Transcriptomic Profile of Lin-Sca1+c-kit (LSK) cells in db/db mice with long-standing diabetes

Abstract

The Lin-Sca1+c-Kit+ (LSK) fraction comprises multipotent hematopoietic stem cells (HSCs), vital to tissue homeostasis and vascular repair. While HSC homeostasis is impaired in diabetes, it is not known how chronic (>6 months) type 2 diabetes (T2D) alters the HSC transcriptome. Herein, we assessed the transcriptomic signature of HSCs in db/db mice employing mRNA and miRNA sequencing. We uncovered 2076 mRNAs and 35 miRNAs differentially expressed in db/db mice, including two novel miRNAs previously unreported in T2D. Further analysis of these transcripts showed a molecular shift with an increase in the pro-inflammatory cytokines and a decrease in anti-inflammatory cytokine expression. Also, pathway mapping unveiled inflammation and angiogenesis as one of the top pathways. These effects were reflected in bone marrow mobilopathy, retinal microglial inflammation, and neurovascular deficits in db/db mice. In conclusion, our study highlights that chronic diabetes alters HSCs at the transcriptomic level, thus potentially contributing to overall homeostasis and neurovascular deficits of diabetes, such as diabetic retinopathy. HighlightsO_LIBone marrow mobilopathy with long-standing diabetes C_LIO_LISwitch in LSK transcriptomic profile towards inflammation and angiogenesis C_LIO_LIDiscovered 35 miRNAs, including two novel miRNAs, miR-3968 and miR-1971 C_LIO_LILSK dysfunction reflected in inflammation and neurovascular deficits of the retina C_LI