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Diabetes disturbs protein secretome of human adipose-derived stem cells and promotes tumorogenesis in hepatic cancer cells

ABSTRACT: Metabolic disorders impact adipose-derived stem cells (ASCs), which play a central role in adipose tissue (AT) homeostasis but might also regulate tumour microenvironments via paracrine signalling routes. Here, we aimed to determine whether type 2 diabetes (T2D) disturbs the protein secretome of human ASCs, and its potential relevance for their pro-tumoral activity. An untargeted proteomics approach by liquid chromatography coupled to tandem mass spectrometry was used to analyse the secretome of ASCs isolated from the subcutaneous AT of subjects with and without T2D. Out of 231 quantified proteins, 52 factors were found differentially secreted on T2D-ASCs. In silico studies revealed that only 46,7% of the total proteins identified used the conventional secretory pathway. Network analysis showed up-secreted factors in T2D were implicated in immune system processes, extracellular matrix organization and endoplasmic reticulum stress. We found that diabetic ASCs secretome increases some inflammatory-, invasiveness- and epithelial-to-mesenchymal transition-related markers in HepG2 cells, an effect that was blocked with an anti-SUB1 antibody. Remarkably, SUB1 neutralization also inhibited invasive capacities of HepG2 in response to T2D-ASCs secretome. Overall, our study demonstrates that T2D-ASCs show an aberrant protein secretome and although further studies will be needed to understand the pathogenic consequences of this disturbance, our findings suggest that SUB1 might serve as a novel molecular link in the interplay between ASCs and tumor cells.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Mesenchymal Stem Cell Of Adipose

DISEASE(S): Type 2 Diabetes Mellitus

SUBMITTER: Eva Borràs

LAB HEAD: Eduard Sabido

PROVIDER: PXD029829 | Pride | 2022-06-03

REPOSITORIES: Pride

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			Action	DRS
	180411_S_SNIA_07_01_45pto.msf	Msf
	180411_S_SNIA_07_01_45pto.raw	Raw
	180411_S_SNIA_08_01_45pto.msf	Msf
	180411_S_SNIA_08_01_45pto.raw	Raw
	180411_S_SNIA_09_01_45pto.msf	Msf

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Project description:The treatment of bone defects caused by infection, trauma or neoplasms remains a clinical challenge. Autologous bone transplantation is limited by availability, donor site morbidity and surgical risk factors. This has given rise to stromal/stem-cell based therapy. Bone marrow derived stromal cells (BMSCs) have been studied to a large extent and show high regenerative potential but their use is limited by availability, donor site morbidity and the relatively low cell yield as they represent only <0.1% of cell harvested from bone marrow aspirate. At the same time, they are the closest mesenchymal stromal cells for bone tissue engineering given their tissue origin and, unlike other mesenchymal stromal cells, can support the formation of hematopoietic marrow. Adipose tissue derived stromal cells (ASCs) as part of the stromal vascular fraction of adipose tissue can as well undergo osteogenic differentiation but can be additionally isolated in a sufficient quantity from lipoaspirate after liposuction of abundant subcutaneous fat tissue. Here, it has been shown that there are no major differences in regard to proliferation or differentiation capacity of ASCs derived from subcutaneous fat of different anatomical regions. It has been shown that BMSCs are more prone to senescence during expansion and passage than ASCs and that ageing impacts proliferative capabilities of BMSCs more than that of ASCs while it has also been reported that osteogenic differentiation capacity is least impacted by age. Multiple studies have compared the characteristics of these two mesenchymal stromal cells in regard to bone tissue engineering in vitro. Most studies point to inferior extracellular matrix mineralization and lower expression of key osteogenic transcription markers like Runx2 in osteogenic differentiated ASCs compared to BMSCs. On the other hand, a study by Rath et al. found contrary results using particular culturing conditions like 3D bioglass scaffolds. An intraindividual comparison of human MSCs of three donors cultured on decellularized porcine bone confirmed superior osteogenic capacity of BMSCs compared to ASCs. In contrast to BMSCs, ASCs were not able to induce heterogenic ossification in a mouse model. In a sheep tibia defect model application of BMSCs resulted in a significantly higher amount of newly formed bone tissue. Importantly, Osteogenic differentiated ASCs do not support the formation of a hematopoietic marrow. Proteomics enables large-scale analysis of proteins present in a cell type and can be used to identify differentially regulated key proteins in a comparative approach. A comparative proteomic analysis of BMSCs and ASCs by Roche et al. in 2009 identified 556 proteins with 78% of these not being differentially regulated between these two cell populations, regarded as high similarity. Another comparative proteomic study of 2016 by Jeon et al. found 90 differentially regulated proteins out of 3000 total identified proteins. Both studies do not specify a number of different tissue donors and in part using cell lines. Looking for differences upon osteogenic differentiation, transcriptomic comparison of osteogenic differentiated porcine ASCs and BMSCs has been performed, resulting in 21 differentially expressed genes after 21 days of osteogenic culture conditions. Still, it remains unanswered, which are the key distinctive features of osteogenic differentiated ASCs and BMSCs at protein level that might help address the abovementioned weaknesses of ASCs in bone tissue engineering/regeneration for translational research. To overcome this need, an intraindividual comparative DIA based proteomic analysis of osteogenic differentiated human BMSC and ASCs was performed in this study.

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Diabetes disturbs protein secretome of human adipose-derived stem cells and promotes tumorogenesis in hepatic cancer cells

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