Exploring the molecular mechanisms underlying defective primary cilia in obese-derived mesenchymal stem cells and its significance in obesity
Cell Biology
Final Report Abstract
Obesity, an imbalance of food uptake and energy consumption, is a predominant health problem worldwide. It associates with various diseases, including type 2 diabetes, cardiovascular diseases and cancer. Obesity alters the composition, structure and function of adipose tissue. Adipose tissue-derived mesenchymal stem/stromal cells (ASCs) are fundamental in the surveillance of adipose tissue homeostasis. We have reported that obesity negatively affects the features and functions of ASCs, in particular, ciliary biogenesis. However, underlying molecular mechanisms are not well understood. To further study how obesity educates ASCs, we have performed multiple molecular and cellular analyses, including transcriptomic gene analysis, real-time PCR, Western blotting, indirect immunofluorescence staining, spheroid formation and differentiation assay with ASCs isolated from obese- and normal donors. We show that obesity leads to transcriptional reprogramming of ASCs, with altered genes related to the extracellular matrix (ECM), the transforming growth factor β (TGFβ) pathway, and myofibroblast-like cell transformation. We further present that the genes associated with ciliogenesis are deregulated in obese ASCs. Of importance, two crucial regulators, clusterin associated protein 1 (CLUAP1) and adenylate cyclase 3 (ADCY3), are down-regulated in obese ASCs. By focusing on ADCY3, an important player in the cyclic adenosine monophosphate (cAMP) axis, we show that NKH447, an activator of ADCY, is able to elongate the ciliary length of obese ASCs, whereas SQ22536, an ADCY inhibitor, reduces the ciliary length of lean ASCs, indicating the importance of the ADCY3/cAMP/PKA (protein kinase A) network in controlling the cilium length. Moreover, we show that the leptin/LepR/JAK/STAT (leptin/leptin receptor/Janus kinase/ signal transducers and activators of transcription) pathway regulates ciliary biogenesis in lean ASCs but not obese ASCs. Functionally, obese ASCs with shorten cilia demonstrate an impaired differentiation. In addition to inflammatory cytokines and hypoxia, these data suggest that obesity reprograms the expression of important cilium related genes and renders ASCs not able to respond to leptin, an important hormone for the regulation of ciliary biogenesis. These defects further impair ASC features and functions. Based on these observations, we suggest that defective ASCs with impaired primary cilia may be key players in promoting the development of obesity by transforming themselves into myofibroblast-like cells that may aberrantly produce and release ECM components, reinforcing inflammation and fibrotic progression. Further work is required to deepen the understanding how obese ASCs affect the composition, structure and function of the ECM in adipose tissue.
Publications
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KIF2C/MCAK a prognostic biomarker and its oncogenic potential in malignant progression, and prognosis of cancer patients: a systematic review and meta-analysis as biomarker. Critical Reviews in Clinical Laboratory Sciences, 61(6), 404-434.
Kreis, Nina-Naomi; Moon, Ha Hyung; Wordeman, Linda; Louwen, Frank; Solbach, Christine; Yuan, Juping & Ritter, Andreas
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Maternal obesity and placental function: impaired maternal–fetal axis. Archives of Gynecology and Obstetrics, 309(6), 2279-2288.
Louwen, Frank; Kreis, Nina-Naomi; Ritter, Andreas & Yuan, Juping
