Am J Stem Cell 2012;1(2):114-127

Original Article
In vitro generation of functional insulin-producing cells from human bone
marrow-derived stem cells, but long-term culture running risk of malignant

Dong-Qi Tang, Qiwei Wang, Brant R. Burkhardt, Sally A Litherland, Mark A Atkinson, Li-Jun Yang

Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, College of Medicine, Gainesville, Florida, 32610;
Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida; Sanford-Burnham Medical Research
Institute at Lake Nona, Orlando, Florida

Received January 5, 2012; accepted March 23, 2012; Epub April 28, 2012; Published June 30, 2012

Abstract: Efforts involving therapeutic islet cell transplantation have been hampered by limited islet availability and immune rejection. In
vitro transdifferentiation of human bone marrow-derived stem (hBMDS) cells into functional insulin-producing cells promises to provide a
tissue source for autologous cell transplantation. In this study, we isolated hBMDS cells, developed a single-cell-derived stem cell line,
and induced the cells to differentiate into islet-like clusters. These islet-like cells expressed multiple genes related to islet development
and beta cell function (e.g., Pdx-1, Ngn-3, Islet-1, Neuro-D, Pax4, IAPP, and insulin) and produced insulin and C-peptide within these
cells. These islet-like cells demonstrated time-dependent glucose-stimulated insulin release, and the ability to ameliorate
hyperglycemia in chemically induced diabetic mice. However, these transplanted differentiated cells became tumorigenic in diabetic
immunocompromised mice and their spontaneous transformation was confirmed by a marked increase in growth rate and inactivation
of tumor suppressor genes (P21 and P16) by promoter hypermethylation. In conclusion, while hBMDS cells can be transdifferentiated
into competent insulin-producing cells, and while such cell might be a potential source for autologous cell therapy for type 1 diabetes,
caution is strongly advised in view of the neoplastic propensity of hBMDS cells, especially after a long-term culture in

Keywords: Bone marrow, mesenchymal stem cells, differentiation, insulin-producing cells, long-term culture, malignant transformation

Address all correspondence to:
Dr. Li-Jun Yang
1600 SW Archer Road
P.O. Box 100275
Gainesville, FL 32610 US.
Tel: (352) 392-0005; Fax: (352) 392-3053
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