Lamin a deregulation in human mesenchymal stem cells promotes an impairment in their chondrogenic potential and imbalance in their response to oxidative stress

In the present study, we examined the effect of the over-expression of LMNA, or its mutant form progerin (PG), on the mesoderm differentiation potential of mesenchymal stem cells (MSCs) from human umbilical cord (UC) stroma using a recently described differentiation model employing spheroid formation. Accumulation of lamin A (LMNA) was previously associated with the osteoarthritis (OA) chondrocyte phenotype. Mutations of this protein are linked to laminopathies and specifically to Hutchinson–Gilford Progeria Syndrome (HGPS), an accelerated aging disease. Some authors have proposed that a deregulation of LMNA affects the differentiation potential of stem cells. The chondrogenic potential is defective in PG-MSCs, although both PG and LMNA transduced MSCs, have an increase in hypertrophy markers during chondrogenic differentiation. Furthermore, both PG and LMNA-MSCs showed a decrease in manganese superoxide dismutase (MnSODM), an increase of mitochondrial MnSODMdependent reactive oxygen species (ROS) and alterations in their migration capacity. Finally, defects in chondrogenesis are partially reversed by periodic incubation with ROS-scavenger agent that mimics MnSODM effect. Our results indicate that over-expression of LMNA or PG by lentiviral gene delivery leads to defects in chondrogenic differentiation potential partially due to an imbalance in oxidative stress. Abbreviations MSCs, mesenchymal stem cells; LMNA, lamin A; PG, progerin; UC, umbilical cord; HGPS, Hutchinson–Gilford Progeria Syndrome; OA, osteoarthritis; ROS, reactive oxygen species; MnSODM, manganese superoxide dismutase; ECM, extracellular matrix; DMEM, Dulbecco's Modified Eagles Medium; GFP, green fluorescent protein; RT-PCR, real-time polymerase chain reaction; LPL, lipoprotein lipase; FABP, fatty acid binding protein; ADIPOQ, adiponectin; ALP, alkaline phosphatase; OC, osteocalcin; AGG, aggrecan; RPLP, Ribosomal Protein Large P1; SDF1, stromal cell-derived factor 1; IL-8, interleukin 8