Neuronal-Hematopoietic Cell Fusion in Diabetic Neuropathy

Abstract

Diabetic neuropathy is a major complication of diabetes mellitus that occurs during the early stages of the disease. Many pathogenic mechanisms are related and induced by hyperglycemia. However, even if these factors improve, diabetic neuropathy cannot go into remission and progresses slowly. Furthermore, diabetic neuropathy often progresses even with proper glycemic control. Recently, bone marrow-derived cells (BMDCs) were reported to be involved in the pathogenesis of diabetic neuropathy. BMDCs expressing proinsulin and TNFα migrate to the dorsal root ganglion and fuse with neurons, and this neuronal-hematopoietic cell fusion induces neuronal dysfunction and apoptosis. The CD106-positive lineage-sca1+c-kit+ (LSK) stem cell fraction in the bone marrow is strongly involved in cell fusion with neurons, leading to diabetic neuropathy. Surprisingly, when CD106-positive LSK stem cells obtained from diabetic mice were transplanted into nondiabetic mice, they fused with dorsal root ganglion neurons and induced neuropathy in non-hyperglycemic normal mice. The transplanted CD106-positive LSK fraction inherited the trait even after transplantation; this "progeny effect" may explain the irreversibility of diabetic neuropathy and is a significant finding for determining the target of radical treatments and provides new directions for developing therapeutic methods for diabetic neuropathy.

Keywords: Sca-1+c-Kit+Lin; bone marrow; diabetes; hematopoietic stem cell; neuropathy.

Graphical Abstract

Figure 1.

Mechanism of the onset in diabetic neuropathy by neuronal-hematopoietic stem cell fusion. Abnormal HSCs expressing TNFα and proinsulin appear in the bone marrow of diabetic mice induced by STZ or HFD. Abnormal HSCs proliferate and differentiate in the bone marrow and migrate to systemic tissues through the bloodstream. Abnormal BMDCs that reach peripheral nerves fuse with nerve fibers and dorsal root ganglion neurons, causing neuropathy. BM, bone marrow; BMDCs, bone marrow-derived cells; DRG, dorsal root ganglion; HFD, high-fat diet; HSCs, hematopoietic stem cells; STZ, streptozotocin; TNFα, tumor necrosis factor α.

Figure 2.

Abnormal homeostasis in bone marrow tissues under diabetic conditions. In physiological conditions (left panel; nondiabetic condition), HSCs retained in MSCs that constitute the vascular niche are released upon sympathetic nerve stimulation and migrate from CAR cells to sinusoids with proliferation and differentiation. Once these cells reach the sinusoids, they migrate through the sinusoidal endothelium to systemic tissues. In the diabetic condition (right panel), normal HSCs are reduced; they are released into the bone marrow upon sympathetic nerve stimulation under hyperglycemia from the condition of retaining in MSCs and migrate to the sinusoids with the help of CAR cells while differentiating to abnormal HSCs expressing proinsulin, TNFα, and CD106. The abnormal HSCs enter into the sinusoids through the sinusoidal endothelium and migrate into systemic tissues as BMDCs, but this mobilization of HSCs exhibits abnormality under the diabetic condition. BMDCs, bone marrow-derived cells; CAR, CXCL12 abundant reticular; HSCs, hematopoietic stem cells; MSCs, mesenchymal stem cells; TNFα, tumor necrosis factor α.

Figure 3.

Abnormal HSCs induced by hyperglycemia have the “progeny effect.” Hyperglycemia induces abnormal HSCs with aberrant programming such as glucotoxic memory. Once programmed with the abnormal features, the HSCs show irreversibility of phenotype and can lead to neuropathy in normal mice, also called the “progeny effect.” HSCs, hematopoietic stem cells.