Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Pathology

Supervisor

Dr. Zia A. Khan

Abstract

Diabetes leads to a variety of secondary complications. At the heart of these complications lies endothelial cells (ECs) – cells that take up unregulated plasma glucose, experience various biochemical alterations, and provide the basis for whole organ vascular dysfunctions. With the purpose of generating new vascular networks for the treatment of these chronic complications, my initial work focused on vascular stem cells (VSCs). VSCs have the ability to differentiate into both endothelial (EPC) and mesenchymal (MPC) progenitor cells, both of which are necessary for the creation of stable and functional blood vessels. To establish whether these progenitor populations retain their integrity in diabetes, we investigated their cellular activity in a high glucose (HG) setting. Contrary to our expectations, EPCs evaded the negative effects of HG while MPCs displayed some functional alterations. Importantly, we noted MPCs in HG to be skewed towards the adipocyte lineage, while differentiation to both osteoblasts and chondrocytes was suppressed.

MPC alterations exposed in our study are reminiscent of phenotypic changes that occur in the bone marrow of long-term diabetic patients. To elucidate the mechanism behind this alteration in MPC differentiation we examined the Wnt signaling pathway in a comprehensive manner. The results of this study have revealed a novel finding. We have demonstrated the autogenous upregulation of non-canonical Wnt11 in HG-treated MPCs, that signals through the Wnt/Ca2+/protein kinase C (PKC) pathway to stimulate adipogenesis. Increase in adipocytes in human diabetic marrow samples correlated with a decrease in the number of stem cells. We have also shown that enhanced adipogenesis in marrow samples may disrupt the stem cell niche by altering Angiopoeitin/Tie signaling axis. Taken together, targeting the conversion of stem cells to adipocytes could be an effective means to combat many chronic diabetic complications. Preventing adipogenesis may restore stem cell numbers in diabetic patients enabling endogenous repair.

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