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Lulu Yan, Hemabindu Chintala, Ashay D Bhatwadekar, Sugata Hazra, Maria B Grant, Brahim Chaqour; Type-2 Diabetes Alters the microRNA Expression Profiles of Progenitor Cell Populations. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4675.
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© ARVO (1962-2015); The Authors (2016-present)
Bone-marrow (BM)-derived and circulating angiogenic cells (CACs) contribute to vascular homeostasis and repair of the retina; however, diabetes induced defects in CACs hamper their participation in vascular repair resulting in diabetic retinopathy. MicroRNAs (miRNAs), small non-coding RNA molecules, regulate progenitor cell function and behavior by modulating gene expression at the post-transcriptional level. In this study, we examined the miRNA expression profile in key progenitor cell populations isolated from db/db mice, a model of type 2 diabetes (T2D), to gain insight into mechanisms responsible for diabetes-induced vascular damage.
We isolated the three following distinct progenitor cell populations from peripheral blood (PB) and BM of T2D and age-sex matched wild-type (WT) mice: i) Lin-Sca1+c-kit (LSK) cells, ii) CACs and iii) endothelial colony forming cells (ECFCs). RNA was extracted and processed for miRNA microarrays with the Qiagen Mouse miRNA Pathway Arrays. The data was analyzed with the Qiagen miScript Data Analysis Tool.
LSK cells, the most primitive population of progenitors, showed minimal differences in their miRNA profiles and only 4 miRNAs changed by at least two-fold between T2D and WT mice. CACs, the population that exhibits the greatest angiogenic capacity, showed upregulation in 5 miRNAs with a downregulation of 30 miRNAs for the PB-CACs, and an upregulation in 6 miRNAs with downregulation in 50 miRNAs for the BM-CACs in T2D mice. Changes in miRNA profiles were also evident in ECFCs, the population of cells most similar to endothelial cells. In PB-ECFCs of T2D mice, 26 miRNAs were upregulated and 17 miRNAs were downregulated while for the BM-ECFCs, 44 miRNAs were upregulated and 25 miRNAs were downregulated. Among the most differentiated cells (CACs and ECFCs) studied 13 miRNA were downregulated in T2D mice. Computational analyses revealed relational patterns between these miRNAs and neurotrophin, Wnt, and TGF-beta signaling pathways.
Our studies suggest that i) LSKs are the least susceptible to alterations of angiogenic miRNA profile in T2D and thus may be less affected by the adverse diabetic milieu; ii) BM-derived cells have distinct miRNA expression signatures from PB-derived cells in T2D mice and iii) T2D affects the same miRNA-targeted pathways in progenitors originating from either BM or PB.
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