Different response to hypoxia of adipose-derived multipotent cells from obese subjects with and without metabolic syndrome

PLoS One. 2017 Nov 22;12(11):e0188324. doi: 10.1371/journal.pone.0188324. eCollection 2017.

Abstract

Background/objectives: Multiple studies suggest that hypoxia, together with inflammation, could be one of the phenomena involved in the onset and progression of obesity-related insulin resistance. In addition, dysfunction of adipose tissue in obese subjects with metabolic syndrome is associated with decreased angiogenesis. However, some subjects with a high body mass index do not develop metabolic abnormalities associated with obesity. The aim of the current study was to examine the neovascular properties of visceral adipose tissue-derived multipotent mesenchymal cells subjected to hypoxia (hypox-visASCs) from normal-weight subjects (Nw) and obese patients with metabolic syndrome (MS) and without metabolic syndrome (NonMS).

Methods: This was a 2-year study to enroll subjects who underwent bariatric surgery or cholecystectomy. Eight patients who underwent either bariatric surgery or cholecystectomy (27 patients) participated in the study. Visceral adipose tissue samples from Nw, MS and NonMS subjects were processed by enzymatic digestion. VisASCs cultured under hypoxic conditions were characterized by tubule formation assay, ELISA, flow cytometry, migration rate, and qRT-PCR, and the effects of visASCs-conditioned medium on survival and endothelial cell tubule formation were evaluated.

Results: Hypox-visASCs from NonMS subjects showed a greater capacity for tubule formation than hypox-visASCs from Nw and MS subjects. The lower percentage of CD140b+/CD44+ and CD140b+/CD184+ cells observed in hypox-visASCs from NonMS subjects compared to MS subjects was accompanied not only by a lower migration rate from the chemotactic effects of stromal cell derived factor 1α, but also by lower levels of NOX5 mRNA expression. While the levels of monocyte chemoattractant protein 1 mRNA expressed by hypox-visASCs correlated positively with the body mass index and waist circumference of the subjects, the concentration of vascular endothelial growth factor present in hypox-visASC-conditioned culture medium decreased significantly with increasing plasma glucose. The survival rate and tubules formed by endothelial cells cultured in hypox-visASC-conditioned medium decreased significantly with increasing homeostasis model assessment to quantify insulin resistance.

Conclusions: Our results suggest that hypox-visASCs from NonMS subjects could promote healthy adipose tissue expansion, while hypox-visASCs from MS subjects appear to contribute to the decreased angiogenic potential and increased inflammation underlying adipose tissue dysfunction in obesity. Our results emphasize the importance of taking into account not only the BMI but also the metabolic profile of the subjects during the implementation of ASCs-based therapy to promote neovascularization.

MeSH terms

  • Adipose Tissue / pathology*
  • Adult
  • Anthropometry
  • Cell Count
  • Cell Movement / drug effects
  • Cells, Cultured
  • Chemokine CXCL12 / pharmacology
  • Culture Media, Conditioned / pharmacology
  • Gene Expression Regulation / drug effects
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • Hypoxia / complications*
  • Hypoxia / genetics
  • Hypoxia / pathology
  • Immunophenotyping
  • Inflammation Mediators / metabolism
  • Metabolic Syndrome / complications*
  • Metabolic Syndrome / genetics
  • Metabolic Syndrome / pathology
  • Models, Biological
  • Multipotent Stem Cells / drug effects
  • Multipotent Stem Cells / metabolism
  • Multipotent Stem Cells / pathology*
  • NADPH Oxidases / metabolism
  • Neovascularization, Physiologic / drug effects
  • Obesity / complications*
  • Obesity / genetics
  • Obesity / pathology
  • Oxidation-Reduction
  • Oxygen / pharmacology
  • Receptor, Platelet-Derived Growth Factor beta / metabolism
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Chemokine CXCL12
  • Culture Media, Conditioned
  • Inflammation Mediators
  • Vascular Endothelial Growth Factor A
  • Hepatocyte Growth Factor
  • NADPH Oxidases
  • Receptor, Platelet-Derived Growth Factor beta
  • Oxygen

Grants and funding

This work was cofunded by the European Union through the European Regional Development Fund (FEDER). The authors wish to thank all the participants for their collaboration. CIBER Fisiopatología de la Obesidad y Nutrición (Pathophysiology of Obesity and Nutrition, CIBEROBN) are part of the Instituto de Salud del Carlos III (Institute of Health Carlos III, ISCIII) Project. We would also like to thank Maria Repice for her help with the English language version of the text. This work was supported by grants from the Ministry of Economy and Competitiveness, Institute of Health Carlos III (PI15/01114, PI13/02628; PI12/02355) and the Ministry of Economy and Knowledge (PI-CTS-08181/2011; CTS-7895/2011). S.F.V. acknowledges support from the “Miguel Servet” tenure-track program (CP10/00438) from the Fondo de Investigación Sanitaria (FIS) co-financed by the European Regional Development Fund (ERDF). R.E. is under a contract of “Nicolás Monardes” programme from the Servicio Andaluz de Salud, Regional Ministry of Health of the Andalusia Government, Andalusia, Spain.