Published online before print January 26, 2009, doi: 10.1161/CIRCULATIONAHA.108.789297
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(Circulation. 2009;119:699-708.)
© 2009 American Heart Association, Inc.
Molecular Cardiology |
Dual Angiogenic and Neurotrophic Effects of Bone Marrow–Derived Endothelial Progenitor Cells on Diabetic Neuropathy
From the Division of Cardiovascular Research, Caritas St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass (J.-O.J., M.-O.K., H.K., S.-W.K., M.I., J.-u.L., J.L., Y.J.C., H.-J.C., N.L., M.S., A.W., Y.-s.Y.); Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Ga (M.-O.K., H.K., M.-Y.L., S.-W.K., J.L., Y.J.C., Y.-S.Y.); Department of Internal Medicine, Seoul National University Hospital, Seoul, South Koria (H.-J.C.); Division of Cardiology, Hallym University School of Medcine, Seoul, South Korea (N.L.); and Stem Cell Research Center, 21C R&D Program of Ministry of Education, Science, and Technology, Yonsei University Medical Center, Seoul, South Korea (D.-W.K.). Dr Jeong is currently at the Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, South Korea. Dr Cho is currently at the Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea. Dr N. Lee is currently at the Division of Cardiology, Hallym University School of Medicine, Seoul, South Korea.
Correspondence to Young-sup Yoon, MD, PhD, Division of Cardiology, Department of Medicine, Emory University School of Medicine, 1639 Pierce Dr, WMB 319, Atlanta, GA 30322. E-mail yyoon5{at}emory.edu
Received April 29, 2008; accepted November 28, 2008.
Background— Endothelial progenitor cells (EPCs) are known to promote neovascularization in ischemic diseases. Recent evidence suggested that diabetic neuropathy is causally related to impaired angiogenesis and deficient growth factors. Accordingly, we investigated whether diabetic neuropathy could be reversed by local transplantation of EPCs.
Methods and Results— We found that motor and sensory nerve conduction velocities, blood flow, and capillary density were reduced in sciatic nerves of streptozotocin-induced diabetic mice but recovered to normal levels after hind-limb injection of bone marrow–derived EPCs. Injected EPCs were preferentially and durably engrafted in the sciatic nerves. A portion of engrafted EPCs were uniquely localized in close proximity to vasa nervorum, and a smaller portion of these EPCs were colocalized with endothelial cells. Multiple angiogenic and neurotrophic factors were significantly increased in the EPC-injected nerves. These dual angiogenic and neurotrophic effects of EPCs were confirmed by higher proliferation of Schwann cells and endothelial cells cultured in EPC-conditioned media.
Conclusions— We demonstrate for the first time that bone marrow-derived EPCs could reverse various manifestations of diabetic neuropathy. These therapeutic effects were mediated by direct augmentation of neovascularization in peripheral nerves through long-term and preferential engraftment of EPCs in nerves and particularly vasa nervorum and their paracrine effects. These findings suggest that EPC transplantation could represent an innovative therapeutic option for treating diabetic neuropathy.
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Circulation 2009 119: 649-651.[Extract] [Full Text]