Hepatic injury and the kinetics of bone marrow-derived hepatocyte transgene expression.
BACKGROUND
Numerous congenital and acquired liver diseases could benefit from a successful hepatic cell therapy strategy. Hepatotypic cells derived from bone marrow have been recognized during liver injury, repair, and regeneration. To study this phenomenon, we compared the effect of several modes of experimental hepatic injury on hepatotypic protein expression in a mouse model after bone marrow transplantation.


METHODS
Male mice transgenic for the liver-specific protein human alpha-1 antitrypsin (hAAT) were used as bone marrow donors. Syngeneic wild-type recipient mice were subjected to 1 of 3 hepatic injuries: (1) sublethal irradiation, (2) injection of a hepatotoxic adenoviral construct, and (3) administration of a hepatotoxic diet. Bone marrow-derived hepatotypic (BMdH) transgene expression was determined by serial serum enzyme-linked immunosorbent assay for hAAT.


RESULTS
In both acute injury models, hAAT expression was detected as early as 1 week, whereas the control group never elicited hAAT expression. The adenovirus-treated group demonstrated transient hAAT level expression lasting up to 2 weeks postinjury, whereas the irradiated group maintained persistent hAAT expression through 4 months. In the chronic injury (hepatotoxin) model, hAAT expression persisted and was noted to increase over time to 200 to 300 ng/mL.


CONCLUSIONS
Irradiation favors long-term establishment of BMdH transgene expression, and chronic injury further promotes this phenomenon.
Perryman
Scott V
SV
Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
Jenkins
D Denny
DD
Streetz
Konrad L
KL
Longaker
Michael T
MT
Sylvester
Karl G
KG
D000208:Acute Disease; D000818:Animals; D016026:Bone Marrow Transplantation; D002465:Cell Movement / Q000235:genetics* / Q000502:physiology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000637:transplantation*; D017404:In Situ Hybridization, Fluorescence; D008099:Liver / Q000293:injuries*; D008107:Liver Diseases / Q000235:genetics / Q000628:therapy; D008115:Liver Regeneration / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011336:Probability; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D019076:Transgenes / Q000235:genetics*