Dual Angiogenic and Neurotrophic Effects of Bone Marrow-Derived Endothelial Progenitor Cells on Diabetic Neuropathy

• Type of Material: Article
• Authors: Jin-Ok Jeong, Chungnam National University; Mee-Ohk Kim, Tufts University School of Medicine; Hyongbum Kim, Tufts University School of Medicine; Min-Young Lee, Tufts University School of Medicine; Sung-Whan Kim, Tufts University School of Medicine; Masaaki Ii, Tufts University School of Medicine; Jung-uek Lee, Tufts University School of Medicine; Jiyoon Lee, Tufts University School of Medicine; Yong Jin Choi, Tufts University School of Medicine; Hyun-Jai Cho, Tufts University School of Medicine; Namho Lee, Hallym University School of Medicine; Marcy Silver, Tufts University School of Medicine; Andrea Wecker, Tufts University School of Medicine; Dong-Wook Kim, Yonsei University Medical Center; Young-sup Yoon, Emory University
• Language: English
• Date: 2009-02-10
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 American Heart Association, Inc
• Final Published Version (URL): http://circ.ahajournals.org/content/119/5/699.long
• Title of Journal or Parent Work: Circulation
• ISSN: 0009-7322
• Volume: 119
• Issue: 5
• Start Page: 699
• End Page: 708
• Grant/Funding Information: This work was supported in part by National Institutes of Health grants (HL079137, HL084471), a Juvenile Diabetic Research Foundation Innovation grant (5-2007-951), and a grant (SC4071) from Stem Cell Research Center of the 21st Century Frontier Research Program funded by the Ministry of Science and Technology, Republic of Korea.
• Keywords: angiogenesis; progenitor cells; diabetic neuropathy; diabetes mellitus
• Research Categories: Health Sciences, General; Biology, Cell

Abstract

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.