Aging, a time-dependent functional decline of biological processes, is the primary risk factor in developing diseases such as cancer, cardiovascular or degenerative diseases. There is a real need to understand the human aging process in order to increase the length of disease-free life, also known as “health span”. Accumulation of progerin and prelamin A are the hallmark of a group of premature aging diseases but have also been found during normal cellular aging strongly suggesting similar mechanisms between healthy aging and LMNA-linked progeroid syndromes. How this toxic accumulation contributes to aging (physiological or pathological) remains unclear. Since affected tissues in age-associated disorders and in pathological aging are mainly of mesenchymal origin we propose a model of human aging based on mesenchymal stem cells (hMSCs) which accumulate prelamin A. We demonstrate that prelamin A-accumulating hMSCs have a premature aging phenotype which affects their functional competence in vivo. The combination of prelamin A accumulation and stress conditions enhance the aging phenotype by dysregulating the activity of the octamer binding protein Oct-1This experimental model has been fundamental to identify a new role for Oct-1 in hMSCs aging.
Lamin A (LMNA)‐linked lipodystrophies may be either genetic (associated with LMNA mutations) or acquired (associated with the use of human immunodeficiency virus protease inhibitors [PIs]), and in both cases they share clinical features such as anomalous distribution of body fat or generalized loss of adipose tissue, metabolic alterations, and early cardiovascular complications. Both LMNA‐linked lipodystrophies are characterized by the accumulation of the lamin A precursor prelamin A. The pathological mechanism by which prelamin A accumulation induces the lipodystrophy associated phenotypes remains unclear. Since the affected tissues in these disorders are of mesenchymal origin, we have generated an LMNA‐linked experimental model using human mesenchymal stem cells treated with a PI, which recapitulates the phenotypes observed in patient biopsies. This model has been demonstrated to be a useful tool to unravel the pathological mechanism of the LMNA‐linked lipodystrophies, providing an ideal system to identify potential targets to generate new therapies for drug discovery screening. We report for the first time that impaired adipogenesis is a consequence of the interaction between accumulated prelamin A and Sp1 transcription factor, sequestration of which results in altered extracellular matrix gene expression. In fact, our study shows a novel, essential, and finely tuned role for Sp1 in adipose lineage differentiation in human mesenchymal stem cells. These findings define a new physiological experimental model to elucidate the pathological mechanisms LMNA‐linked lipodystrophies, creating new opportunities for research and treatment not only of LMNA‐linked lipodystrophies but also of other adipogenesis‐associated metabolic diseases.
The study was conducted to evaluate the cytocompatibility and hydrolytic degradability of the new poly(lactic acid)/polyethylene glycol-polyhedral oligomeric silsesquioxane (peg-POSS/PLLA) nanocomposite as potential material for cartilage regeneration. PLLA scaffolds containing 0 to 5% of peg-POSS were fabricated by electrospinning. Human mesenchymal stem cells (hMSC's) were cultured in vitro to evaluate the cytocompatibility of the new nanocomposite material. Hydrolytic degradation studies were also carried out to analyze the mass loss rate of the nanocomposites through time. The addition of the peg-POSS to the PLLA did not affect the processability of the nanocomposite by electrospinning. It was also observed that peg-POSS did not show any relevant change in fibers morphology, concluding that it was well dispersed. However, addition of peg-POSS caused noticeable decrease in mean fiber diameter, which made the specific surface area of the scaffold to rise. hMSC's were able to attach, to proliferate, and to differentiate into chondrocytes in a similar way onto the different types of electrospun peg-POSS/PLLA and pure PLLA scaffolds, showing that the peg-POSS as nano-additive does not exhibit any cytotoxicity. The hydrolytic degradation rate of the material was lower when peg-POSS was added, showing a higher durability of the nanocomposites through time. Results demonstrate that the addition of peg-POSS to the PLLA scaffolds does not affect its cytocompatibility to obtain hyaline cartilage from hMSC's.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.