Mechanisms underlying cytokine-induced changes in homing and engraftment of human haemopoietic stem and progenitor cells

The reduced engraftment potential of cytokine cultured haemopoietic stem/progenitor cells from adult mobilised peripheral blood has been associated with their defective homing to bone marrow niches. In this work, using established in vivo systems and a novel ex vivo model, an additional cytokine-induced attachment defect is described that reduces the retention of these cells in the bone marrow, post-transplantation. This defect was found to be related to specific niche ligands and was not caused by downregulation of their respective receptors on the expanded cells. CD26 is a protease that cleaves SDF-1 abrogating its chemotactic effect. CD26 inhibition on the transplanted cells was not sufficient to reverse the engraftment defect, although infusion of the inhibitor in immunodeficient animals, together with ex vivo treated cells, significantly increased engraftment. Finally, mobilised peripheral blood stem/progenitor cells were found to express neuroreceptors and their expression was altered after exposure to cytokines. Epinephrine pre-treatment of these cells rescued their adhesion to specific niche ligands, increased their short-term homing and improved their long-term engraftment in immunodeficient animals

Diabetic neuropathy in children and adolescents with type 1 diabetes mellitus: Diagnosis, pathogenesis, and associated genetic markers

Diabetic neuropathy (DN) is a common long-term complication of type 1 (T1D) and type 2 (T2D) diabetes mellitus, with significant morbidity and mortality. DN is defined as impaired function of the autonomic and/or peripheral nervous system, often subclinical, particularly in children and adolescents with T1D. Nerve conduction studies (NCS) and skin biopsies are considered gold-standard methods in the assessment of DN. Multiple environmental and genetic factors are involved in the pathogenesis of DN. Specifically, the role of metabolic control and glycemic variability is of paramount importance. A number of recently identified genes, including the AKR1B1, VEGF, MTHFR, APOE, and ACE genes, contribute significantly in the pathogenesis of DN. These genes may serve as biomarkers to predict future DN development or treatment response. In addition, they may serve as the basis for the development of new medications or gene therapy. In this review, the diagnostic evaluation, pathogenesis, and associated genetic markers of DN in children and adolescents with T1D are presented and discussed. © 2019 John Wiley & Sons, Ltd

The prevalence of early subclinical somatic neuropathy in children and adolescents with Type 1 diabetes mellitus and its association with the persistence of autoantibodies to glutamic acid decarboxylase (GAD) and islet antigen-2 (IA-2)

Aim: To evaluate the prevalence of early somatic neuropathy in children and adolescents with Type 1 diabetes mellitus (Type 1 DM) and its association with the presence of glutamic acid decarboxylase and islet antigen-2 autoantibodies (GADA and IA-2A). Methods: A cross-sectional study was conducted in a hospital-based cohort of pediatric Type 1 DM patients (n = 85, mean(±SD) age: 13.5 ± 3.4 years, mean(±SD) disease duration 5.5 ± 3.4 years). Peripheral neuropathy was assessed with nerve conduction studies (NCS). GADA and IA-2A titers were measured with radioligand assays. Results: Among the study population, 34.1% had at least one abnormal electrophysiological parameter, although predominantly asymptomatic. The highest rates of abnormality were detected in sensory peroneal nerve (25.9%) followed by sural nerve (15.3%). Affected patients were not different in terms of age, diabetes duration or glycaemic control. Among the participants, 62.4% had positive GADA, 58.8% positive IA-2A and 42.4% double antibody positivity. Abnormal NCS correlated neither with GADA nor with IA-2A levels or positivity. However lower sensory nerve action potential in the peroneal nerve, indicative of early axonal dysfunction, was observed in patients with GADA or IA-2A positivity. Absence of both antibodies was associated with better action potentials in all the examined nerves of the lower limbs. Conclusions: Impaired indices of subclinical peripheral primarily sensory neuropathy were present among one third of Type 1 DM children and adolescents, with no impact of diabetes duration or glycaemic control. GADA and IA-2A seem to be involved in the development of axonal degeneration, in a pathway which remains to be identified. © 2016