Theranostic effect of serial manganese-enhanced magnetic resonance imaging of human embryonic stem cell derived teratoma.

Journal: 
Magn Reson Med
Publication Year: 
2011
Authors: 
J Chung , R Dash , K Kee , J K Barral , H Kosuge , R C Robbins , D Nishimura , Pera R Reijo , P C Yang
Public Summary: 
Although human embryonic stem cells (hESCs) hold therapeutic potential, teratoma formation has deterred clinical applications. Manganese (Mn2+) enters metabolically active cells and can generate high signal intensity on the T1 weighted magnetic resonance imaging. We hypothesized that serial manganese-enhanced MRI could assess hESC-derived teratoma formation and eliminate the teratoma by inducing cytotoxicity through intracellular accumulation of Mn2+. hESCs were transplanted into severe combined immunodeficient mouse (SCID) hindlimbs to form teratoma. Then, these mice were divided into the two groups: chemotherapy group and control group. The chemotherapy group was injected with MnCl2 intraperitoneally three times a week. The control group was given MnCl2 only prior to MRI. Longitudinal evaluation by manganese-enhanced MRI was performed till 8 weeks post-transplant. The chemotherapy group showed significant reduction in the teratoma volume at weeks 6 and 8. Histology revealed increased proportion of dead cells and caspase 3 (apoptosis marker) positive cells in the chemotherapy group. In conclusion, systemic administration of MnCl2 enabled simultaneous monitoring and elimination of hESC-derived teratoma cells by higher intracellular accumulation of Mn2+.
Scientific Abstract: 
Although human embryonic stem cell (hESC) hold therapeutic potential, teratoma formation has deterred clinical translation. Manganese (Mn(2+) ) enters metabolically active cells through voltage-gated calcium channels and subsequently, induces T(1) shortening. We hypothesized that serial manganese-enhanced MRI would have theranostic effect to assess hESC survival, teratoma formation, and hESC-derived teratoma reduction through intracellular accumulation of Mn(2+) . Firefly luciferase transduced hESCs (hESC-Lucs) were transplanted into severe combined immunodeficient mouse hindlimbs to form teratoma. The chemotherapy group was injected with MnCl(2) intraperitoneally three times a week. The control group was given MnCl(2) only prior to manganese-enhanced MRI. Longitudinal evaluation by manganese-enhanced MRI and bioluminescence imaging was performed. The chemotherapy group showed significant reduction in the teratoma volume and luciferase activity at weeks 6 and 8. Histology revealed increased proportion of dead cells and caspase 3 positive cells in the chemotherapy group. Systemic administration of MnCl(2) enabled simultaneous monitoring and elimination of hESC-derived teratoma cells by higher intracellular accumulation of Mn(2+) . Magn Reson Med, 2011. (c) 2011 Wiley Periodicals, Inc.

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