Diabetic retinopathy is associated with bone marrow neuropathy and a depressed peripheral clock

Abstract

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.

Autonomic regulation of hematopoiesis and cancer

“…The disautonomia associated to diabetes has been shown to affect also the BM, disrupt the peripheral clock and compromise the mobilization of endothelial and hematopoietic progenitors from the BM. 30,31 In addition, the BM neuropathy caused by chemotherapy has been shown to compromise hematopoietic recovery 4 ( Figure 1). Psychological and behavioral factors, including stress, depression and social isolation, are considered to contribute to the progression of certain types of cancer in humans.…”

Adeno-Associated Virus Overexpression of Angiotensin-Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice

“…(Am J Pathol 2016, 186: 1688e1700; http://dx.doi.org/10.1016/j.ajpath.2016.01.023) Microvascular complications of diabetes constitute a number of painful and debilitating conditions. Previously, we found that the bone marrow is susceptible to diabetic neuropathy, 1,2 which leads to denervation of stromal cells and altered secretion of growth factors and cytokines that ultimately shifts hematopoiesis toward a disproportionate increase of proinflammatory monocytes. 3,4 Consequently, monocytes are increased in the circulation and subsequently in tissues subject to diabetic complications, including retina, kidney, and brain.…”

The stereotypical molecular cascade in neovascular age-related macular degeneration: the role of dynamic reciprocity

“…[82][83][84]136 The abnormal local response may also compromise the systemic input from the bone marrow or both local and systemic components could be blunted by co-existent disease. 34,71,121,137 In summary, it appears that the process that is DyR generates the stereotypical and even predictable wound response that is seen in AMD. As outlined in the previous sections of this study, all the necessary molecular ingredients appear to be present, to generate a normal reparative response.…”