Metastable Reprogramming State of Single Transcription Factor-Derived Induced Hepatocyte-Like Cells
We previously described the generation of induced hepatocyte-like cells (iHeps) using the hepatic transcription factor Hnf1a together with small molecules. These iHeps represent a hepatic state that is more mature compared with iHeps generated with multiple hepatic factors. However, the underlying m...
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Wiley
2019-01-01
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| Series: | Stem Cells International |
| Online Access: | http://dx.doi.org/10.1155/2019/6937257 |
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| author | Seon In Hwang Tae Hwan Kwak Ji Hyun Kang Jonghun Kim Hyunseong Lee Kee-Pyo Kim Kinarm Ko Hans R. Schöler Dong Wook Han |
| author_facet | Seon In Hwang Tae Hwan Kwak Ji Hyun Kang Jonghun Kim Hyunseong Lee Kee-Pyo Kim Kinarm Ko Hans R. Schöler Dong Wook Han |
| author_sort | Seon In Hwang |
| collection | DOAJ |
| description | We previously described the generation of induced hepatocyte-like cells (iHeps) using the hepatic transcription factor Hnf1a together with small molecules. These iHeps represent a hepatic state that is more mature compared with iHeps generated with multiple hepatic factors. However, the underlying mechanism of hepatic conversion involving transgene dependence of the established iHeps is largely unknown. Here, we describe the generation of transgene-independent iHeps by inducing the ectopic expression of Hnf1a using both an episomal vector and a doxycycline-inducible lentivirus. In contrast to iHeps with sustained expression of Hnf1a, transgene-independent Hnf1a iHeps lose their typical morphology and in vitro functionality with rapid downregulation of hepatic markers upon withdrawal of small molecules. Taken together, our data indicates that the reprogramming state of single factor Hnf1a-derived iHeps is metastable and that the hepatic identity of these cells could be maintained only by the continuous supply of either small molecules or the master hepatic factor Hnf1a. Our findings emphasize the importance of a factor screening strategy for inducing specific cellular identities with a stable reprogramming state in order to eventually translate direct conversion technology to the clinic. |
| format | Article |
| id | doaj-art-28ac5f0f5ff1484e9d31ae5dd7ccf5c9 |
| institution | OA Journals |
| issn | 1687-966X 1687-9678 |
| language | English |
| publishDate | 2019-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Stem Cells International |
| spelling | doaj-art-28ac5f0f5ff1484e9d31ae5dd7ccf5c92025-08-20T02:03:54ZengWileyStem Cells International1687-966X1687-96782019-01-01201910.1155/2019/69372576937257Metastable Reprogramming State of Single Transcription Factor-Derived Induced Hepatocyte-Like CellsSeon In Hwang0Tae Hwan Kwak1Ji Hyun Kang2Jonghun Kim3Hyunseong Lee4Kee-Pyo Kim5Kinarm Ko6Hans R. Schöler7Dong Wook Han8Department of Stem Cell Biology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of KoreaDepartment of Stem Cell Biology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of KoreaDepartment of Stem Cell Biology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of KoreaDepartment of Stem Cell Biology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of KoreaDepartment of Stem Cell Biology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of KoreaDepartment of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstraße 20, 48149 Münster, GermanyDepartment of Stem Cell Biology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of KoreaDepartment of Stem Cell Biology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of KoreaDepartment of Stem Cell Biology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of KoreaWe previously described the generation of induced hepatocyte-like cells (iHeps) using the hepatic transcription factor Hnf1a together with small molecules. These iHeps represent a hepatic state that is more mature compared with iHeps generated with multiple hepatic factors. However, the underlying mechanism of hepatic conversion involving transgene dependence of the established iHeps is largely unknown. Here, we describe the generation of transgene-independent iHeps by inducing the ectopic expression of Hnf1a using both an episomal vector and a doxycycline-inducible lentivirus. In contrast to iHeps with sustained expression of Hnf1a, transgene-independent Hnf1a iHeps lose their typical morphology and in vitro functionality with rapid downregulation of hepatic markers upon withdrawal of small molecules. Taken together, our data indicates that the reprogramming state of single factor Hnf1a-derived iHeps is metastable and that the hepatic identity of these cells could be maintained only by the continuous supply of either small molecules or the master hepatic factor Hnf1a. Our findings emphasize the importance of a factor screening strategy for inducing specific cellular identities with a stable reprogramming state in order to eventually translate direct conversion technology to the clinic.http://dx.doi.org/10.1155/2019/6937257 |
| spellingShingle | Seon In Hwang Tae Hwan Kwak Ji Hyun Kang Jonghun Kim Hyunseong Lee Kee-Pyo Kim Kinarm Ko Hans R. Schöler Dong Wook Han Metastable Reprogramming State of Single Transcription Factor-Derived Induced Hepatocyte-Like Cells Stem Cells International |
| title | Metastable Reprogramming State of Single Transcription Factor-Derived Induced Hepatocyte-Like Cells |
| title_full | Metastable Reprogramming State of Single Transcription Factor-Derived Induced Hepatocyte-Like Cells |
| title_fullStr | Metastable Reprogramming State of Single Transcription Factor-Derived Induced Hepatocyte-Like Cells |
| title_full_unstemmed | Metastable Reprogramming State of Single Transcription Factor-Derived Induced Hepatocyte-Like Cells |
| title_short | Metastable Reprogramming State of Single Transcription Factor-Derived Induced Hepatocyte-Like Cells |
| title_sort | metastable reprogramming state of single transcription factor derived induced hepatocyte like cells |
| url | http://dx.doi.org/10.1155/2019/6937257 |
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