Molecular Imaging of Stem Cell-Induced Reversal of Vascular Complications and Functions in DM
Peripheral arterial disease (PAD) is more common and severe among patients with type-1 diabetes mellitus (DM), results in peripheral ischemia, and is associated with poor clinical outcome. Traditionally, the treatment of PAD has centered on smoking cessation, physical exercise, pharmaceutical vasodilation, whereas current therapies rely on mechanical revascularization through either percutaneous or surgical approaches. More recently, with the evolving knowledge of the potential of progenitor and stem cells as agents of tissue repair, the field of regenerative medicine has moved toward the use of cell based approaches including use of tissue-derived mesenchymal stem cells (MSCs). Indeed, initial clinical trials demonstrated safety and bioactivity of stem cells injected intramuscularly into the ischemic limbs of patients with PAD. However, there is a need to develop imaging strategies which will aid to predict hard end points in long-term outcomes. The principal goal of this project will be to assess the potency of muscle-derived MSCs (mMSCs) as a novel regenerative therapy to repair and reverse diabetic vascular complications. During the course of this study, the mMSCs will be transplanted into ischemic muscle of diabetic and non-diabetic animals subjected to the surgical ligation of right femoral artery, a well-characterized animal model of hindlimb ischemia. Following the transplantation, the pro-angiogenic response of the treatment with mMSCs will be serially monitored using novel, non-invasive imaging strategy including evaluation of peripheral angiogenesis (with PET-CT imaging of avb3 integrin activation), flow recovery (with SPECT-CT imaging of perfusion), and arteriogenesis (with contrast X-ray CT). These imaging indices will be directly related to the measures of muscular function and histopathological evaluations to investigate whether the mMSCs-associated changes in angiogenesis, arteriogenesis, and flow will result in the repair and functional recovery of diabetic muscle. It is worth to emphasize the translational nature of this project - proposed use of clinically available imaging modalities and radiotracers currently approved or being approved in the near future grants potential translation of this technology to diabetic patients with PAD.

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