<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Aging of human bone marrow – functional and\r\nepigenetic changes in senescent mesenchymal\r\nstromal cells"^^ . "Aging is a complex process that is associated with changes in many parts of the body\r\nover the lifespan of an individual. In this work, various aspects of aging in the human\r\nbone marrow were investigated.\r\nAs the regenerative power of a tissue is linked to the potential of its stem cells to\r\nreplace the accumulated damages, the aging process in somatic stem cells was\r\nstudied focusing on the influence of the niche in regulating stem cell aging. The\r\nhematopoietic stem cells (HSC) together with elements that constitute the bone\r\nmarrow niche were investigated as a model for somatic stem cell aging as HSCs are\r\naccessible in healthy human individuals. The subjects ranged from 20 to 60 years\r\nwith a median age of 33.2 years.\r\nFrom each bone marrow sample, the CD34+ population as HSCs and four other cell\r\nsubpopulations, lymphocytes and precursors (LYM), monocytes/macrophages\r\nprecursors (MON), granulocytic (GRA), and erythroid precursors (ERP) were isolated\r\nby flow cytometry. The mesenchymal stromal cells (MSC) were isolated by in vitro\r\nculture. We found that the relative proportions, cell size as well as cell granularity of\r\nthe major bone marrow constituents did not correlate with the biological age of the\r\ndonors. However, further downstream analysis indicated that age-associated\r\nchanges were prominent on protein level in HSCs as well as in other cell types of the\r\nniche such as MSCs.\r\nThe interactions between the HSCs and the niche were studied in vitro using a coculture\r\nsystem of CD34+ cells and mesenchymal stromal cells (MSC). As previous\r\nstudies indicated that the supportive function of MSCs as well as their differentiation\r\npotentials towards adipocytes and osteocytes change significantly with age, we have\r\nexamined the supportive ability of the undifferentiated MSCs versus adipogenically\r\ndifferentiated MSCs (ADI-MSCs) and osteogenically differentiated MSCs (OST-MSCs)\r\nfor HSCs. We showed that MSCs, ADI-MSCs and OST-MSCs were able to support\r\nthe proliferation of HSCs and maintain their primitive immunephenotype. Compared\r\nto undifferentiated MSCs and OST-MSCs, the co-culture with ADI-MSCs increased\r\nthe proliferation of HSCs much stronger while still maintaining the HSCs at a high\r\nexpression level of CD34.\r\nAs the impact of the MSCs on HSCs might be caused by epigenetic changes, the\r\naging-associated alterations in the marrow niche were studied at the chromatin level.\r\nTo this end, changes in chromatin accessibility were studied in MSCs by ATAC-seq.\r\nAfter establishing the protocol for performing ATAC-seq using primary MSCs, we\r\nstudied the MSC samples derived from 16 healthy human subjects of different ages\r\nbetween 21 and 59 years. A set of 122,884 ATAC-seq peaks was identified. We have\r\ndemonstrated that donor age is associated with alterations in open chromatin profiles.\r\nMoreover, at a false discovery rate of 5%, we could identify 4,579 differential\r\nchromatin accessible sites upon aging. A functional analysis of these sites showed\r\nenrichment of cell development and differentiation processes. Additionally, genes of\r\nthe hippo signaling pathway, TGF-beta signaling pathway, cancer pathways and cell\r\nadhesion pathways were also found to be enriched. A motif enrichment analysis\r\nsuggested that TATA box motifs and binding sites for transcription factors TFAP2C,\r\nKLF16, HIC1.p2, WT1 and MTF.p2 were enriched in promoter regions of differential\r\nchromatin accessible sites upon aging.\r\nIn conclusion, this study showed that the interplay with the stem cell niche controls\r\nHSC functions. The differentiation of MSCs affects the proliferation and stemness of\r\nHSCs in vitro. Furthermore, we have demonstrated that aging is associated with\r\nchromatin accessibility alterations in MSCs, which provides a foundation for further\r\nin-depth mechanistic analyses."^^ . "2018" . . . . . . . "Ximing"^^ . "Ding"^^ . "Ximing Ding"^^ . . . . . . "Aging of human bone marrow – functional and\r\nepigenetic changes in senescent mesenchymal\r\nstromal cells (PDF)"^^ . . . "thesis_ding.pdf"^^ . . . "Aging of human bone marrow – functional and\r\nepigenetic changes in senescent mesenchymal\r\nstromal cells (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Aging of human bone marrow – functional and\r\nepigenetic changes in senescent mesenchymal\r\nstromal cells (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Aging of human bone marrow – functional and\r\nepigenetic changes in senescent mesenchymal\r\nstromal cells (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Aging of human bone marrow – functional and\r\nepigenetic changes in senescent mesenchymal\r\nstromal cells (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Aging of human bone marrow – functional and\r\nepigenetic changes in senescent mesenchymal\r\nstromal cells (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #23963 \n\nAging of human bone marrow – functional and \nepigenetic changes in senescent mesenchymal \nstromal cells\n\n" . "text/html" . . . "500 Naturwissenschaften und Mathematik"@de . "500 Natural sciences and mathematics"@en . .