Mesenchymal stem cells from rats with chronic kidney disease exhibit premature senescence and loss of regenerative potential

PLoS One. 2014 Mar 25;9(3):e92115. doi: 10.1371/journal.pone.0092115. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cells, Cultured
  • Cellular Senescence / physiology*
  • Culture Media, Conditioned / pharmacology
  • Cytokines / genetics
  • Cytokines / metabolism
  • Disease Models, Animal
  • Fibroblasts / cytology
  • Humans
  • Immunoenzyme Techniques
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Kidney Glomerulus / pathology*
  • Male
  • Mesenchymal Stem Cell Transplantation
  • Mesenchymal Stem Cells / cytology*
  • Nephritis / immunology
  • Nephritis / pathology*
  • Nephritis / therapy
  • RNA, Messenger / genetics
  • Rats
  • Rats, Inbred F344
  • Real-Time Polymerase Chain Reaction
  • Regeneration / physiology*
  • Renal Insufficiency, Chronic / pathology*
  • Renal Insufficiency, Chronic / therapy
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thy-1 Antigens / immunology
  • Tissue Donors

Substances

  • Culture Media, Conditioned
  • Cytokines
  • Intercellular Signaling Peptides and Proteins
  • RNA, Messenger
  • Thy-1 Antigens

Grant support

European Community's Seventh Framework Programme [FP7/2007–2013] under grant agreement n° HEALTH-F5-2008-223007 STAR-TREK; German Research Foundation (Deutsche Forschungsgemeinschaft, SFB TRR57 P19 and RO4036/1); Medical Faculty of the RWTH Aachen (START grant). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.