title: 1,25-dihydroxyvitamin D3 treatment delays cellular aging in human mesenchymal stem cells while maintaining their multipotent capacity.
abstract: 1,25-dihydroxyvitamin D3 (1,25D3) was reported to induce premature organismal aging in fibroblast growth factor-23 (Fgf23) and klotho deficient mice, which is of main interest as 1,25D3 supplementation of its precursor cholecalciferol is used in basic osteoporosis treatment. We wanted to know if 1,25D3 is able to modulate aging processes on a cellular level in human mesenchymal stem cells (hMSC). Effects of 100 nM 1,25D3 on hMSC were analyzed by cell proliferation and apoptosis assay, β-galactosidase staining, VDR and surface marker immunocytochemistry, RT-PCR of 1,25D3-responsive, quiescence- and replicative senescence-associated genes. 1,25D3 treatment significantly inhibited hMSC proliferation and apoptosis after 72 h and delayed the development of replicative senescence in long-term cultures according to β-galactosidase staining and P16 expression. Cell morphology changed from a fibroblast like appearance to broad and rounded shapes. Long term treatment did not induce lineage commitment in terms of osteogenic pathways but maintained their clonogenic capacity, their surface marker characteristics (expression of CD73, CD90, CD105) and their multipotency to develop towards the chondrogenic, adipogenic and osteogenic pathways. In conclusion, 1,25D3 delays replicative senescence in primary hMSC while the pro-aging effects seen in mouse models might mainly be due to elevated systemic phosphate levels, which propagate organismal aging.
authors.affiliation: Orthopedic Center for Musculoskeletal Research, University of Würzburg, Würzburg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Klotz
authors.forename: Birgit
authors.initials: B
authors.lastname: Mentrup
authors.forename: Martina
authors.initials: M
authors.lastname: Regensburger
authors.forename: Sabine
authors.initials: S
authors.lastname: Zeck
authors.forename: Jutta
authors.initials: J
authors.lastname: Schneidereit
authors.forename: Nicole
authors.initials: N
authors.lastname: Schupp
authors.forename: Christian
authors.initials: C
authors.lastname: Linden
authors.forename: Cornelia
authors.initials: C
authors.lastname: Merz
authors.forename: Regina
authors.initials: R
authors.lastname: Ebert
authors.forename: Franz
authors.initials: F
authors.lastname: Jakob
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002461:Cell Line, Transformed; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D003114:Colony-Forming Units Assay; D000089703:Fibroblast Growth Factor-23; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism; D013997:Time Factors; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D015415:Biomarkers; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D017382:Reactive Oxygen Species; D018167:Receptors, Calcitriol; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D000089703:Fibroblast Growth Factor-23; D001616:beta-Galactosidase