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Stress as an instructive determinant of mesenchymal stem cell fate
Abstracts
Association between plasma homocysteine levels and signs of axonal injury in untreated HIV Erika Ahlgrena, Lars Hagberga, Henrik Zetterbergb, Magnus Gissléna a Institute of Biomedicine, Department of Infectious Diseases, University of Gothenburg, Gothenburg, Sweden b Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden Background: Many HIV infected patients without antiretroviral treatment suffer from neurological symptoms in a varying range of severity. Most patients with and several without neurological symptoms have elevated levels of neurofilament protein light (NFL) in CSF, as a marker of ongoing axonal injury. Hyperhomocysteinemia is associated with diseases of neurological impairment. The metabolism of homocysteine is related to levels of B12-vitamin and folic acid. Patients with hyperhomocysteinemia suffering from mild cognitive impairment, who were treated with B-vitamins showed a significant reduction of the rate of brain atrophy in parts of the brain related to Alzheimer’s disease. Our aim was to investigate the correlation between homocysteine levels and axonal injury in HIV infected patients. Methods: Homocysteine and B12-vitamin levels were analyzed in plasma with stable isotope dilution liquid chromatography tandem mass spectrometry (LC–MS/MS), and electrochemiluminescence immunoassay respectively, from 80 neurological asymptomatic HIV-infected patients without antiretroviral treatment. Those results were compared to CSF levels of NFL analyzed with ELISA. Results: We found a significant correlation between the plasma level of homocysteine and CSF level of NFL in untreated patients, r = 0.52, p b 0.0001. 20 patients had hyperhomocysteinemia (N15 μmol/L) and 20 had elevated levels of CSF NFL (age dependent). There were also a significant inverse correlation between homocysteine and B12 levels (r = −0.41. p b 0.001) but no significant correlation between B12 and CSF NFL. Conclusions: A significant correlation was found between plasma homocysteine and CSF NFL levels in neurologically asymptomatic HIV-infected subjects without antiretroviral treatment. These data call for further research into the role of homocysteine or functional vitamin B12 deficiency in CNS injury in HIV-infected patients. doi:10.1016/j.exger.2015.01.039
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Stress as an instructive determinant of mesenchymal stem cell fate S. Klepsch, S. Reitinger, G. Lepperdinger Stem Cell Aging Research Group, Institute for Biomedical Aging Research, Leopold-Franzens University, Innsbruck, Austria Stem cells are vitally involved in tissue regeneration and homeostasis in later life. Mesenchymal stem cells (MSC) are one particular type of tissue specific adult stem cells that can differentiate into mesoderm-type cells, such as osteoblasts, chondrocytes and adipocytes. The progressive loss of differentiation capacity during aging is well acknowledged and is known to cause attenuated regeneration. Various biological stresses are well acknowledged to be drivers of the ageing process. MSC's ageassociated altered capabilities, regarding both intrinsic as well as extrinsic parameters in particular appropriately handling and responding to biological stressors is poorly understood. A common stress response in most eukaryotic cells is to inhibit translation initiation leading to the formation of cytoplasmic RNA-protein complexes referred to as stress granules. Stress granules (SG) contain non-translating mRNAs, translation initiation components, and many additional proteins affecting mRNA function. Stress granules are believed to serve as a decision point for untranslated mRNAs to become stored, degraded or rerouted for translational re-initiation. We have first investigated how 4methylumbelliferrone (4-MU), a known inhibitor of the extracellular polysaccharide hyaluronan, impinges on the stemness of MSC. We observed that 4-MU specifically triggers SG formation. Notably, 4-MU induced SG contained distinct mRNA species and thus inferring that through this mechanism stemness and differentiation, especially along the osteogenic lineage are being specified. We could further show that 4MU treatment of MSC mesenspheres leads to 3D assemble, closely resembling the in vivo situation of trabecular bone marrow. doi:10.1016/j.exger.2015.01.040
Association between plasma homocysteine levels and signs of axonal injury in untreated HIV Erika Ahlgrena, Lars Hagberga, Henrik Zetterbergb, Magnus Gissléna a Institute of Biomedicine, Department of Infectious Diseases, University of Gothenburg, Gothenburg, Sweden b Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden Background: Many HIV infected patients without antiretroviral treatment suffer from neurological symptoms in a varying range of severity. Most patients with and several without neurological symptoms have elevated levels of neurofilament protein light (NFL) in CSF, as a marker of ongoing axonal injury. Hyperhomocysteinemia is associated with diseases of neurological impairment. The metabolism of homocysteine is related to levels of B12-vitamin and folic acid. Patients with hyperhomocysteinemia suffering from mild cognitive impairment, who were treated with B-vitamins showed a significant reduction of the rate of brain atrophy in parts of the brain related to Alzheimer’s disease. Our aim was to investigate the correlation between homocysteine levels and axonal injury in HIV infected patients. Methods: Homocysteine and B12-vitamin levels were analyzed in plasma with stable isotope dilution liquid chromatography tandem mass spectrometry (LC–MS/MS), and electrochemiluminescence immunoassay respectively, from 80 neurological asymptomatic HIV-infected patients without antiretroviral treatment. Those results were compared to CSF levels of NFL analyzed with ELISA. Results: We found a significant correlation between the plasma level of homocysteine and CSF level of NFL in untreated patients, r = 0.52, p b 0.0001. 20 patients had hyperhomocysteinemia (N15 μmol/L) and 20 had elevated levels of CSF NFL (age dependent). There were also a significant inverse correlation between homocysteine and B12 levels (r = −0.41. p b 0.001) but no significant correlation between B12 and CSF NFL. Conclusions: A significant correlation was found between plasma homocysteine and CSF NFL levels in neurologically asymptomatic HIV-infected subjects without antiretroviral treatment. These data call for further research into the role of homocysteine or functional vitamin B12 deficiency in CNS injury in HIV-infected patients. doi:10.1016/j.exger.2015.01.039
105
Stress as an instructive determinant of mesenchymal stem cell fate S. Klepsch, S. Reitinger, G. Lepperdinger Stem Cell Aging Research Group, Institute for Biomedical Aging Research, Leopold-Franzens University, Innsbruck, Austria Stem cells are vitally involved in tissue regeneration and homeostasis in later life. Mesenchymal stem cells (MSC) are one particular type of tissue specific adult stem cells that can differentiate into mesoderm-type cells, such as osteoblasts, chondrocytes and adipocytes. The progressive loss of differentiation capacity during aging is well acknowledged and is known to cause attenuated regeneration. Various biological stresses are well acknowledged to be drivers of the ageing process. MSC's ageassociated altered capabilities, regarding both intrinsic as well as extrinsic parameters in particular appropriately handling and responding to biological stressors is poorly understood. A common stress response in most eukaryotic cells is to inhibit translation initiation leading to the formation of cytoplasmic RNA-protein complexes referred to as stress granules. Stress granules (SG) contain non-translating mRNAs, translation initiation components, and many additional proteins affecting mRNA function. Stress granules are believed to serve as a decision point for untranslated mRNAs to become stored, degraded or rerouted for translational re-initiation. We have first investigated how 4methylumbelliferrone (4-MU), a known inhibitor of the extracellular polysaccharide hyaluronan, impinges on the stemness of MSC. We observed that 4-MU specifically triggers SG formation. Notably, 4-MU induced SG contained distinct mRNA species and thus inferring that through this mechanism stemness and differentiation, especially along the osteogenic lineage are being specified. We could further show that 4MU treatment of MSC mesenspheres leads to 3D assemble, closely resembling the in vivo situation of trabecular bone marrow. doi:10.1016/j.exger.2015.01.040