ABSTRACT
BACKGROUND: Mesenchymal stem cells (MSC) are easily harvested, and possess anti-inflammatory and trophic properties. Furthermore, MSC promote neuroprotection and neurogenesis, which could greatly benefit neurodegenerative disorders, such as Parkinson's disease. METHODS: MSC were transplanted one week after 6-hydroxydopamine lesioning and effects were evaluated after 6 months. RESULTS: MSC localized around the substantia nigra and the arachnoid mater, expressing pericyte and endothelial markers. MSC protected dopamine levels and upregulated peripheral anti-inflammatory cytokines. Furthermore, adipose-derived MSC increased neurogenesis in hippocampal and subventricular regions, and boosted memory functioning. CONCLUSION: Considering that hyposmia and loss of memory function are two major nonmotor symptoms in Parkinson's disease, transplants with modulatory effects on the hippocampus and subventricular zone could provide a disease-modifying therapy.
Subject(s)
Adipose Tissue/cytology , Anti-Inflammatory Agents/metabolism , Cognition , Mesenchymal Stem Cells/cytology , Motor Activity , Neurogenesis , Parkinson Disease/physiopathology , Parkinson Disease/therapy , Amphetamine , Animals , Disease Models, Animal , Dopaminergic Neurons/pathology , Enzyme-Linked Immunosorbent Assay , Female , Hippocampus/pathology , Humans , Male , Maze Learning , Memory, Short-Term , Mesenchymal Stem Cell Transplantation , Nerve Degeneration/pathology , Parkinson Disease/pathology , Rats, Wistar , Rotation , Substantia Nigra/pathology , Time Factors , Tyrosine 3-Monooxygenase/metabolism , Young AdultABSTRACT
BACKGROUND AIMS: In Parkinson's disease (PD), neurogenesis in the subventricular zone (SVZ)-olfactory bulb (OB) axis is affected as the result of the lack of dopaminergic innervations reaching the SVZ. This aberrant network has been related to the hyposmia of PD patients, which is an early diagnostic marker of the disease. Consequently, much interest arose in finding mechanisms to modulate the SVZ-OB axis. Direct modulation of this axis could be achieved by transplantation of mesenchymal stromal cells (MSC), as it has been shown in rat and mouse PD models. However, the neurogenic effect of MSC in PD was thus far only analyzed weeks after transplantation, and little is known about effects immediately after transplantation. METHODS: We assessed the acute neuroprotective and neurogenic effects of adipose-derived MSC transplanted into the rat substantia nigra in the 6-hydroxydopamine model of PD. RESULTS: Three days after transplantation, subventricular neurogenesis was significantly increased in MSC-transplanted versus non-transplanted animals. Most MSC were found in the region of the substantia nigra and the surrounding arachnoid mater, expressing S100ß and brain-derived neurotrophic factor, whereas some MSC showed an endothelial phenotype and localized around blood vessels. CONCLUSIONS: The acute neurogenic effects and neurotrophic factor expression of MSC could help to restore the SVZ-OB axis in PD.
Subject(s)
Adipose Tissue/cytology , Lateral Ventricles/growth & development , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/cytology , Neurogenesis/physiology , Parkinson Disease/therapy , Adult , Animals , Brain-Derived Neurotrophic Factor/biosynthesis , Cell Proliferation/drug effects , Cell- and Tissue-Based Therapy , Cells, Cultured , Disease Models, Animal , Female , Humans , Lateral Ventricles/cytology , Obesity/metabolism , Olfactory Bulb/cytology , Oxidopamine/adverse effects , Rats , Rats, Wistar , S100 Calcium Binding Protein beta Subunit/biosynthesis , Substantia Nigra/cytology , Young AdultABSTRACT
Adult human adipose-derived mesenchymal stem cells (MSC) have been reported to induce neuroprotective effects in models for Parkinson's disease (PD). However, these effects strongly depend on the most optimal application of the transplant. In the present study we compared monolayer-cultured (aMSC) and spheroid (sMSC) MSC following transplantation into the substantia nigra (SN) of 6-OHDA lesioned rats regarding effects on the local microenvironment, degeneration of dopaminergic neurons, neurogenesis in the hippocampal DG as well as motor and memory function in the 6-OHDA-rat model for PD. aMSC transplantation significantly increased tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF) levels in the SN, increased the levels of the glial fibrillary acidic protein (GFAP) and improved motor functions compared to untreated and sMSC treated animals. In contrast, sMSC grafting induced an increased local microgliosis, decreased TH levels in the SN and reduced numbers of newly generated cells in the dentate gyrus (DG) without yet affecting hippocampal learning and memory function. We conclude that the neuroprotective potential of adipose-derived MSC in the rat model of PD crucially depends on the applied cellular phenotype.
Subject(s)
Cell Culture Techniques/methods , Hippocampus/physiology , Memory/physiology , Mesenchymal Stem Cells/physiology , Motor Activity/physiology , Parkinsonian Disorders/physiopathology , Adipose Tissue/cytology , Adult , Animals , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , Cell Differentiation/genetics , Cells, Cultured , Disease Models, Animal , Female , Glial Fibrillary Acidic Protein/genetics , Glial Fibrillary Acidic Protein/metabolism , Hippocampus/cytology , Humans , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Microscopy, Confocal , Neurogenesis , Neuroprotection/physiology , Oxidopamine , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/therapy , Rats, Wistar , Reverse Transcriptase Polymerase Chain Reaction , Transplantation, Heterologous , Tyrosine 3-Monooxygenase/genetics , Tyrosine 3-Monooxygenase/metabolismABSTRACT
A growing body of evidence suggests a role for soluble alpha-amyloid precursor protein (sAPPalpha) in pathomechanisms of Alzheimer disease (AD). This cleavage product of APP was identified to have neurotrophic properties. However, it remained enigmatic what proteins, targeted by sAPPalpha, might be involved in such neuroprotective actions. Here, we used high-resolution two-dimensional polyacrylamide gel electrophoresis to analyze proteome changes downstream of sAPPalpha in neurons. We present evidence that sAPPalpha regulates expression and activity of CDK5, a kinase that plays an important role in AD pathology. We also identified the cytoprotective chaperone ORP150 to be induced by sAPPalpha as part of this protective response. Finally, we present functional evidence that the sAPPalpha receptor SORLA is essential to mediate such molecular functions of sAPPalpha in neurons.
Subject(s)
Amyloid beta-Protein Precursor/pharmacology , Cyclin-Dependent Kinase 5/metabolism , Neurons/drug effects , Neurons/metabolism , Animals , Cells, Cultured , Electrophoresis, Gel, Two-Dimensional , Mass Spectrometry , Mice , Mice, Inbred BALB CABSTRACT
Mesenchymal stem cells (MSC) from bone marrow induce neuroprotective effects and improve clinical symptoms in animal models for acute cerebral ischemia. So far only few data are available from the murine system. Moreover, no data exist regarding neuroprotective effects depending on the application route. Because most preclinical trials regarding restorative therapy in stroke are performed in mice, we aimed to investigate the neuroprotective capacities of human MSC (hMSC) in the middle cerebral artery occlusion (MCAo)-mouse model of cerebral ischemia. As systemic transplantation of MSC could provide a gentle therapeutic procedure for the (mostly elderly) stroke patients, we analyzed effects of this application at a clinically relevant time point. Bone marrow-derived hMSCs were administered intravenously 24 h after MCAo. Mortality and clinical outcome of the transplanted mice did not differ from PBS-treated controls. After 3 and 7 days hMSC were robustly detected in lung, spleen, kidney and intestine, but not in the brain. MRI measurements revealed no differences in infarct size in hMSC injected animals compared to controls. In the neurogenic subventricular zone and the dentate gyrus no significant increase of endogenous cell proliferation was detected following systemic hMSC transplantation. This data further prove the week neurogenic and neuroprotective effect and the limitations of systemically administered hMSCs in cerebral ischemia.
