Stem cell mobilization is life saving in an animal model of acute liver failure.
OBJECTIVE
No therapy except liver transplantation currently exists for patients with acute liver failure (ALF). The aim of this study was to determine whether pharmacologic mobilization of endogenous hematopoietic stem cells (HSCs) can aid in liver repair and improve survival in an animal model of ALF.


METHODS
Rodents were treated with a single near-lethal intraperitoneal injection of carbon tetrachloride (CCl4). After 12 hours, animals were randomized to receive plerixafor and granulocyte colony-stimulating factor (G-CSF), agents known to mobilize marrow-derived stem cells, or saline vehicle injection. Mice were observed for survival, and serial assessment of liver injury by serum transaminase measurements, and histologic analysis was performed.


RESULTS
In our ALF model, 7-day survival after injection of CCl4 was 25%. Administration of plerixafor and G-CSF following CCl4 resulted in 87% survival (n = 8, P < 0.05). On serial histopathologic analysis, animals treated with plerixafor and G-CSF demonstrated less hepatic injury compared with control animals. Evaluation of peripheral blood demonstrated an increase in circulating HSCs in response to plerixafor and G-CSF, and immunostaining suggested the infiltration of HSCs into the hepatic parenchyma after stem cell mobilization.


CONCLUSIONS
Our results suggest a possible new treatment strategy for patients with ALF, a group for whom either liver transplantation or death is frequently the outcome. Pharmacologic agents that mobilize HSCs may lead to an infiltration of the injured liver with cells that may participate in or expedite liver regeneration. This therapy has the potential to avert liver transplantation in some patients with ALF and may be of benefit in a wide variety of medical and surgical patients with liver injury.
Mark
Anthony L
AL
Department of Surgery, Walter Reed Army Hospital, Bethesda, MD, USA.
Sun
Zhaoli
Z
Warren
Daniel S
DS
Lonze
Bonnie E
BE
Knabel
Matthew K
MK
Melville Williams
George M
GM
Locke
Jayme E
JE
Montgomery
Robert A
RA
Cameron
Andrew M
AM
D000818:Animals; D018952:Antigens, CD34 / Q000276:immunology; D001596:Benzylamines; D002251:Carbon Tetrachloride; D000080027:Cyclams; D005260:Female; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006571:Heterocyclic Compounds / Q000627:therapeutic use*; D007150:Immunohistochemistry; D008099:Liver / Q000276:immunology / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D051381:Rats; D011917:Rats, Inbred Lew; D000637:Transaminases / Q000097:blood
D018952:Antigens, CD34; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D016179:Granulocyte Colony-Stimulating Factor; D002251:Carbon Tetrachloride; D000637:Transaminases; C088327:plerixafor