopaminergic cells, the prospect of replacing the missing or damaged cells is very attractive in PD. Thus, mesencephalic NSCs might serve as a new and continuous source of dopaminergic neurons for regenerative strategies in this neurodegenerative disorder. This review discusses new data concerning the cell biology and therapeutic potential of NSCs derived from the midbrain region of the central nervous system.

Animals↗

PubMed2003

RGS9 modulates dopamine signaling in the basal ganglia.

Regulators of G protein signaling (RGS) modulate heterotrimeric G proteins in part by serving as GTPase-activating proteins for Galpha subunits. We examined a role for RGS9-2, an RGS subtype highly enriched in striatum, in modulating dopamine D2 receptor function. Viral-mediated overexpression of RGS9-2 in rat nucleus accumbens (ventral striatum) reduced locomotor responses to cocaine (an indirect dopamine agonist) and to D2 but not to D1 receptor agonists. Conversely, RGS9 knockout mice showed heightened locomotor and rewarding responses to cocaine and related psychostimulants. In vitro expression of RGS9-2 in Xenopus oocytes accelerated the off-kinetics of D2 receptor-induced GIRK currents, consistent with the in vivo data. Finally, chronic cocaine exposure increased RGS9-2 levels in nucleus accumbens. Together, these data demonstrate a functional interaction between RGS9-2 and D2 receptor signaling and the behavioral actions of psychostimulants and suggest that psychostimulant induction of RGS9-2 represents a compensatory adaptation that diminishes drug responsiveness.

Animals↗