Abstract
Transplantation and drug discovery programs for liver diseases are hampered by the shortage of donor tissue. While recent studies have shown that hepatic cells can be derived from human embryonic stem cells (hESCs), few cases have shown selective enrichment of hESC-derived hepatocytes and their integration into host liver tissues. Here we demonstrate that the dissociation and reaggregation procedure after an endodermal differentiation of hESC produces spheroids mainly consisted of cells showing hepatic phenotypes in vitro and in vivo. A combined treatment with Wnt3a and bone morphogenic protein 4 efficiently differentiated hESCs into definitive endoderm in an adherent culture. Dissociation followed by reaggregation of these cells in a nonadherent condition lead to the isolation of spheroid-forming cells that preferentially expressed early hepatic markers from the adherent cell population. Further differentiation of these spheroid cells in the presence of the hepatocyte growth factor, oncostatin M, and dexamethasone produced a highly enriched population of cells exhibiting characteristics of early hepatocytes, including glycogen storage, indocyanine green uptake, and synthesis of urea and albumin. Furthermore, we show that grafted spheroid cells express hepatic features and attenuate the serum aspartate aminotransferase level in a model of acute liver injury. These data suggest that hepatic progenitor cells can be enriched by the spheroid formation of differentiating hESCs and that these cells have engraftment potential to replace damaged liver tissues.
| Original language | English |
|---|---|
| Pages (from-to) | 1818-1829 |
| Number of pages | 12 |
| Journal | Stem Cells and Development |
| Volume | 22 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 2013 Jun 15 |
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ASJC Scopus subject areas
- Cell Biology
- Developmental Biology
- Hematology
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Engraftment potential of spheroid-forming hepatic endoderm derived from human embryonic stem cells. / Kim, Sung Eun; An, Su Yeon; Woo, Dong Hun; Han, Jiyou; Kim, Jong Hyun; Jang, Yu Jin; Son, Jeong Sang; Yang, Hyunwon; Cheon, Yong Pil; Kim, Jong-Hoon.
In: Stem Cells and Development, Vol. 22, No. 12, 15.06.2013, p. 1818-1829.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Engraftment potential of spheroid-forming hepatic endoderm derived from human embryonic stem cells
AU - Kim, Sung Eun
AU - An, Su Yeon
AU - Woo, Dong Hun
AU - Han, Jiyou
AU - Kim, Jong Hyun
AU - Jang, Yu Jin
AU - Son, Jeong Sang
AU - Yang, Hyunwon
AU - Cheon, Yong Pil
AU - Kim, Jong-Hoon
PY - 2013/6/15
Y1 - 2013/6/15
N2 - Transplantation and drug discovery programs for liver diseases are hampered by the shortage of donor tissue. While recent studies have shown that hepatic cells can be derived from human embryonic stem cells (hESCs), few cases have shown selective enrichment of hESC-derived hepatocytes and their integration into host liver tissues. Here we demonstrate that the dissociation and reaggregation procedure after an endodermal differentiation of hESC produces spheroids mainly consisted of cells showing hepatic phenotypes in vitro and in vivo. A combined treatment with Wnt3a and bone morphogenic protein 4 efficiently differentiated hESCs into definitive endoderm in an adherent culture. Dissociation followed by reaggregation of these cells in a nonadherent condition lead to the isolation of spheroid-forming cells that preferentially expressed early hepatic markers from the adherent cell population. Further differentiation of these spheroid cells in the presence of the hepatocyte growth factor, oncostatin M, and dexamethasone produced a highly enriched population of cells exhibiting characteristics of early hepatocytes, including glycogen storage, indocyanine green uptake, and synthesis of urea and albumin. Furthermore, we show that grafted spheroid cells express hepatic features and attenuate the serum aspartate aminotransferase level in a model of acute liver injury. These data suggest that hepatic progenitor cells can be enriched by the spheroid formation of differentiating hESCs and that these cells have engraftment potential to replace damaged liver tissues.
AB - Transplantation and drug discovery programs for liver diseases are hampered by the shortage of donor tissue. While recent studies have shown that hepatic cells can be derived from human embryonic stem cells (hESCs), few cases have shown selective enrichment of hESC-derived hepatocytes and their integration into host liver tissues. Here we demonstrate that the dissociation and reaggregation procedure after an endodermal differentiation of hESC produces spheroids mainly consisted of cells showing hepatic phenotypes in vitro and in vivo. A combined treatment with Wnt3a and bone morphogenic protein 4 efficiently differentiated hESCs into definitive endoderm in an adherent culture. Dissociation followed by reaggregation of these cells in a nonadherent condition lead to the isolation of spheroid-forming cells that preferentially expressed early hepatic markers from the adherent cell population. Further differentiation of these spheroid cells in the presence of the hepatocyte growth factor, oncostatin M, and dexamethasone produced a highly enriched population of cells exhibiting characteristics of early hepatocytes, including glycogen storage, indocyanine green uptake, and synthesis of urea and albumin. Furthermore, we show that grafted spheroid cells express hepatic features and attenuate the serum aspartate aminotransferase level in a model of acute liver injury. These data suggest that hepatic progenitor cells can be enriched by the spheroid formation of differentiating hESCs and that these cells have engraftment potential to replace damaged liver tissues.
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UR - http://www.scopus.com/inward/citedby.url?scp=84881094106&partnerID=8YFLogxK
U2 - 10.1089/scd.2012.0401
DO - 10.1089/scd.2012.0401
M3 - Article
C2 - 23373441
AN - SCOPUS:84881094106
VL - 22
SP - 1818
EP - 1829
JO - The BMJ
JF - The BMJ
SN - 0730-6512
IS - 12
ER -