Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion

Yasushi Sato, Hironobu Araki, Junji Kato, Kiminori Nakamura, Yutaka Kawano, Masayoshi Kobune, Tsutomu Sato, Koji Miyanishi, Tetsuji Takayama, Minoru Takahashi, Rishu Takimoto, Satoshi Iyama, Takuya Matsunaga, Seiji Ohtani, Akihiro Matsuura, Hirofumi Hamada, Yoshiro Niitsu

Research output: Contribution to journalArticle

503 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)756-763
Number of pages8
JournalBlood
Volume106
Issue number2
DOIs
Publication statusPublished - 15-07-2005

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Stem cells
Mesenchymal Stromal Cells
Liver
Rats
Hepatocytes
Fusion reactions
Bone
alpha-Fetoproteins
Genes
Heterologous Transplantation
Albumins
Cells
Asialoglycoprotein Receptor
Bone Marrow Cells
Keratin-18
Keratin-19
Polymerase chain reaction
Bone Marrow
Transcription
Chromosomes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Sato, Y., Araki, H., Kato, J., Nakamura, K., Kawano, Y., Kobune, M., ... Niitsu, Y. (2005). Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion. Blood, 106(2), 756-763. https://doi.org/10.1182/blood-2005-02-0572
Sato, Yasushi ; Araki, Hironobu ; Kato, Junji ; Nakamura, Kiminori ; Kawano, Yutaka ; Kobune, Masayoshi ; Sato, Tsutomu ; Miyanishi, Koji ; Takayama, Tetsuji ; Takahashi, Minoru ; Takimoto, Rishu ; Iyama, Satoshi ; Matsunaga, Takuya ; Ohtani, Seiji ; Matsuura, Akihiro ; Hamada, Hirofumi ; Niitsu, Yoshiro. / Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion. In: Blood. 2005 ; Vol. 106, No. 2. pp. 756-763.
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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.",
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Sato, Y, Araki, H, Kato, J, Nakamura, K, Kawano, Y, Kobune, M, Sato, T, Miyanishi, K, Takayama, T, Takahashi, M, Takimoto, R, Iyama, S, Matsunaga, T, Ohtani, S, Matsuura, A, Hamada, H & Niitsu, Y 2005, 'Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion', Blood, vol. 106, no. 2, pp. 756-763. https://doi.org/10.1182/blood-2005-02-0572

Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion. / Sato, Yasushi; Araki, Hironobu; Kato, Junji; Nakamura, Kiminori; Kawano, Yutaka; Kobune, Masayoshi; Sato, Tsutomu; Miyanishi, Koji; Takayama, Tetsuji; Takahashi, Minoru; Takimoto, Rishu; Iyama, Satoshi; Matsunaga, Takuya; Ohtani, Seiji; Matsuura, Akihiro; Hamada, Hirofumi; Niitsu, Yoshiro.

In: Blood, Vol. 106, No. 2, 15.07.2005, p. 756-763.

Research output: Contribution to journalArticle

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T1 - Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion

AU - Sato, Yasushi

AU - Araki, Hironobu

AU - Kato, Junji

AU - Nakamura, Kiminori

AU - Kawano, Yutaka

AU - Kobune, Masayoshi

AU - Sato, Tsutomu

AU - Miyanishi, Koji

AU - Takayama, Tetsuji

AU - Takahashi, Minoru

AU - Takimoto, Rishu

AU - Iyama, Satoshi

AU - Matsunaga, Takuya

AU - Ohtani, Seiji

AU - Matsuura, Akihiro

AU - Hamada, Hirofumi

AU - Niitsu, Yoshiro

PY - 2005/7/15

Y1 - 2005/7/15

N2 - 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.

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