Extrahepatic stem cells mobilized from the bone marrow by the supplementation of branched-chain amino acids ameliorate liver regeneration in an animal model.
OBJECTIVE
In recent years, bone marrow (BM)-derived stem cell repopulation of injured organs has been increasingly observed; however, the extent to which it occurs and its clinical relevance remain unclear. Here, we investigated on the potential of extrahepatic stem cells to become hepatocytes using the treatment of the oral supplementation of branched-chain amino acids (BCAA).


METHODS
In the first, Sprague-Dawley (SD) rats were administered BCAA to promote liver regeneration; in the second, syngenic liver transplantations using wild-type SD rats that do not express green fluorescent protein (GFP) as syngenic donors and GFP-transgenic SD rats as recipients to confirm that an extrahepatic source of cells (GFP(+)) could repopulate the transplanted (GFP(-)) liver were performed.


RESULTS
Treatment of the oral supplementation of BCAA for 2-3 weeks before transplantation to promote liver regeneration resulted in greater than 7 days graft volume, with extensive spotty conversion of a small wild-type graft to the recipient GFP(+) genotype. The treatment by oral supplementation of BCAA resulted in higher levels of CD34+SDF+c-kit+ stem cells in the blood and liver after liver transplantation. Liver repopulation could be achieved with hepatocytes that bone marrow-derived from stem cells proliferated.


CONCLUSIONS
We have identified extrahepatic stem cell migration from the BM to the injured liver as a mechanism underlying liver regeneration that supports hepatocyte proliferation in diseased liver. Our results suggested that BCAA is able to mobilize a population of BM-derived cells that contribute to hepatic regeneration.
Department of Surgery, Kochi Medical School, Kochi, Japan; Department of Biostatistics, Kochi Medical School, Kochi, Japan.
Takehiro
T
Okabayashi
Yasuo
Y
Shima
Tatsuaki
T
Sumiyoshi
Akihito
A
Kozuki
Tatsuo
T
Iiyama
Teppei
T
Tokumaru
Tsutomu
T
Namikawa
Takeki
T
Sugimoto
Yuka
Y
Takezaki
Hiromichi
H
Maeda
Michiya
M
Kobayashi
Kazuhiro
K
Hanazaki
D000284:Administration, Oral; D000597:Amino Acids, Branched-Chain / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D022781:Hepatocytes; D008099:Liver / Q000166:cytology* / Q000502:physiology*; D008115:Liver Regeneration / Q000187:drug effects; D023421:Models, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects*; D013268:Stimulation, Chemical; D013997:Time Factors
D000597:Amino Acids, Branched-Chain
CD34; CXCR4; SDF-1; branched-chain amino-acids; liver regeneration; stem cell