Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
J Exp Med. 2009 Dec 21;206(13):2897-906. doi: 10.1084/jem.20090889. Epub 2009 Nov 23.
The present epidemic of diabetes is resulting in a worldwide increase in cardiovascular and microvascular complications including retinopathy. Current thinking has focused on local influences in the retina as being responsible for development of this diabetic complication. However, the contribution of circulating cells in maintenance, repair, and dysfunction of the vasculature is now becoming appreciated. Diabetic individuals have fewer endothelial progenitor cells (EPCs) in their circulation and these cells have diminished migratory potential, which contributes to their decreased reparative capacity. Using a rat model of type 2 diabetes, we show that the decrease in EPC release from diabetic bone marrow is caused by bone marrow neuropathy and that these changes precede the development of diabetic retinopathy. In rats that had diabetes for 4 mo, we observed a dramatic reduction in the number of nerve terminal endings in the bone marrow. Denervation was accompanied by increased numbers of EPCs within the bone marrow but decreased numbers in circulation. Furthermore, denervation was accompanied by a loss of circadian release of EPCs and a marked reduction in clock gene expression in the retina and in EPCs themselves. This reduction in the circadian peak of EPC release led to diminished reparative capacity, resulting in the development of the hallmark feature of diabetic retinopathy, acellular retinal capillaries. Thus, for the first time, diabetic retinopathy is related to neuropathy of the bone marrow. This novel finding shows that bone marrow denervation represents a new therapeutic target for treatment of diabetic vascular complications.
目前糖尿病的流行导致心血管和微血管并发症（包括视网膜病变）在全球范围内增加。目前的研究重点集中在视网膜的局部影响，认为其是导致这种糖尿病并发症的原因。然而，循环细胞在维持、修复和血管功能障碍中的作用现在正受到关注。糖尿病患者的循环中内皮祖细胞（EPCs）较少，这些细胞的迁移能力减弱，导致其修复能力下降。我们使用 2 型糖尿病大鼠模型表明，糖尿病患者骨髓中 EPC 释放减少是由骨髓神经病变引起的，这些变化先于糖尿病视网膜病变的发生。在患有糖尿病 4 个月的大鼠中，我们观察到骨髓中神经末梢数量明显减少。去神经支配伴随着骨髓中 EPC 数量的增加和循环中数量的减少。此外，去神经支配伴随着 EPC 昼夜释放的丧失以及视网膜和 EPC 本身中时钟基因表达的明显减少。EPC 释放昼夜高峰的减少导致修复能力下降，从而导致糖尿病视网膜病变的标志性特征，无细胞视网膜毛细血管的形成。因此，这是首次将糖尿病视网膜病变与骨髓神经病变联系起来。这一新发现表明，骨髓去神经支配代表了治疗糖尿病血管并发症的一个新的治疗靶点。
