title: Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion.
abstract: Hepatic transdifferentiation of bone marrow cells has been previously demonstrated by intravenous administration of donor cells, which may recirculate to the liver after undergoing proliferation and differentiation in the recipient's bone marrow. In the present study, to elucidate which cellular components of human bone marrow more potently differentiate into hepatocytes, we fractionated human bone marrow cells into mesenchymal stem cells (MSCs), CD34+ cells, and non-MSCs/CD34- cells and examined them by directly xenografting to allylalcohol (AA)-treated rat liver. Hepatocyte-like cells, as revealed by positive immunostaining for human-specific alpha-fetoprotein (AFP), albumin (Alb), cytokeratin 19 (CK19), cytokeratin 18 (CK18), and asialoglycoprotein receptor (AGPR), and by reverse transcription-polymerase chain reaction (RT-PCR) for expression of AFP and Alb mRNA, were observed only in recipient livers with MSC fractions. Cell fusion was not likely involved since both human and rat chromosomes were independently identified by fluorescence in situ hybridization (FISH). The differentiation appeared to follow the process of hepatic ontogeny, reprogramming of gene expression in the genome of MSCs, as evidenced by expression of the AFP gene at an early stage and the albumin gene at a later stage. In conclusion, we have demonstrated that MSCs are the most potent component in hepatic differentiation, as revealed by directly xenografting into rat livers.
authors.affiliation: Fourth Department of Internal Medicine, Sapporo Medical University, School of Medicine, Sapporo, 060-8543, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sato
authors.forename: Hironobu
authors.initials: H
authors.lastname: Araki
authors.forename: Junji
authors.initials: J
authors.lastname: Kato
authors.forename: Kiminori
authors.initials: K
authors.lastname: Nakamura
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawano
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kobune
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sato
authors.forename: Koji
authors.initials: K
authors.lastname: Miyanishi
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Takayama
authors.forename: Minoru
authors.initials: M
authors.lastname: Takahashi
authors.forename: Rishu
authors.initials: R
authors.lastname: Takimoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Iyama
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsunaga
authors.forename: Seiji
authors.initials: S
authors.lastname: Ohtani
authors.forename: Akihiro
authors.initials: A
authors.lastname: Matsuura
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hamada
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Niitsu
mesh_terms: D000418:Albumins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D037263:Asialoglycoprotein Receptor / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation; D005260:Female; D015870:Gene Expression; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007633:Keratins / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000378:metabolism / Q000601:surgery*; D008561:Membrane Fusion; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014183:Transplantation, Heterologous; D000509:alpha-Fetoproteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000418:Albumins; D018952:Antigens, CD34; D037263:Asialoglycoprotein Receptor; D012333:RNA, Messenger; D000509:alpha-Fetoproteins; D007633:Keratins