期刊
STEM CELLS TRANSLATIONAL MEDICINE
卷 1, 期 4, 页码 309-321出版社
ALPHAMED PRESS
DOI: 10.5966/sctm.2011-0010
关键词
Mesenchymal stem cells; Adipogenesis; Experimental models; Transcription factor; Differentiation
资金
- European Union
- Marie Curie International Reintegration Grant [MIRG-CT-2006-044914]
- Fondo de Investigacion Sanitaria (Instituto de Salud Carlos III, Madrid, Spain) [PI06-1335]
- Department of Industry, Tourism and Trade of the Government of the Autonomous Community of the Basque Country (Etortek Research Programs)
- Innovation Technology Department of Bizkaia County
- FPI Grant from the Basque Department of Education, Universities and Research [BFI09-135]
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. STEM CELLS TRANSLATIONAL MEDICINE 2012;1:309-321
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