Bone marrow isolated from pre-clinical models of diabetes contains significantly fewer multipotential progenitor cells with reduced osteo-, chondro-, angiogenic differentiation capacity as compared to non-diabetic marrow isolates. A return to glucose homeostasis does not restore the capacity of previously diabetic mesenchymal stromal cells (MSCs). This application proposes that malfunctioning MSCs in diabetic patients significantly contribute to the pathology underlying diabetes-associated complications through their inability to support organ homeostasis. Clarification of the aetiology suppressing MSC function in the setting of hyperglycaemia provides an underpinning pathologic mechanism for diabetesassociated complications. Of particular interest is the dysfunction of bone marrow MSCs leading to an imbalance in bone organ homeostasis, culminating in diabetes-associated osteoporosis. Bone fragility due to diabetes-associated osteoporosis is an underappreciated complication of type 1 diabetes (T1DM) where an imbalance in osteoblast differentiation and activity result in instability in bone architecture and decreased bone mineral content. Together, the
insufficient bone composition results in an increased incidence of long bone fracture in T1DM patients. This project therefore aims to identify diabetes-associated changes in MSCs gene expression resulting in their dysfunction in a diabetic environment. This goal will be accomplished by 1) studies in humans profiling the mRNA of diabetic bone marrow derived MSCs, age-matched MSCs from osteoporotic donors and young, non-diabetic MSCs thereby identifying transcriptionally dysregulated genes, 2) modify the potential of diabetic MSCs with factors identified in Aim 1 and evaluate their efficacy to rejuvenate organ homeostasis in a murine model of diabetes induced osteoporosis and 3) to collaborate with T1DM patients in designing these studies to address health concerns and priorities.