TY - JOUR
T1 - Direct reprogramming of human umbilical vein- and peripheral blood-derived endothelial cells into hepatic progenitor cells
AU - Inada, Hiroki
AU - Udono, Miyako
AU - Matsuda-Ito, Kanae
AU - Horisawa, Kenichi
AU - Ohkawa, Yasuyuki
AU - Miura, Shizuka
AU - Goya, Takeshi
AU - Yamamoto, Junpei
AU - Nagasaki, Masao
AU - Ueno, Kazuko
AU - Saitou, Daisuke
AU - Suyama, Mikita
AU - Maehara, Yoshihiko
AU - Kumamaru, Wataru
AU - Ogawa, Yoshihiro
AU - Sekiya, Sayaka
AU - Suzuki, Atsushi
N1 - Funding Information:
We thank Dr. Atsushi Iwama, Dr. Shinya Yamanaka, Dr. Masafumi Onodera, Dr. Hir-oyuki Miyoshi, and Dr. Masatoshi Takeichi for sharing reagents; Dr. Taito Matsuda for supporting transcriptome data analyses; and Yuuki Honda, Chiaki Kaieda, Kanako Ichikawa, Ryo Ugawa, and Emiko Koba for excellent technical assistance. This work was supported in part by the JSPS KAKENHI (Grant Numbers: JP16H01850, JP16K08592, JP18H05102, JP18K18369, JP19H01177, JP19H05267, JP20K12624, and JP20H05040), the Core Research for Evolutional Science and Technology (CREST) Program of the Japan Agency for Medical Research and Development (AMED) (JP16gm0510006), the Program for Basic and Clinical Research on Hepatitis of AMED (JP17fk0210307), the Research Center Network for Realization of Regenerative Medicine of AMED (JP20bm0704034), the Cooperative Research Project Program of the Medical Institute of Bioregulation in Kyushu University, the Takeda Science Foundation, the Uehara Memorial Foundation, the Japan Intractable Diseases Research Foundation, and the Mitsubishi Foundation.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Recent advances have enabled the direct induction of human tissue-specific stem and progenitor cells from differentiated somatic cells. However, it is not known whether human hepatic progenitor cells (hHepPCs) can be generated from other cell types by direct lineage reprogramming with defined transcription factors. Here, we show that a set of three transcription factors, FOXA3, HNF1A, and HNF6, can induce human umbilical vein endothelial cells to directly acquire the properties of hHepPCs. These induced hHepPCs (hiHepPCs) propagate in long-term monolayer culture and differentiate into functional hepatocytes and cholangiocytes by forming cell aggregates and cystic epithelial spheroids, respectively, under three-dimensional culture conditions. After transplantation, hiHepPC-derived hepatocytes and cholangiocytes reconstitute damaged liver tissues and support hepatic function. The defined transcription factors also induce hiHepPCs from endothelial cells circulating in adult human peripheral blood. These expandable and bipotential hiHepPCs may be useful in the study and treatment of human liver diseases.
AB - Recent advances have enabled the direct induction of human tissue-specific stem and progenitor cells from differentiated somatic cells. However, it is not known whether human hepatic progenitor cells (hHepPCs) can be generated from other cell types by direct lineage reprogramming with defined transcription factors. Here, we show that a set of three transcription factors, FOXA3, HNF1A, and HNF6, can induce human umbilical vein endothelial cells to directly acquire the properties of hHepPCs. These induced hHepPCs (hiHepPCs) propagate in long-term monolayer culture and differentiate into functional hepatocytes and cholangiocytes by forming cell aggregates and cystic epithelial spheroids, respectively, under three-dimensional culture conditions. After transplantation, hiHepPC-derived hepatocytes and cholangiocytes reconstitute damaged liver tissues and support hepatic function. The defined transcription factors also induce hiHepPCs from endothelial cells circulating in adult human peripheral blood. These expandable and bipotential hiHepPCs may be useful in the study and treatment of human liver diseases.
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U2 - 10.1038/s41467-020-19041-z
DO - 10.1038/s41467-020-19041-z
M3 - Article
C2 - 33087715
AN - SCOPUS:85093834026
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5292
ER -
