Targeting sensory neurons to restore bone marrow regenerative potential in diabetes

糖尿病约占总死亡率的6%，其中50%的糖尿病相关死亡是由心血管和神经病变并发症造成的。此外，与非糖尿病患者相比，糖尿病患者从心脏病发作或中风中恢复得更差。现在很明显，在这种糟糕的结果中，全球弥补机制的不足起到了关键作用。因此，人们对新疗法的兴趣与日俱增，这种疗法可以提高因衰老和疾病而受损的组织的自发再生能力。成年期再生细胞的一个重要来源是骨骼中的骨髓。这些细胞定期被释放到循环中，以取代已经完成生命周期的其他细胞。通常情况下，这一过程最受欢迎的是周转率高的细胞，如血液中的红细胞和白细胞。然而，周转率低的细胞，如血管细胞和心脏细胞，也需要用新的细胞取代。当急性损伤介入时，心血管细胞的替换成为迫切需要。对损伤后骨髓中新细胞的激活和释放的调节机制知之甚少，但众所周知，糖尿病患者的这些机制是有缺陷的。由于糖尿病改变了神经功能和对疼痛的感知，我们认为这种功能障碍会损害骨髓对压力的感知和充分反应的能力。我们收集了支持这一理论的初步数据：1.骨髓高度神经纤维支配，2.神经纤维通过其表面表达的特定受体释放由骨髓再生细胞感受到的信号，3.这些信号强度的变化将细胞推到骨髓外的循环中，4.心脏病发作后，对神经元信号反应的细胞被释放到循环中，5.将这些特定细胞直接移植到受损组织中加速恢复，6.这些再生细胞枯竭，对糖尿病的应激信号不敏感。现在，我们建议通过三项工作来扩大我们的调查范围。首先，我们将描述糖尿病模型中不同神经纤维和对神经元信号反应的细胞的解剖分布，其次，我们将研究信号从神经到骨髓细胞的传递缺陷，第三，我们将比较经典药物降低血液中葡萄糖水平的效果与针对神经元信号的特定疗法。我们最终会调查这两种方法是否相辅相成。如果我们的假设被证明是正确的，那么很有可能出现新的有效的再生疗法来减轻糖尿病的破坏性作用。

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.