Malignant tumor formation after transplantation of short-term cultured bone marrow mesenchymal stem cells in experimental myocardial infarction and diabetic neuropathy

Jin Ok Jeong, Ji Woong Han, Jin Man Kim, Hyun Jai Cho, Changwon Park, Namho Lee, Dong Wook Kim, Young Sup Yoon

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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 4 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 peri-infarct 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 to 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. Histological examination of the tumors revealed hypercelluarity, pleomorphic nucleoli, cytological 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.

Original languageEnglish
Pages (from-to)1340-1347
Number of pages8
JournalCirculation Research
Volume108
Issue number11
DOIs
Publication statusPublished - 2011 May 27

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Diabetic Neuropathies
Mesenchymal Stromal Cells
Transplantation
Bone Marrow
Myocardial Infarction
Neoplasms
Hindlimb
Cell- and Tissue-Based Therapy
Chromosome Aberrations
Cell Transplantation
Therapeutic Uses
Bone Marrow Cells
Sarcoma
Ligation
Smooth Muscle
Actins
Cultured Cells
Coronary Vessels
Flow Cytometry
Necrosis

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Jeong, Jin Ok ; Han, Ji Woong ; Kim, Jin Man ; Cho, Hyun Jai ; Park, Changwon ; Lee, Namho ; Kim, Dong Wook ; Yoon, Young Sup. / Malignant tumor formation after transplantation of short-term cultured bone marrow mesenchymal stem cells in experimental myocardial infarction and diabetic neuropathy. In: Circulation Research. 2011 ; Vol. 108, No. 11. pp. 1340-1347.
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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 4 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 peri-infarct 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 to 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. Histological examination of the tumors revealed hypercelluarity, pleomorphic nucleoli, cytological 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.",
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Malignant tumor formation after transplantation of short-term cultured bone marrow mesenchymal stem cells in experimental myocardial infarction and diabetic neuropathy. / Jeong, Jin Ok; Han, Ji Woong; Kim, Jin Man; Cho, Hyun Jai; Park, Changwon; Lee, Namho; Kim, Dong Wook; Yoon, Young Sup.

In: Circulation Research, Vol. 108, No. 11, 27.05.2011, p. 1340-1347.

Research output: Contribution to journalArticle

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AU - Jeong, Jin Ok

AU - Han, Ji Woong

AU - Kim, Jin Man

AU - Cho, Hyun Jai

AU - Park, Changwon

AU - Lee, Namho

AU - Kim, Dong Wook

AU - Yoon, Young Sup

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