title: Mesenchymal stem cells from rats with chronic kidney disease exhibit premature senescence and loss of regenerative potential.
abstract: Mesenchymal stem cell (MSC) transplantation has the potential for organ repair. Nevertheless, some factors might lessen the regenerative potential of MSCs, e.g. donor age or systemic disease. It is thus important to carefully assess the patient's suitability for autologous MSC transplantation. Here we investigated the effects of chronic kidney disease (CKD) on MSC function. We isolated bone marrow MSCs from remnant kidney rats (RK) with CKD (CKD-RK-MSC) and found signs of premature senescence: spontaneous adipogenesis, reduced proliferation capacity, active senescence-associated-β-galactosidase, accumulation of actin and a modulated secretion profile. The functionality of CKD-RK-MSCs in vivo was tested in rats with acute anti-Thy1.1-nephritis, where healthy MSCs have been shown to be beneficial. Rats received healthy MSCs, CKD-RK-MSC or medium by injection into the left renal artery. Kidneys receiving healthy MSCs exhibited accelerated healing of glomerular lesions, whereas CKD-RK-MSC or medium exerted no benefit. The negative influence of advanced CKD/uremia on MSCs was confirmed in a second model of CKD, adenine nephropathy (AD). MSCs from rats with adenine nephropathy (CKD-AD-MSC) also exhibited cellular modifications and functional deficits in vivo. We conclude that CKD leads to a sustained loss of in vitro and in vivo functionality in MSCs, possibly due to premature cellular senescence. Considering autologous MSC therapy in human renal disease, studies identifying uremia-associated mechanisms that account for altered MSC function are urgently needed.
authors.affiliation: Division of Nephrology and Immunology, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Barbara Mara
authors.initials: BM
authors.lastname: Klinkhammer
authors.affiliation: Division of Nephrology and Immunology, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Rafael
authors.initials: R
authors.lastname: Kramann
authors.affiliation: Division of Nephrology and Immunology, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Mallau
authors.affiliation: Division of Nephrology and Immunology, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Makowska
authors.affiliation: Division of Nephrology and Immunology, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Claudia Renate
authors.initials: CR
authors.lastname: van Roeyen
authors.affiliation: Division of Nephrology and Immunology, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Song
authors.initials: S
authors.lastname: Rong
authors.affiliation: Division of Nephrology and Immunology, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Eva Bettina
authors.initials: EB
authors.lastname: Buecher
authors.affiliation: Division of Nephrology and Immunology, RWTH Aachen University Hospital, Aachen, Germany; Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany; Institute of Molecular Biomedicine, Comenius University, Bratislava, Slovakia.
authors.forename: Peter
authors.initials: P
authors.lastname: Boor
authors.affiliation: Division of Nephrology and Immunology, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Katarina
authors.initials: K
authors.lastname: Kovacova
authors.affiliation: Division of Nephrology and Immunology, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Zok
authors.affiliation: Interdisciplinary Centre for Clinical Research, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Denecke
authors.affiliation: Division of Nephrology and Immunology, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Stuettgen
authors.affiliation: Division of Nephrology and Immunology, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Otten
authors.affiliation: Division of Nephrology and Immunology, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Juergen
authors.initials: J
authors.lastname: Floege
authors.affiliation: Division of Nephrology and Immunology, RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Kunter
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D007124:Immunoenzyme Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007678:Kidney Glomerulus / Q000473:pathology*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D009393:Nephritis / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D012038:Regeneration / Q000502:physiology*; D051436:Renal Insufficiency, Chronic / Q000473:pathology* / Q000628:therapy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018800:Thy-1 Antigens / Q000276:immunology; D014019:Tissue Donors
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D018800:Thy-1 Antigens