Abstract
Several studies have shown that hepatocytes can be generated from hematopoietic stem cells, but this event is believed to be rare and to require hepatic damage. To investigate this phenomenon in human cells, we used a NOD/SCID/γcnull (NOG) mouse model that can achieve a tremendously high level of chimerism when transplanted with human hematopoietic cells. Even without hepatotoxic treatment other than irradiation, human albumin and α-1-antitrypsin-positive cells were invariably detected in the livers of NOG mice after i.v. transplantation of human cord blood CD34+ cells. Human albumin was detected in the murine sera, indicating functional maturation of the human hepatocytes. Flow cytometric analysis of recipient liver cells in single-cell suspension demonstrated that human albumin-positive cells were also positive for both murine and human MHC and were negative for human CD45. PCR analysis of recipient livers revealed the expression of a wide variety of human hepatocyte- or cholangiocyte-specific mRNAs. These results show that human CD34+ cells fuse with hepatocytes of NOG mice without liver injury, lose their hematopoietic phenotype, and begin hepatocytespecific gene transcription. These phenomena were not observed when CD34- cells were transplanted. Thus, our model revealed a previously unidentified pathway of human hematopoietic stem/progenitor cell differentiation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3499-3510 |
| Number of pages | 12 |
| Journal | FASEB Journal |
| Volume | 21 |
| Issue number | 13 |
| DOIs | |
| State | Published - Nov 2007 |
| Externally published | Yes |
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Keywords
- Bone marrow-derived cell
- Hematopoietic stem/progenitor cell
- Liver regeneration
- Mature hepatocyte
ASJC Scopus subject areas
- Agricultural and Biological Sciences (miscellaneous)
- Biochemistry, Genetics and Molecular Biology(all)
- Biochemistry
- Cell Biology
Cite this
Human cord blood CD34+ cells develop into hepatocytes in the livers of NOD/SCID/γcnull mice through cell fusion. / Fujino, Hisanori; Hiramatsu, Hidefumi; Tsuchiya, Atsunori; Niwa, Akira; Noma, Haruyoshi; Shiota, Mitsutaka; Umeda, Katsutsugu; Yoshimoto, Momoko; Ito, Mamoru; Heike, Toshio; Nakahata, Tatsutoshi.
In: FASEB Journal, Vol. 21, No. 13, 11.2007, p. 3499-3510.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Human cord blood CD34+ cells develop into hepatocytes in the livers of NOD/SCID/γcnull mice through cell fusion
AU - Fujino, Hisanori
AU - Hiramatsu, Hidefumi
AU - Tsuchiya, Atsunori
AU - Niwa, Akira
AU - Noma, Haruyoshi
AU - Shiota, Mitsutaka
AU - Umeda, Katsutsugu
AU - Yoshimoto, Momoko
AU - Ito, Mamoru
AU - Heike, Toshio
AU - Nakahata, Tatsutoshi
PY - 2007/11
Y1 - 2007/11
N2 - Several studies have shown that hepatocytes can be generated from hematopoietic stem cells, but this event is believed to be rare and to require hepatic damage. To investigate this phenomenon in human cells, we used a NOD/SCID/γcnull (NOG) mouse model that can achieve a tremendously high level of chimerism when transplanted with human hematopoietic cells. Even without hepatotoxic treatment other than irradiation, human albumin and α-1-antitrypsin-positive cells were invariably detected in the livers of NOG mice after i.v. transplantation of human cord blood CD34+ cells. Human albumin was detected in the murine sera, indicating functional maturation of the human hepatocytes. Flow cytometric analysis of recipient liver cells in single-cell suspension demonstrated that human albumin-positive cells were also positive for both murine and human MHC and were negative for human CD45. PCR analysis of recipient livers revealed the expression of a wide variety of human hepatocyte- or cholangiocyte-specific mRNAs. These results show that human CD34+ cells fuse with hepatocytes of NOG mice without liver injury, lose their hematopoietic phenotype, and begin hepatocytespecific gene transcription. These phenomena were not observed when CD34- cells were transplanted. Thus, our model revealed a previously unidentified pathway of human hematopoietic stem/progenitor cell differentiation.
AB - Several studies have shown that hepatocytes can be generated from hematopoietic stem cells, but this event is believed to be rare and to require hepatic damage. To investigate this phenomenon in human cells, we used a NOD/SCID/γcnull (NOG) mouse model that can achieve a tremendously high level of chimerism when transplanted with human hematopoietic cells. Even without hepatotoxic treatment other than irradiation, human albumin and α-1-antitrypsin-positive cells were invariably detected in the livers of NOG mice after i.v. transplantation of human cord blood CD34+ cells. Human albumin was detected in the murine sera, indicating functional maturation of the human hepatocytes. Flow cytometric analysis of recipient liver cells in single-cell suspension demonstrated that human albumin-positive cells were also positive for both murine and human MHC and were negative for human CD45. PCR analysis of recipient livers revealed the expression of a wide variety of human hepatocyte- or cholangiocyte-specific mRNAs. These results show that human CD34+ cells fuse with hepatocytes of NOG mice without liver injury, lose their hematopoietic phenotype, and begin hepatocytespecific gene transcription. These phenomena were not observed when CD34- cells were transplanted. Thus, our model revealed a previously unidentified pathway of human hematopoietic stem/progenitor cell differentiation.
KW - Bone marrow-derived cell
KW - Hematopoietic stem/progenitor cell
KW - Liver regeneration
KW - Mature hepatocyte
UR - http://www.scopus.com/inward/record.url?scp=35948953564&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=35948953564&partnerID=8YFLogxK
U2 - 10.1096/fj.06-6109com
DO - 10.1096/fj.06-6109com
M3 - Article
VL - 21
SP - 3499
EP - 3510
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 13
ER -