P291Wnt canonical pathway downregulation in bone marrow cells of subjects with cardiovascular risk factors can limit their regenerative potential

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Abstract

Purpose

Bone marrow and adipose derived autologous stem cells have been considered as ideal candidates to repair cardiac tissue after myocardial infarction. However, results obtained so far with such procedure have been disappointing, as only scarce improvements in heart function have been achieved. Therefore, it was the aim of this study to analyze if the presence of cardiovascular risk factors in the stem cell donor could limit their regenerative potential.

Methods

Zucker Diabetic Fatty (ZD) rats are obese and dyslipidemic and develop type 2 diabetes (T2D) by 12 weeks of age. Therefore, bone marrow was extracted from femurs and tibias of 7-week old Zucker Diabetic Fatty (ZD) rats (pre-diabetic), 17-week old ZD rats (diabetic), and 17-week old lean-normoglycemic controls (ZC). Gene expression of 84 genes, comprising stem cell markers, differentiation markers, and genes involved in the Wnt and Notch pathways, were analyzed with a rat-specific stem cell PCR array. In silico analysis with Ingenuity Pathway Analysis software (IPA) allowed to identify statistically significant canonical pathways, functions, and networks in which genes differentially expressed are involved.

Results

Comparison of gene expression data showed that 27 genes were altered in diabetics compared to controls. All such genes were downregulated in diabetics, reflecting a marked reduction in the stemness of their bone marrow cell population. 11 genes were also found downregulated in pre-diabetics compared to controls, while comparison between pre-diabetic and diabetic animals allowed to identify 3 genes susceptible of being considered as markers of T2D development. An additional analysis comparing gene expression data between all ZD animals (pre-diabetic and diabetic together) and ZC animals showed 55 genes significantly modified (all downregulated) in ZD rats, 30 of which had not been previously identified. IPA analysis showed the Wnt/β-catenin pathway among the top 10 statistically significant canonical pathways in which differentially expressed genes (identified comparing diabetics vs. controls, pre-diabetics vs. controls, and ZD vs. ZC) were involved, being the most significant among the stem cell-related pathways in all cases.

Conclusions

The bone marrow cell population of subjects with cardiovascular risk factors (with or without diabetes), like those needing cardiovascular repair, show a diminished stemness and a marked downregulation of the Wnt/β-catenin canonical pathway that could limit their regenerative potential.

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