title: A Distinct Subpopulation of Bone Marrow Mesenchymal Stem Cells, Muse Cells, Directly Commit to the Replacement of Liver Components.
abstract: Genotyping graft livers by short tandem repeats after human living-donor liver transplantation (n = 20) revealed the presence of recipient or chimeric genotype cases in hepatocytes (6 of 17, 35.3%), sinusoidal cells (18 of 18, 100%), cholangiocytes (15 of 17, 88.2%) and cells in the periportal areas (7 of 8, 87.5%), suggesting extrahepatic cell involvement in liver regeneration. Regarding extrahepatic origin, bone marrow mesenchymal stem cells (BM-MSCs) have been suggested to contribute to liver regeneration but compose a heterogeneous population. We focused on a more specific subpopulation (1-2% of BM-MSCs), called multilineage-differentiating stress-enduring (Muse) cells, for their ability to differentiate into liver-lineage cells and repair tissue. We generated a physical partial hepatectomy model in immunodeficient mice and injected green fluorescent protein (GFP)-labeled human BM-MSC Muse cells intravenously (n = 20). Immunohistochemistry, fluorescence in situ hybridization and species-specific polymerase chain reaction revealed that they integrated into regenerating areas and expressed liver progenitor markers during the early phase and then differentiated spontaneously into major liver components, including hepatocytes (≈74.3% of GFP-positive integrated Muse cells), cholangiocytes (≈17.7%), sinusoidal endothelial cells (≈2.0%), and Kupffer cells (≈6.0%). In contrast, the remaining cells in the BM-MSCs were not detected in the liver for up to 4 weeks. These results suggest that Muse cells are the predominant population of BM-MSCs that are capable of replacing major liver components during liver regeneration.
authors.affiliation: Molecular Therapeutics Laboratory, Iwate Medical University School of Medicine, Morioka, Japan.|Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Katagiri
authors.affiliation: Department of Anatomy and Anthropology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kushida
authors.affiliation: Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Nojima
authors.affiliation: Department of Anatomy and Anthropology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kuroda
authors.affiliation: Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Wakao
authors.affiliation: Molecular Therapeutics Laboratory, Iwate Medical University School of Medicine, Morioka, Japan.|Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ishida
authors.affiliation: Molecular Therapeutics Laboratory, Iwate Medical University School of Medicine, Morioka, Japan.|Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan.
authors.forename: F
authors.initials: F
authors.lastname: Endo
authors.affiliation: Molecular Therapeutics Laboratory, Iwate Medical University School of Medicine, Morioka, Japan.|Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan.|Institute for Biomedical Sciences, Iwate Medical University, Yahaba, Japan.|Medical Innovation by Advanced Science and Technology Program, Iwate Medical University, Morioka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kume
authors.affiliation: Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Takahara
authors.affiliation: Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Nitta
authors.affiliation: Diagnostic Pathology Section, Clinical Laboratory Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Tsuda
authors.affiliation: Department of Anatomy and Anthropology, Tohoku University Graduate School of Medicine, Sendai, Japan.|Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Dezawa
authors.affiliation: Molecular Therapeutics Laboratory, Iwate Medical University School of Medicine, Morioka, Japan.|Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan.|Institute for Biomedical Sciences, Iwate Medical University, Yahaba, Japan.|Medical Innovation by Advanced Science and Technology Program, Iwate Medical University, Morioka, Japan.|Department of Surgery, Iwate Medical University School of Dentistry, Morioka, Japan.|Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Yahaba, Japan.
authors.forename: S S
authors.initials: SS
authors.lastname: Nishizuka
mesh_terms: D000328:Adult; D000818:Animals; D016026:Bone Marrow Transplantation; D002648:Child; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008107:Liver Diseases / Q000601:surgery*; D008115:Liver Regeneration / Q000502:physiology*; D016031:Liver Transplantation / Q000009:adverse effects; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D011183:Postoperative Complications / Q000628:therapy*; D011379:Prognosis
keywords: basic (laboratory) research; hepatology; liver transplantation; living donor; regenerative medicine; science; stem cells; translational research