Diabetes Causes Bone Marrow Autonomic Neuropathy and Impairs Stem Cell Mobilization via Dysregulated p66Shc and Sirt1

Abstract

Diabetes compromises the bone marrow (BM) microenvironment and reduces the number of circulating CD34(+) cells. Diabetic autonomic neuropathy (DAN) may impact the BM, because the sympathetic nervous system is prominently involved in BM stem cell trafficking. We hypothesize that neuropathy of the BM affects stem cell mobilization and vascular recovery after ischemia in patients with diabetes. We report that, in patients, cardiovascular DAN was associated with fewer circulating CD34(+) cells. Experimental diabetes (streptozotocin-induced and ob/ob mice) or chemical sympathectomy in mice resulted in BM autonomic neuropathy, impaired Lin(-)cKit(+)Sca1(+) (LKS) cell and endothelial progenitor cell (EPC; CD34(+)Flk1(+)) mobilization, and vascular recovery after ischemia. DAN increased the expression of the 66-kDa protein from the src homology and collagen homology domain (p66Shc) and reduced the expression of sirtuin 1 (Sirt1) in mice and humans. p66Shc knockout (KO) in diabetic mice prevented DAN in the BM, and rescued defective LKS cell and EPC mobilization. Hematopoietic Sirt1 KO mimicked the diabetic mobilization defect, whereas hematopoietic Sirt1 overexpression in diabetes rescued defective mobilization and vascular repair. Through p66Shc and Sirt1, diabetes and sympathectomy elevated the expression of various adhesion molecules, including CD62L. CD62L KO partially rescued the defective stem/progenitor cell mobilization. In conclusion, autonomic neuropathy in the BM impairs stem cell mobilization in diabetes with dysregulation of the life-span regulators p66Shc and Sirt1.

P66SHC deletion improves fertility and progeric phenotype of late-generation TERC-deficient mice but not their short lifespan

“…Thus, the predictive value of telomere length on organ aging depends on genetic background. Then, p66SHC expression and activity is induced in several tissues by obesogenic diets (Giorgio et al ., 2012) or hyperglycemia (Albiero et al ., 2014) that are known to affect telomere length as well (Laimer et al ., 2015). The interaction of aging and metabolic pathways, including p66SHC, SIRT1, or AMPK/mTOR/S6K (Fadini et al ., 2011), with telomere erosion in the presence of diabetes or obesity is a promising field to reveal how metabolic disorders impact on aging.…”

Pathophysiological role of enhanced bone marrow adipogenesis in diabetic complications

“…7,36,37 Studies have also shown that diabetes leads to reduced mobilization of stem cells from the marrow. 38,39 A number of signaling mechanisms have been identified underlying this abnormality. And finally, we have shown that high levels of glucose decrease endothelial and mesenchymal progenitor cell numbers acutely (within 24 h of culture).…”

The p66Shc redox adaptor protein is induced by saturated fatty acids and mediates lipotoxicity-induced apoptosis in pancreatic beta cells

“…p66 Shc signalling is strictly dependent upon phosphorylation of Ser 36 in the protein CH2 domain, triggered by cell exposure to oxidative stress-inducing agents [18]. Recently, p66 Shc knockout mice were found to exhibit protection from hyperglycaemiainduced microvascular disease [19] and from development of diabetic autonomic neuropathy [20]. Levels of p66 Shc mRNA and p66 Shc protein were found to be increased in the kidney cortex of diabetic mice [19] and in circulating leucocytes from diabetic patients [21], suggesting that p66 Shc could 'sense' the impaired metabolic milieu in diabetes and promote cellular dysfunction.…”