In vivo differentiation of magnetically labeled mesenchymal stem cells into hepatocytes for cell therapy to repair damaged liver.
OBJECTIVE
It was unclear whether systemically administered mesenchymal stem cells (MSCs) labeled with magnetic nanoparticles can transdifferentiate into hepatocytes. In the present study, we built a new in vivo murine model for monitoring the transdifferentiation of magnetically labeled green fluorescent protein (GFP) positive MSCs into albumin-positive hepatocytes, under the carbon tetrachloride (CCl4) induced persistent liver damage. We also tracked magnetically labeled MSCs by using magnetic resonance imaging (MRI) in vivo.


METHODS
Among the liver damage groups, magnetically labeled GFP-positive MSCs (group A), GFP-positive MSCs (group B), and saline alone (group C) were intravenously injected. In control groups without CCl4 administration magnetically labeled GFP-positive MSCs (group D) were infused, whereas nothing was given in group E. MRI examinations were performed 24 hours and 4 weeks after cell injection in group A, B, and C. Liver-to-muscle contrast-to-noise ratios on T2*-weighted MR images were measured. At 4 weeks, 3 serum biologic liver function markers were analyzed, and mice in all groups were killed for histologic examination.


RESULTS
The results showed that migration of transplanted magnetic labeled cells to the liver was successfully documented with in vivo MRI. Serum liver function markers were changed for all liver damage groups than nondamage control groups (P < 0.05), but still insignificant compared with group C (P > 0.05). Hematoxylin and eosin and Masson staining confirmed the presence of liver damage and hepatic fibrosis in group A, B, and C. Positive Prussian blue stained cells were highly correlated with GFP-positive cells in group A with an average matching rate of 95%. In group D, no iron-GFP-positive cells can be found in the liver. Albumin was expressed in (34% ± 6%) and (35% ± 7%) of GFP-positive cells in group A and B, respectively, and there was no significant difference between the 2 groups.


CONCLUSIONS
Our data demonstrate that magnetic labeling technique synchronized well in GFP expressing MSCs and did not interfere with the transdifferentiation process and amending function of MSCs in vivo. Both magnetically labeled and unlabeled MSCs appeared to have the potential to differentiate into hepatocytes.
Ju
Shenghong
S
Laboratory of Molecular Imaging, Department of Radiology, Zhongda Hospital, Southeast University, Nanjing, China. jsh0836@hotmail.com
Teng
Gao-Jun
GJ
Lu
Haihua
H
Jin
JiYang
J
Zhang
Yu
Y
Zhang
Aifeng
A
Ni
Yicheng
Y
D000818:Animals; D015415:Biomarkers; D064987:Cell- and Tissue-Based Therapy; D004195:Disease Models, Animal; D005260:Female; D005290:Ferric Compounds; D022781:Hepatocytes / Q000000981:diagnostic imaging / Q000637:transplantation*; D007150:Immunohistochemistry; D008099:Liver / Q000000981:diagnostic imaging / Q000473:pathology*; D008103:Liver Cirrhosis / Q000000981:diagnostic imaging / Q000628:therapy*; D008107:Liver Diseases / Q000000981:diagnostic imaging / Q000628:therapy*; D008111:Liver Function Tests; D008279:Magnetic Resonance Imaging; D045164:Mesenchymal Stem Cell Transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles; D011877:Radionuclide Imaging
D015415:Biomarkers; D005290:Ferric Compounds; C000499:ferric oxide