Impaired Hematopoietic Stem/Progenitor Cell Traffic and Multi-organ Damage in Diabetes.

Abstract

During antenatal development, hematopoietic stem/progenitor cells (HSPCs) arise from a specialized endothelium and migrate from the extraembryonic mesoderm to the fetal liver before establishing hematopoiesis in the bone marrow (BM). It is still debated whether, in adulthood, HSPCs display such ontologic overlap with vascular cells and capacity for endothelial differentiation. Yet, adult HSPCs retain a prominent migratory activity and traffic in the bloodstream to secondary lymphoid organs and all peripheral tissues, before eventually returning to the BM. While patrolling parenchymatous organs, HSPCs locate close to the vasculature, where they establish local hematopoietic islands and contribute to tissue homeostasis by paracrine signals. Solid evidence shows that diabetes mellitus jeopardizes the traffic of HSPCs from BM to the circulation and peripheral tissues, a condition called “mobilopathy.” A reduction in the levels of circulating HSPCs is the most immediate and apparent consequence, which has been consistently observed in human diabetes, and is strongly associated with future risk for multi-organ damage, including micro- and macro-angiopathy. But the shortage of HSPCs in the blood is only the visible tip of the iceberg. Abnormal HSPC traffic results from a complex interplay among metabolism, innate immunity, and hematopoiesis. Notably, mobilopathy is mechanistically connected with diabetes-induced myelopoiesis. Impaired traffic of HSPCs and enhanced generation of pro-inflammatory cells synergize for tissue damage and impair the resolution of inflammation. We herein summarize the current evidence that diabetes affects HSPC traffic, which are the causes and consequences of such alteration, and how it contributes to the overall disease burden.