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Bone Marrow (BM) Transplantation Promotes ß-Cell Regeneration after Acute Injury through BM Cell Mobilization

Division of Advanced Therapeutics for Metabolic Diseases (Y.H., T.O., J.I., K.U., J.G., K.K., H.K.), Center for Translational and Advanced Animal Research, Division of Molecular Metabolism and Diabetes (Y.H., T.Y., Y.I., J.I., K.U., J.G., K.K., H.I., Y.O.), and Department of Pathology (H.S.), Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; and Laboratory of Stem Cell Therapy (H.N.), Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan

Address all correspondence and requests for reprints to: Hideki Katagiri, M.D., Ph.D., Division of Advanced Therapeutics for Metabolic Diseases, Center for Translational and Advanced Animal Research, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. E-mail: katagiri{at}mail.tains.tohoku.ac.jp.

There is controversy regarding the roles of bone marrow (BM)-derived cells in pancreatic ß-cell regeneration. To examine these roles in vivo, mice were treated with streptozotocin (STZ), followed by bone marrow transplantation (BMT; lethal irradiation and subsequent BM cell infusion) from green fluorescence protein transgenic mice. BMT improved STZ-induced hyperglycemia, nearly normalizing glucose levels, with partially restored pancreatic islet number and size, whereas simple BM cell infusion without preirradiation had no effects. In post-BMT mice, most islets were located near pancreatic ducts and substantial numbers of bromodeoxyuridine-positive cells were detected in islets and ducts. Importantly, green fluorescence protein-positive, i.e. BM-derived, cells were detected around islets and were CD45 positive but not insulin positive. Then to examine whether BM-derived cell mobilization contributes to this process, we used Nos3^–/– mice as a model of impaired BM-derived cell mobilization. In streptozotocin-treated Nos3^–/– mice, the effects of BMT on blood glucose, islet number, bromodeoxyuridine-positive cells in islets, and CD45-positive cells around islets were much smaller than those in streptozotocin-treated Nos3^+/+ controls. A series of BMT experiments using Nos3^+/+ and Nos3^–/– mice showed hyperglycemia-improving effects of BMT to correlate inversely with the severity of myelosuppression and delay of peripheral white blood cell recovery. Thus, mobilization of BM-derived cells is critical for BMT-induced ß-cell regeneration after injury. The present results suggest that homing of donor BM-derived cells in BM and subsequent mobilization into the injured periphery are required for BMT-induced regeneration of recipient pancreatic ß-cells.

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