Keunhee Oh†‡∇, Sae Rom Kim§∇, Dae-Kyum Kim§, Myung Won Seo†‡, Changjin Lee§, Hak Mo Lee∥, Ju-Eun Oh#, Eun Young Choi†, Dong-Sup Lee*†‡, Yong Song Gho*§, and Kyong Soo Park*∥⊥#
†Department of Biomedical Sciences, ‡Transplantation Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea
§ Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, Korea
∥ Biomedical Research Institute, Seoul National University Hospital, Seoul 110-744, Korea
⊥ Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea
# Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 110-799, Korea
∇Author Contributions
These authors contributed equally to this work.
*Correspondence to : Dong-Sup Lee, Yong Song Gho, Kyong Soo Park
Abstract
The current diabetes mellitus pandemic constitutes an important global health problem. Reductions in the mass and function of β-cells contribute to most of the pathophysiology underlying diabetes. Thus, physiological control of blood glucose levels can be adequately restored by replacing functioning β-cell mass. Sources of functional islets for transplantation are limited, resulting in great interest in the development of alternate sources, and recent progress regarding cell fate change via utilization of extracellular vesicles, also known as exosomes and microvesicles, is notable. Thus, this study investigated the therapeutic capacity of extracellular vesicle-mimetic nanovesicles (NVs) derived from a murine pancreatic β-cell line. To differentiate insulin-producing cells effectively, a three-dimensional in vivo microenvironment was constructed in which extracellular vesicle-mimetic NVs were applied to subcutaneous Matrigel platforms containing bone marrow (BM) cells in diabetic immunocompromised mice. Long-term control of glucose levels was achieved over 60 days, and differentiation of donor BM cells into insulin-producing cells in the subcutaneous Matrigel platforms, which were composed of islet-like cell clusters with extensive capillary networks, was confirmed along with the expression of key pancreatic β-cell markers. The resectioning of the subcutaneous Matrigel platforms caused a rebound in blood glucose levels and confirmed the source of functioning β-cells. Thus, efficient differentiation of therapeutic insulin-producing cells was attained in vivo through the use of extracellular vesicle-mimetic NVs, which maintained physiological glucose levels.
Keywords: exosome-mimetic; exosome; regenerative medicine; diabetes; β-cell differentiation; mesenchymal stem cell