Direct and indirect contribution of human embryonic stem cellderived hepatocyte-like cells to liver repair in mice

Dong Hun Woo, Suel Kee Kim, Hee Joung Lim, Jeonghoon Heo, Hyung Soon Park, Gum Yong Kang, Sung Eun Kim, Hyun Ju You, Daniel J. Hoeppner, Youngchul Kim, Heechung Kwon, Tae Hyun Choi, Joo Hee Lee, Su Hee Hong, Kang Won Song, Eun Kyung Ahn, Josh G. Chenoweth, Paul J. Tesar, Ronald D G McKay, Jong-Hoon Kim

Research output: Contribution to journalArticle

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Abstract

Background & Aims: Many studies of embryonic stem cells have investigated direct cell replacement of damaged tissues, but little is known about how donor cellderived signals affect host tissue regeneration. We investigated the direct and indirect roles of human embryonic stem cellderived cells in liver repair in mice. Methods: To promote the initial differentiation of human embryonic stem cells into mesendoderm, we activated the β-catenin signaling pathway with lithium; cells were then further differentiated into hepatocyte-like cells. The differentiated cells were purified by indocyanine green staining and laser microdissection and characterized by immunostaining, polymerase chain reaction, biochemical function, electron microscopy, and transplantation analyses. To investigate indirect effects of these cells, secreted proteins (secretomes) were analyzed by a label-free quantitative mass spectrometry. Carbon tetrachloride was used to induce acute liver injury in mice; cells or secreted proteins were administered by intrasplenic or intraperitoneal injection, respectively. Results: The differentiated hepatocyte-like cells had multiple features of normal hepatocytes, engrafted efficiently into mice, and continued to have hepatic features; they promoted proliferation of host hepatocytes and revascularization of injured host liver tissues. Proteomic analysis identified proteins secreted from these cells that might promote host tissue repair. Injection of the secreted proteins into injured livers of mice promoted significant amounts of tissue regeneration without cell grafts. Conclusions: Hepatocyte-like cells derived from human embryonic stem cells contribute to recovery of injured liver tissues in mice, not only by cell replacement but also by delivering trophic factors that support endogenous liver regeneration.

Original languageEnglish
Pages (from-to)602-611
Number of pages10
JournalGastroenterology
Volume142
Issue number3
DOIs
Publication statusPublished - 2012 Mar 1

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Hepatocytes
Liver
Regeneration
Proteins
Catenins
Microdissection
Liver Regeneration
Indocyanine Green
Carbon Tetrachloride
Embryonic Stem Cells
Intraperitoneal Injections
Lithium
Proteomics
Mass Spectrometry
Electron Microscopy
Lasers
Transplantation
Staining and Labeling
Transplants
Polymerase Chain Reaction

Keywords

  • Hepatitis
  • hES Cells
  • Mouse Model
  • Stem Cell Therapy

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Direct and indirect contribution of human embryonic stem cellderived hepatocyte-like cells to liver repair in mice. / Woo, Dong Hun; Kim, Suel Kee; Lim, Hee Joung; Heo, Jeonghoon; Park, Hyung Soon; Kang, Gum Yong; Kim, Sung Eun; You, Hyun Ju; Hoeppner, Daniel J.; Kim, Youngchul; Kwon, Heechung; Choi, Tae Hyun; Lee, Joo Hee; Hong, Su Hee; Song, Kang Won; Ahn, Eun Kyung; Chenoweth, Josh G.; Tesar, Paul J.; McKay, Ronald D G; Kim, Jong-Hoon.

In: Gastroenterology, Vol. 142, No. 3, 01.03.2012, p. 602-611.

Research output: Contribution to journalArticle

Woo, DH, Kim, SK, Lim, HJ, Heo, J, Park, HS, Kang, GY, Kim, SE, You, HJ, Hoeppner, DJ, Kim, Y, Kwon, H, Choi, TH, Lee, JH, Hong, SH, Song, KW, Ahn, EK, Chenoweth, JG, Tesar, PJ, McKay, RDG & Kim, J-H 2012, 'Direct and indirect contribution of human embryonic stem cellderived hepatocyte-like cells to liver repair in mice', Gastroenterology, vol. 142, no. 3, pp. 602-611. https://doi.org/10.1053/j.gastro.2011.11.030
Woo, Dong Hun ; Kim, Suel Kee ; Lim, Hee Joung ; Heo, Jeonghoon ; Park, Hyung Soon ; Kang, Gum Yong ; Kim, Sung Eun ; You, Hyun Ju ; Hoeppner, Daniel J. ; Kim, Youngchul ; Kwon, Heechung ; Choi, Tae Hyun ; Lee, Joo Hee ; Hong, Su Hee ; Song, Kang Won ; Ahn, Eun Kyung ; Chenoweth, Josh G. ; Tesar, Paul J. ; McKay, Ronald D G ; Kim, Jong-Hoon. / Direct and indirect contribution of human embryonic stem cellderived hepatocyte-like cells to liver repair in mice. In: Gastroenterology. 2012 ; Vol. 142, No. 3. pp. 602-611.
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AU - Woo, Dong Hun

AU - Kim, Suel Kee

AU - Lim, Hee Joung

AU - Heo, Jeonghoon

AU - Park, Hyung Soon

AU - Kang, Gum Yong

AU - Kim, Sung Eun

AU - You, Hyun Ju

AU - Hoeppner, Daniel J.

AU - Kim, Youngchul

AU - Kwon, Heechung

AU - Choi, Tae Hyun

AU - Lee, Joo Hee

AU - Hong, Su Hee

AU - Song, Kang Won

AU - Ahn, Eun Kyung

AU - Chenoweth, Josh G.

AU - Tesar, Paul J.

AU - McKay, Ronald D G

AU - Kim, Jong-Hoon

PY - 2012/3/1

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N2 - Background & Aims: Many studies of embryonic stem cells have investigated direct cell replacement of damaged tissues, but little is known about how donor cellderived signals affect host tissue regeneration. We investigated the direct and indirect roles of human embryonic stem cellderived cells in liver repair in mice. Methods: To promote the initial differentiation of human embryonic stem cells into mesendoderm, we activated the β-catenin signaling pathway with lithium; cells were then further differentiated into hepatocyte-like cells. The differentiated cells were purified by indocyanine green staining and laser microdissection and characterized by immunostaining, polymerase chain reaction, biochemical function, electron microscopy, and transplantation analyses. To investigate indirect effects of these cells, secreted proteins (secretomes) were analyzed by a label-free quantitative mass spectrometry. Carbon tetrachloride was used to induce acute liver injury in mice; cells or secreted proteins were administered by intrasplenic or intraperitoneal injection, respectively. Results: The differentiated hepatocyte-like cells had multiple features of normal hepatocytes, engrafted efficiently into mice, and continued to have hepatic features; they promoted proliferation of host hepatocytes and revascularization of injured host liver tissues. Proteomic analysis identified proteins secreted from these cells that might promote host tissue repair. Injection of the secreted proteins into injured livers of mice promoted significant amounts of tissue regeneration without cell grafts. Conclusions: Hepatocyte-like cells derived from human embryonic stem cells contribute to recovery of injured liver tissues in mice, not only by cell replacement but also by delivering trophic factors that support endogenous liver regeneration.

AB - Background & Aims: Many studies of embryonic stem cells have investigated direct cell replacement of damaged tissues, but little is known about how donor cellderived signals affect host tissue regeneration. We investigated the direct and indirect roles of human embryonic stem cellderived cells in liver repair in mice. Methods: To promote the initial differentiation of human embryonic stem cells into mesendoderm, we activated the β-catenin signaling pathway with lithium; cells were then further differentiated into hepatocyte-like cells. The differentiated cells were purified by indocyanine green staining and laser microdissection and characterized by immunostaining, polymerase chain reaction, biochemical function, electron microscopy, and transplantation analyses. To investigate indirect effects of these cells, secreted proteins (secretomes) were analyzed by a label-free quantitative mass spectrometry. Carbon tetrachloride was used to induce acute liver injury in mice; cells or secreted proteins were administered by intrasplenic or intraperitoneal injection, respectively. Results: The differentiated hepatocyte-like cells had multiple features of normal hepatocytes, engrafted efficiently into mice, and continued to have hepatic features; they promoted proliferation of host hepatocytes and revascularization of injured host liver tissues. Proteomic analysis identified proteins secreted from these cells that might promote host tissue repair. Injection of the secreted proteins into injured livers of mice promoted significant amounts of tissue regeneration without cell grafts. Conclusions: Hepatocyte-like cells derived from human embryonic stem cells contribute to recovery of injured liver tissues in mice, not only by cell replacement but also by delivering trophic factors that support endogenous liver regeneration.

KW - Hepatitis

KW - hES Cells

KW - Mouse Model

KW - Stem Cell Therapy

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