Y Naaldijk1,2, C Jäger3, C Fabian1,2, C Leovsky1, A Blüher1, L Rudolph1, A Hinze1, A Stolzing1,2,4. 1. Fraunhofer Institute for Cell Therapy and Immunology (IZI), Leipzig, Germany. 2. Translational Centre for Regenerative Medicine (TRM), University of Leipzig, Leipzig, Germany. 3. Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany. 4. Loughborough University, Loughborough, UK.
Abstract
AIMS: Mesenchymal stem cells (MSC) have recently attracted interest as a potential basis for a cell-based therapy of AD. We investigated the putative immune-modulatory effects in neuroinflammation of systemic transplantation of MSC into APP/PS1 transgenic mice. METHODS: 106 MSC were injected into APP/PS1 mice via the tail vein and histological analysis was performed for microglia and amyloid (pE3-Aβ) plaque numbers, glial distribution and pE3-Aβ plaque size. In addition, a biochemical analysis by qPCR for pro-inflammatory, chemoattractant and neurotrophic factors was performed. RESULTS: MSC are associated with pE3-Aβ plaques. The effects of transplantation on microglia-associated pathology could be observed after 28 days. Animals showed a reduction in microglial numbers in the cortex and in microglia size. Gene expression was reduced for TNF-α, IL-6, MCP-1, and for NGF, in MSC recipients. Also, we investigated for the first time and found no changes in expression of IL-10, CCR5, BDNF, VEGF and IFNγ. PTGER2 expression levels were increased in the hippocampus but were reduced in the cortex of MSC recipients. While there were no transplant-related changes in pE3-Aβ plaque numbers, a reduction in the size of pE3-Aβ plaques was observed in the hippocampus of transplant recipients. CONCLUSION: This is the first study to show reduction in pE3-Aβ plaque size. pE3-Aβ plaques have gained attention as potential key participants in AD due to their increased aggregation propensity, the possibility for the initial seeding event, resistance against degradation and neurotoxicity. These findings support the hypothesis that MSC-transplants may affect AD pathology via an immune-modulatory function that includes an effect on microglial cells.
AIMS: Mesenchymal stem cells (MSC) have recently attracted interest as a potential basis for a cell-based therapy of AD. We investigated the putative immune-modulatory effects in neuroinflammation of systemic transplantation of MSC into APP/PS1transgenic mice. METHODS: 106 MSC were injected into APP/PS1mice via the tail vein and histological analysis was performed for microglia and amyloid (pE3-Aβ) plaque numbers, glial distribution and pE3-Aβ plaque size. In addition, a biochemical analysis by qPCR for pro-inflammatory, chemoattractant and neurotrophic factors was performed. RESULTS: MSC are associated with pE3-Aβ plaques. The effects of transplantation on microglia-associated pathology could be observed after 28 days. Animals showed a reduction in microglial numbers in the cortex and in microglia size. Gene expression was reduced for TNF-α, IL-6, MCP-1, and for NGF, in MSC recipients. Also, we investigated for the first time and found no changes in expression of IL-10, CCR5, BDNF, VEGF and IFNγ. PTGER2 expression levels were increased in the hippocampus but were reduced in the cortex of MSC recipients. While there were no transplant-related changes in pE3-Aβ plaque numbers, a reduction in the size of pE3-Aβ plaques was observed in the hippocampus of transplant recipients. CONCLUSION: This is the first study to show reduction in pE3-Aβ plaque size. pE3-Aβ plaques have gained attention as potential key participants in AD due to their increased aggregation propensity, the possibility for the initial seeding event, resistance against degradation and neurotoxicity. These findings support the hypothesis that MSC-transplants may affect AD pathology via an immune-modulatory function that includes an effect on microglial cells.
Authors: Mariana A de Godoy; Leonardo M Saraiva; Luiza R P de Carvalho; Andreia Vasconcelos-Dos-Santos; Hellen J V Beiral; Alane Bernardo Ramos; Livian R de Paula Silva; Renata B Leal; Victor H S Monteiro; Carolina V Braga; Carlla A de Araujo-Silva; Leandro C Sinis; Victor Bodart-Santos; Tais Hanae Kasai-Brunswick; Carolina de Lima Alcantara; Ana Paula C A Lima; Narcisa L da Cunha-E Silva; Antonio Galina; Adalberto Vieyra; Fernanda G De Felice; Rosalia Mendez-Otero; Sergio T Ferreira Journal: J Biol Chem Date: 2017-12-28 Impact factor: 5.157