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.

Keywords: CD34+; adult hematopoietic stem cells; bone marrow; diabetes; mobilization.

Graphical abstract

Figure 1.

Circulating HSPC during the natural history of type 2 diabetes. Modified from Fadini et al..

Figure 2.

Three-compartment model of HSPC traffic. According to a simplistic 3-compartment model, changes in the levels of circulating HSPCs can derived from alterations in replenishment from the bone marrow reservoir, reduced survival in the bloodstream, and excess homing to the target tissues. T1D, type 1 diabetes.

Figure 3.

Mechanistic link between myelopoiesis and mobilopathy in diabetes. The figure reads from left to right and in a circular manner. Hyperglycemia in people with diabetes, possibly through the release of alarmins (like S100A8/9 proteins) from activated granulocytes, promotes the myeloid biased differentiation of hematopoietic stem/progenitor cells (HSPCs), resulting in an exceeding amount of myeloid progenitors in the diabetic bone marrow. Myelopoiesis leads to an increased release of pro-inflammatory neutrophils and macrophages that spread through the bloodstream and reach targets organs of diabetic complications like the heart. Within the bone marrow, pro-inflammatory cells produce Oncostatin M (OSM), which signals through its receptor (OSMR) via non-mitochondrial p66Shc to induce CXCL12 by niche stromal cells and itself alimenting myelopoiesis. Local production of CXCL12 retains HSPCs in the niche, preventing them from being mobilized, and nourishing the vicious cycle of the myelopoiesis-mobilopathy combo.