Restoration of primary cilia in obese adipose-derived mesenchymal stem cells by inhibiting Aurora A or extracellular signal-regulated kinase

Abstract

Background Obesity 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. Methods Obese 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. Results The 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). Conclusion This 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. Electronic supplementary material The online version of this article (10.1186/s13287-019-1373-z) contains supplementary material, which is available to authorized users.

Obesity and COVID-19: Molecular Mechanisms Linking Both Pandemics

“…Moreover, as we reported, obesity impairs the ASC primary cilium, a unique signaling organelle on the cell surface, further contributing to their dysfunction in obese patients [66]. Interestingly, obesity-associated cytokines like IL-6 and TNF-α are able to influence many signaling pathways and induce defects in the ciliogenesis of ASCs [66,77,85]. Ciliary defective ASCs are not able to fulfill their physiological functions.…”

Potential Roles of O-GlcNAcylation in Primary Cilia- Mediated Energy Metabolism

“…The proposal is supported by observations of dampened adipocyte differentiating rates and shortened primary cilia length of adipose-derived mesenchymal stem cells (ASCs) in obese individuals. Restoration of primary cilia in obese ASCs improves their differentiation capacity [36,116]. Because O-GlcNAc is a negative regulator of primary cilia, elevated cellular OGN levels may cause defects in primary cilia and adipocyte differentiation in obese individuals.…”

<p>Identification of Aurora Kinase A as a Biomarker for Prognosis in Obesity Patients with Early Breast Cancer</p>

“…Although Aurora A has been intensively studied in series of human malignancies as a carcinogenic factor, [21][22][23] the impact of Aurora A on the malignant behavior among obesity breast cancer remains elusive. Consistent with previous studies, 16 our study also indicated a poor prognosis biomarker in breast cancer and its expression was correlated to high malignant aggressiveness.…”

“…Previous studies highlighted that high Aurora A expression was strongly associated with worse survival of breast cancer and as an independent prognostic marker. 16,21 In particular, among TNBC patients with high level of Aurora A expression, the peak time of distant recurrence risk was at the first 3 years and declined rapidly thereafter, whereas patients with low Aurora A expression showed a relatively constant risk of recurrence during the entire follow-up period, 16 it indicated that TNBC with high Aurora A expression may be the basal-like intrinsic subtype by PAM50 analysis and TNBC with low Aurora A expression was luminal subtype. The underlying mechanism of Aurora A in triple-negative breast cancer requires further investigation.…”