Malignant Tumor Formation after Transplantation of Short-Term Cultured Bone Marrow Mesenchymal Stem Cells in Experimental Myocardial Infarction and Diabetic Neuropathy

• Type of Material: Article
• Authors: Jin-Ok Jeong, Tufts University; Ji Woong Han, Emory University; Jin-Man Kim, Chungnam National University; Hyun-Jai Cho, Tufts University; Changwon Park, Emory University; Namho Lee, Tufts University; Dong-Wook Kim, Yonsei University; Young Sup Yoon, Emory University
• Language: English
• Date: 2011-05-27
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 American Heart Association, Inc.
• Final Published Version (URL): http://circres.ahajournals.org/content/108/11/1340
• Title of Journal or Parent Work: Circulation Research
• ISSN: 0009-7330
• Volume: 108
• Issue: 11
• Start Page: 1340
• End Page: 1347
• Grant/Funding Information: This work was supported in part by NIH grants, RO1HL084471, R21HL097353, RC1 GM092035, P01GM85354, and HHSN268201000043C (Program of Excellence in Nanotechnology Award); and Stem Cell Research Center of the 21st Century Frontier Research Program grant SC4300, funded by the Ministry of Science and Technology, Republic of Korea.
• Keywords: transplantation; malignant tumors; Bone marrow; mesenchymal stem cells; ischemia
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Cell

Abstract

Rationale Bone marrow (BM)-derived mesenchymal stem cells (MSCs) hold great promise for cardiovascular cell therapy owing to their multipotency and culture-expandability. Objective The aim of the study was to investigate whether MSCs can treat experimental acute myocardial infarction (MI) and diabetic neuropathy. Methods and Results We isolated mononuclear cells from mouse BM and cultured MSCs in a conventional manner. Flow cytometry analyses of these cultured cells at passage four showed expression of typical MSC markers such as CD44 and CD29, but not hematopoietic markers such as c-kit, flk1 and CD34. To determine the therapeutic effects of MSCs, we injected MSCs into the periinfarct area after ligation of the left anterior descending coronary arteries of mice, and as separate experiments injected the same batch of MSCs into hindlimb muscles of mice with diabetic neuropathy. During the follow-up at 4–8 weeks after cell transplantation, growing tumors were observed in 30% of hearts in the MI model, and in 46% of hindlimbs in the diabetic neuropathy model. Histologic examination of the tumors revealed hypercelluarity, pleomorphic nucleoli, cytologic atypia and necrosis, and positive staining for α-smooth muscle actin, indicative of malignant sarcoma with myogenic differentiation. Chromosomal analysis of these MSCs showed multiple chromosomal aberrations including fusion, fragmentation, and ring formation. Conclusions Genetically unmodified MSCs can undergo chromosomal abnormalities even at early passages and form malignant tumors when transplanted in vivo. These results suggest that careful monitoring of chromosomal status is warranted when in vitro expanded MSCs are used for cell therapy such as for MI.