Abstract
BackgroundObesity impairs a variety of cell types including adipose-derived mesenchymal stem cells (ASCs). ASCs are indispensable for tissue homeostasis/repair, immunomodulation, and cell renewal. It has been demonstrated that obese ASCs are defective in differentiation, motility, immunomodulation, and replication. We have recently reported that some of these defects are linked to impaired primary cilia, which are unable to properly convey and coordinate a variety of signaling pathways. We hypothesized that the rescue of the primary cilium in obese ASCs would restore their functional properties.MethodsObese ASCs derived from subcutaneous and visceral adipose tissues were treated with a specific inhibitor against Aurora A or with an inhibitor against extracellular signal-regulated kinase 1/2 (Erk1/2). Multiple molecular and cellular assays were performed to analyze the altered functionalities and their involved pathways.ResultsThe treatment with low doses of these inhibitors extended the length of the primary cilium, restored the invasion and migration potential, and improved the differentiation capacity of obese ASCs. Associated with enhanced differentiation ability, the cells displayed an increased expression of self-renewal/stemness-related genes like SOX2, OCT4, and NANOG, mediated by reduced active glycogen synthase kinase 3 β (GSK3β).ConclusionThis work describes a novel phenomenon whereby the primary cilium of obese ASCs is rescuable by the low-dose inhibition of Aurora A or Erk1/2, restoring functional ASCs with increased stemness. These cells might be able to improve tissue homeostasis in obese patients and thereby ameliorate obesity-associated diseases. Additionally, these functionally restored obese ASCs could be useful for novel autologous mesenchymal stem cell-based therapies.
Highlights
Obesity impairs a variety of cell types including adipose-derived mesenchymal stem cells (ASCs)
In the present work we show that the treatment with low dose of the inhibitor MLN8054 (MLN) against the Aurora A kinase or PD98059 (PD) against extracellular signal-regulated kinase 1/2 (Erk1/2) rescues the length and functionality of primary cilia of obese ASCs, accompanied by increased levels of the genes related to self-renewal/stemness
Low dose of Aurora A or Erk1/2 inhibitor restores the cilium length in obese ASCs Ciliogenesis is tightly associated with the cell cycle [13] and the assembly as well as the disassembly of the primary cilium depend on a variety of kinases like Aurora A and Polo-like kinase 1 (Plk1) [16]
Summary
Obesity impairs a variety of cell types including adipose-derived mesenchymal stem cells (ASCs). Obesity is one of the most serious and fastest-growing health problem in the world [1] It significantly increases the risk for the development of multiple disorders including cardiovascular diseases and various cancer entities [2,3,4,5]. Defective ASCs might contribute to the development of obesity and its related diseases by interfering with adipose tissue remodeling, fueling the pro-inflammatory milieu, and deteriorating hypoxia [3, 12]. Primary cilia are microtubule-based organelles protruding from the surface of almost all vertebrate cells They conduct a multitude of different signals from the extracellular environment via diverse receptors regulating the cell cycle, cell growth, development, and cellular homeostasis [13, 14], turning them into central platforms for cell-cell interaction and signaling [15]. The primary cilium transduces Hedgehog (Hh) signaling [15] and is involved in maintaining self-renewal and differentiation of ASCs [9, 17, 18]
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