Bone marrow progenitor cells repair rat hepatic sinusoidal endothelial cells after liver injury.
OBJECTIVE
Damage to hepatic sinusoidal endothelial cells (SECs) initiates sinusoidal obstruction syndrome (SOS), which is most commonly a consequence of myeloablative chemoirradiation or ingestion of pyrrolizidine alkaloids such as monocrotaline (Mct). This study examines whether SECs are of bone marrow origin, whether bone marrow repair can be a determinant of severity of liver injury, and whether treatment with progenitor cells is beneficial.


METHODS
Mct-treated female rats received infusion of male whole bone marrow or CD133(+) cells at the peak of sinusoidal injury. The Y chromosome was identified in isolated SECs by fluorescent in situ hybridization. Bone marrow suppression was induced by irradiation of both lower extremities with shielding of the abdomen.


RESULTS
SECs in uninjured liver have both hematopoietic (CD45, CD33) and endothelial (CD31) markers. After Mct-induced SOS, infusion of bone marrow-derived CD133(+) progenitor cells replaces more than one quarter of SECs. All CD133(+) cells recovered from the SEC fraction after injury are CD45(+). CD133(+)/CD45(+) progenitors also repaired central vein endothelium. Mct suppresses CD133(+)/CD45(+) progenitors in bone marrow by 50% and in the circulation by 97%. Irradiation-induced bone marrow suppression elicited SOS from a subtoxic dose of Mct, whereas infusion of bone marrow during the necrotic phase of SOS nearly eradicates histologic features of SOS.


CONCLUSIONS
SECs have both hematopoietic and endothelial markers. Bone marrow-derived CD133(+)/CD45(+) progenitors replace SECs and central vein endothelial cells after injury. Toxicity to bone marrow progenitors impairs repair and contributes to the pathogenesis of SOS, whereas timely infusion of bone marrow has therapeutic benefit.
Harb
Rula
R
Division of Gastrointestinal and Liver Diseases and the USC Research Center for Liver Diseases, University of Southern California Keck School of Medicine, Los Angeles, California 90033, USA.
Xie
Guanhua
G
Lutzko
Carolyn
C
Guo
Yumei
Y
Wang
Xiangdong
X
Hill
Colin K
CK
Kanel
Gary C
GC
DeLeve
Laurie D
LD
D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis; D016026:Bone Marrow Transplantation / Q000379:methods*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D006504:Hepatic Veno-Occlusive Disease / Q000473:pathology* / Q000628:therapy*; D007150:Immunohistochemistry; D008115:Liver Regeneration / Q000502:physiology; D008297:Male; D011336:Probability; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D063268:Sialic Acid Binding Ig-like Lectin 3; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015415:Biomarkers; D063268:Sialic Acid Binding Ig-like Lectin 3