title: Human peripheral blood CD34-positive cells enhance therapeutic regeneration of chronically injured liver in nude rats.
abstract: We investigated whether transplantation of purified human peripheral blood CD34(+) cells could reduce established liver fibrosis and up-regulate therapeutic regeneration. Human peripheral blood CD34(+) cells were isolated from total mononuclear cells of healthy volunteers by magnetic cell sorting. Recipient nude rats were injected intraperitoneally with carbon tetrachloride (CCl(4)) twice weekly for 3 weeks before single administration of CD34(+) cells. CCl(4) was then re-administered twice weekly for 3 more weeks, and the nude rats were sacrificed. Saline (control group), 1 × 10(5) (low-dose group), 5 × 10(5) (middle-dose group), or 2 × 10(6) (high-dose group) CD34(+) cells/kg body weight were intrasplenically transplanted after CCl(4) treatment for 3 weeks. Reverse transcriptase-polymerase chain reaction analysis of the freshly isolated CD34(+) cells revealed the expression of CD31, keratin19, α-smooth muscle actin (α-SMA), and epithelial growth factor, but not other liver related markers. The transplanted cells differentiated into vascular and sinusoidal endothelial cells, and vascular smooth muscle cells. CD34(+) cell transplantation reduced liver fibrosis in a dose-dependent fashion, with decreased collagen type-I and α-SMA-positive cells after 6 weeks of CCl(4) treatment by Mallory's Azan and immunohistochemical staining. Gelatin zymography showed that the expression levels of active matrix metalloproteinase-2 and -9 in CD34(+) cell transplanted livers were significantly stronger than those in saline-infused livers. In recipients of high-doses of CD34(+) cells, the number of PCNA-positive hepatocyte increased 6 weeks after CCl(4) treatment compared with saline-infused livers. We conclude that human peripheral blood CD34(+) cell transplantation halts established liver fibrosis and promotes hepatic regeneration in CCl(4)-induced chronic liver injury.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan. ntoru@med.kurume-u.ac.jp
authors.forename: Toru
authors.initials: T
authors.lastname: Nakamura
authors.forename: Victor
authors.initials: V
authors.lastname: Tsutsumi
authors.forename: Takuji
authors.initials: T
authors.lastname: Torimura
authors.forename: Masako
authors.initials: M
authors.lastname: Naitou
authors.forename: Hideki
authors.initials: H
authors.lastname: Iwamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Masuda
authors.forename: Osamu
authors.initials: O
authors.lastname: Hashimoto
authors.forename: Hironori
authors.initials: H
authors.lastname: Koga
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Abe
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ii
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Kawamoto
authors.forename: Takayuki
authors.initials: T
authors.lastname: Asahara
authors.forename: Takato
authors.initials: T
authors.lastname: Ueno
authors.forename: Michio
authors.initials: M
authors.lastname: Sata
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001483:Base Sequence; D002251:Carbon Tetrachloride / Q000633:toxicity; D002454:Cell Differentiation; D002470:Cell Survival; D056487:Chemical and Drug Induced Liver Injury, Chronic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D017931:DNA Primers / Q000235:genetics; D042783:Endothelial Cells / Q000473:pathology; D015870:Gene Expression; D055166:Hepatic Stellate Cells / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology / Q000628:therapy; D008115:Liver Regeneration / Q000235:genetics / Q000502:physiology; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D036102:Peripheral Blood Stem Cell Transplantation; D051381:Rats; D011916:Rats, Inbred F344; D011923:Rats, Nude; D014183:Transplantation, Heterologous
chemical_list: D018952:Antigens, CD34; D017931:DNA Primers; D002251:Carbon Tetrachloride