Targeting sensory neurons to restore bone marrow regenerative potential in diabetes

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Diabetes accounts for ~6% of general mortality, with 50% of diabetes-associated deaths being caused by cardiovascular and neuropathic complications. Moreover, diabetic patients recover much worst from a heart attacks or stroke compared to non-diabetic patients. It is now clear that a global deficit in reparative mechanisms plays a key role in such a poor outcome. Hence, interest is growing on new therapies that improve the spontaneous ability to regenerate tissues damaged by aging and disease. One important source of regenerative cells in the adulthood is the marrow contained in bones. These cells are regularly released into the circulation to replace other cells that have completed their lifecycle. This process is normally best appreciated for cells with high turnover, like red and white cells of the blood. However, also cells with low turnover, like vascular cells and cardiac cells, need to be replaced with new cells. The replacement of cardiovascular cells becomes an urgent need when an acute injury intervenes. The mechanisms regulating the activation and release of new cells from the marrow after an injury are poorly understood, but it is well acknowledged that they are defective in patients with diabetes. Since diabetes alters nerve function and perception of pain, we propose that this dysfunction can compromise the ability of bone marrow to sense the stress and respond adequately. We have collected preliminary data in support of this theory: 1. the bone marrow is highly innervated with neuronal fibres, 2. the nerve fibres release signals that are sensed by regenerative cells of the marrow via specific receptors expressed on their surface, 3. variations in the intensity of these signals push cells outside the marrow in the circulation, 4. likewise, after a heart attack, cells responsive to neuronal signalling are released to the circulation, 5. transplanting those specific cells directly into damaged tissues accelerate recovery, 6. those regenerative cells are depleted and insensitive to stress signals in diabetes. Now, we propose to extend our investigation through three pieces of work. First, we will characterize the anatomical distribution of different neuronal fibres in the marrow and of cells responsive to neuronal signals in models of diabetes, second we will investigate the defective transmission of the signalling from nerves to cells of the marrow, and third we will compare the effect of classical drugs that reduce glucose levels in blood with a specific therapy targeting the neuronal signalling. We will eventually investigate if the two approaches are complementary. If our hypothesis is proved true, there is a real possibility that new effective regenerative treatments become available to attenuate the damaging action of diabetes.