Small molecule-mediated reprogramming of human hepatocytes into bipotent progenitor cells

Kim, Young S.; Kang, Kyojin; Lee, Seung Bum; Seo, Daekwan; Yoon, Sangtae; Kim, Sung Joo; Jang, Kiseok; Jung, Yun Kyung; Lee, Kyeong Geun; Factor, Valentina M.; Jeong, Jae‐Weon; Choi, Dongho

doi:10.1016/j.jhep.2018.09.007

Cited by 106 publications

(107 citation statements)

References 51 publications

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“…The RI of laboratory-generated hepatocytes is typically less than 5% 10 . After our report of rodent CLiPs 16 , four groups recently reported methods for in vitro generation of proliferative human liver (progenitor) cells from human hepatocytes [27][28][29][30] . In three of these studies [27][28][29] , the generated cells exhibited relatively low repopulative efficiency, approximately 13% of RI at maximum.…”

Section: Discussionmentioning

confidence: 99%

Generation of human hepatic progenitor cells with regenerative and metabolic capacities from primary hepatocytes

Katsuda¹,

Matsuzaki²,

Yamaguchi

et al. 2019

Preprint

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Hepatocytes are regarded as the only effective cell source for cell transplantation to treat liver diseases; however, their availability is limited due to a donor shortage. Thus, a novel cell source must be developed. We recently reported that mature rodent hepatocytes can be reprogrammed into progenitor-like cells with a repopulative capacity using small molecule inhibitors. Here, we demonstrate that hepatic progenitor cells can be obtained from human infant hepatocytes using the same strategy. These cells, named human chemically induced liver progenitors (hCLiPs), had a significant repopulative capacity in injured mouse livers following transplantation. hCLiPs redifferentiated into mature hepatocytes in vitro upon treatment with hepatic maturation-inducing factors. These redifferentiated cells exhibited cytochrome P450 (CYP) enzymatic activities in response to CYP-inducing molecules and these activities were comparable with those in primary human hepatocytes. These findings will facilitate liver cell transplantation therapy and drug discovery studies.were related to hepatic function ( Fig. 1G, Table S1), suggesting that AC also helped to maintain the hepatocytic characteristics of cultured hepatocytes. Although cell cycle-related gene sets were also identified by GSEA, their enrichment scores were relatively low ( Fig. S2B, Table S1). This is likely because cell proliferation was also increased by culture in the presence of FBS. However, proliferating cells were contaminated by fibroblast-like NPCs upon culture in the presence of FBS. Proliferation-related gene sets were enriched in cells cultured in the presence of FBS and in FAC compared with cells at 1 day after plating (D1 hepatocytes) ( Fig. S2C, S2D, Table S3 and S4). However, gene sets related to liver fibrogenesis, such as "p75 NTR receptor-mediated signaling", "PDGF signaling", and "TGF signaling", were also enriched in cells cultured in the presence of FBS ( Fig. 1H, Table S2). Accordingly, expression of the hepatocytic connexin genes GJB1 (also known as CX32)and GJB2 (also known as CX26) was low in cells cultured in the presence of FBS, while the NPC connexin gene GJA1 (also known as CX43) was sharply upregulated 18 ( Fig. S2E). In addition, the gene set "epithelial to mesenchymal transition" was enriched in cells cultured in the presence of FBS compared with cells cultured in FAC ( Fig. 1H), suggesting that the former cells acquired a mesenchymal phenotype. Overrepresentation of TGF signaling in hepatocytes reportedly leads to acquisition of a fibroblast-like dedifferentiated state both in vitro and in vivo 19,20 . In summary, two small molecules, AC, together with FBS, support the proliferation of hepatic epithelial cells with characteristics of both hepatocytes and LPCs/BECs. Hepatic differentiation capacity of the proliferative cellsA hepatic differentiation capacity is an important feature of LPCs, particularly for their potential use as a candidate cell source for transplantation therapy. To investigate the hepatic differentiation capacity...

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Section: Discussionmentioning

confidence: 99%

Generation of human hepatic progenitor cells with regenerative and metabolic capacities from primary hepatocytes

Katsuda¹,

Matsuzaki²,

Yamaguchi

et al. 2019

Preprint

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“…To the Editor: With great interest, we read the article written by Kim et al in a recent issue of Journal of Hepatology. 1 The authors developed a successful HAC culture system for reprogramming mature human hepatocytes into bipotential progenitor cells treated with 2 small molecules A83-01 and CHIR99021 (AC) in combination with hepatocyte growth factor (HGF). Their chemically derived human hepatocyte progenitors could sustain themselves as a population of progenitor cells over a long period while maintaining chromosomal stability and the capacity to differentiate into functional hepatocytes and biliary epithelial cells in vitro and in vivo.…”

Section: Role Of Hgf For Reprogramming Human Liver Progenitor Cellsmentioning

confidence: 99%

Role of HGF for reprogramming human liver progenitor cells: Non-essential but stimulative supplement

Huang

Miyoshi

Sakai

et al. 2019

Journal of Hepatology

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“…Author names in bold designate shared co-first authorship [1] Kim Y, Kang K, Lee SB, Seo D, Yoon S, Kim SJ, et al Small Reply to: ''Role of HGF for reprogramming human liver progenitor cells: Non-essential but stimulative supplement''…”

Section: Referencesmentioning

confidence: 99%

“…We thank Dr. Huang and colleagues for their interest and comments on our recent study, ''Small molecule-mediated reprogramming of human hepatocytes into bipotent progenitor cells" published in the Journal of Hepatology. 1 We learnt with great interest from the Dr. Huang's letter that the YAC cocktail (Y27632, A83-01, and CHIR99021) originally developed by Katsuda et al 2 for reprogramming of rodent hepatocytes was also effective in human hepatocytes. The process of conversion of human hepatocytes into stemness state using the YAC system took a long time and was independent of HGF supplementation.…”

Section: Referencesmentioning

confidence: 99%

“…Therefore, we believe that combined HAC treatment played an essential role in reprogramming human hepatocytes into chemically derived hepatic progenitors (hCdHs). 1 It is worth noting that Y27632, one of the components used by Huang and colleagues for reprogramming human hepatocytes, is an inhibitor of a Rho-associated protein kinase (ROCK) known to affect various cellular functions by modulating diverse signaling pathways. 3,4 More specifically, it was reported that ROCK inhibition promoted cancer stem cell characteristics by activating the phosphorylation of the MET receptor.…”

Section: Referencesmentioning

confidence: 99%

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Reply to: “Role of HGF for reprogramming human liver progenitor cells: Non-essential but stimulative supplement”

Lee

Kim

Kang

et al. 2019

Journal of Hepatology

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fact which was believed to enhance the cell attachment. 5,6 Hence, we are curious about whether this phenomenon of fibroblast-like cells is also observed in the HAC culture system. Thirdly, the authors used 6 cases of mature human hepatocytes isolated from healthy and diseased donor livers. To our knowledge, we only isolated the mature hepatocytes from the normal parts of the diseased liver, which are termed non-tumor liver. Strictly speaking, we only use the hepatocytes either from the healthy liver or the non-tumor part of a diseased liver. This is a vital point to consider when interpreting this data, otherwise one may be misled into believing that the culture system can also reprogram the diseased hepatocytes (tumor cells etc.) into progenitor cells. We applaud Kim and colleagues for providing the successful HAC culture system for reprogramming human liver progenitor cells with a rapid expansion rate. It not only overcomes the low conversion efficiency but also reported no other fibroblast-like cells in YAC culture system. Their important work also advances our understanding of the chemical reprogramming of human progenitor cells in vitro, offering a different view for the optimization of culture systems in the future.

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Small molecule-mediated reprogramming of human hepatocytes into bipotent progenitor cells

Cited by 106 publications

References 51 publications

Generation of human hepatic progenitor cells with regenerative and metabolic capacities from primary hepatocytes

Generation of human hepatic progenitor cells with regenerative and metabolic capacities from primary hepatocytes

Role of HGF for reprogramming human liver progenitor cells: Non-essential but stimulative supplement

Reply to: “Role of HGF for reprogramming human liver progenitor cells: Non-essential but stimulative supplement”

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