Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Kenichi Horisawa Last modified date:2021.10.04

Associate Professor / Division of Organogenesis and Regeneration / Department of Molecular and Cellular Biology / Medical Institute of Bioregulation

1. Shimokihara S, Shitara S, Oyobiki R, Watanabe T, Einaga Y, Matsumoto Y, Fujiwara K, Horisawa K, Doi N, Development of μtas for high-throughput screening of nad(p)-dependent oxidoreductases., MicroTAS 2015 - 19th International Conference on Miniaturized Systems for Chemistry and Life Sciences, 1302-1304, 2015.10.
2. Horisawa-Takada Y., Kodera C., Takemoto K., Sakashita A., Horisawa K., Maeda R., Shimada R., Usuki S., Fujimura S., Tani N., Matsuura K., Akiyama T., Suzuki A., Niwa H., Tachibana M., Ohba T., Katabuchi H., Namekawa S., Araki K., Ishiguro K., Meiosis-specific ZFP541 repressor complex promotes developmental progression of meiotic prophase towards completion during mouse spermatogenesis., Nat comm, 10.1038/s41467-021-23378-4, 12, 1, 3184, 2021.06.
3. Inada H., Udono M., Matsuda-Ito K., Horisawa K., Ohkawa Y., Miura S., Goya T., Yamamoto J., Nagasaki M., Ueno K., Saitou D., Suyama M., Maehara Y., Kumamaru W., Ogawa Y., Sekiya S., Suzuki A., Direct reprogramming of human umbilical vein- and peripheral blood-derived endothelial cells into hepatic progenitor cells., Nat comm, 10.1038/s41467-020-19041-z, 11, 5292, 2020.12, Recent advances have enabled the direct induction of human tissue-specific stem and pro- genitor 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 tran- scription 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..
4. Horisawa K., Udono M., Ueno K., Ohkawa Y., Nagasaki M., Sekiya S., Suzuki A., The Dynamics of Transcriptional Activation by Hepatic Reprogramming Factors., Mol Cell, 10.1016/j.molcel.2020.07.012, 79, 660-676, 2020.08, Specific combinations of two transcription factors (Hnf4a plus Foxa1, Foxa2, or Foxa3) can induce direct conversion of mouse fibroblasts into hepatocyte-like cells. However, the molecular mechanisms underlying hepatic reprogramming are largely unknown. Here, we show that the Foxa protein family members and Hnf4a sequentially and cooperatively bind to chromatin to activate liver-specific gene expression. Although all Foxa proteins bind to and open regions of closed chromatin as pioneer factors, Foxa3 has the unique potential of transferring from the distal to proximal regions of the transcription start site of target genes, binding RNA polymerase II, and co-traversing target genes. These distinctive characteristics of Foxa3 are essential for inducing the hepatic fate in fibroblasts. Similar functional coupling of transcription factors to RNA polymerase II may occur in other contexts whereby transcriptional activation can induce cell differentiation..
5. Terada, Maiko; Kawamata, Masaki; Kimura, Ryota; Sekiya, Sayaka; Nagamatsu, Go; Hayashi, Katsuhiko; Horisawa, Kenichi; Suzuki, Atsushi, Generation of Nanog reporter mice that distinguish pluripotent stem cells from unipotent primordial germ cells, GENESIS, 10.1002/dvg.23334, 57, 11-12, 2019.11.
6. Takashima Y, Horisawa K, Udono M, Ohkawa Y, Suzuki A., Prolonged inhibition of hepatocellular carcinoma cell proliferation by combinatorial expression of defined transcription factors., Cancer Sci., 10.1111/cas.13798., 109, 11, 3543-3553, 2018.11.
7. Maiko Terada, Horisawa K, Shizuka Miura, 高島 康郎, Ohkawa, Y, Sayaka Sekiya, 松田 花菜江, Atsushi Suzuki, Kupffer cells induce Notch-mediated hepatocyte conversion in a common mouse model of intrahepatic cholangiocarcinoma., Sci Rep., doi: 10.1038/srep34691., 6, 34691-34691, 2016.10, Intrahepatic cholangiocarcinoma (ICC) is a malignant epithelial neoplasm composed of cells resembling cholangiocytes that line the intrahepatic bile ducts in portal areas of the hepatic lobule. Although ICC has been defined as a tumor arising from cholangiocyte transformation, recent evidence from genetic lineage-tracing experiments has indicated that hepatocytes can be a cellular origin of ICC by directly changing their fate to that of biliary lineage cells. Notch signaling has been identified as an essential factor for hepatocyte conversion into biliary lineage cells at the onset of ICC. However, the mechanisms underlying Notch signal activation in hepatocytes remain unclear. Here, using a mouse model of ICC, we found that hepatic macrophages called Kupffer cells transiently congregate around the central veins in the liver and express the Notch ligand Jagged-1 coincident with Notch activation in pericentral hepatocytes. Depletion of Kupffer cells prevents the Notch-mediated cell-fate conversion of hepatocytes to biliary lineage cells, inducing hepatocyte apoptosis and increasing mortality in mice. These findings will be useful for uncovering the pathogenic mechanism of ICC and developing prevenient and therapeutic strategies for this refractory disease..
8. Nagumo Y, Fujiwara K, Horisawa K, Yanagawa H, Doi N, PURE mRNA display for in vitro selection of single-chain antibodies., J Biochem., doi: 10.1093/jb/mvv131, 5, 159, 519-526, 2016.05, mRNA display is a method to form a covalent linkage between a cell-free synthesized protein (phenotype) and its encoding mRNA (genotype) through puromycin for in vitro selection of proteins. Although a wheat germ cell-free translation system has been previously used in our mRNA display system, a protein synthesis using recombinant elements (PURE) system is a more attractive approach because it contains no endogenous nucleases and proteases and is optimized for folding of antibodies with disulphide bonds. However, when we used the PURE system for mRNA display of single-chain Fv (scFv) antibodies, the formation efficiency of the mRNA-protein conjugates was quite low. To establish an efficient platform for the PURE mRNA display of scFv, we performed affinity selection of a library of scFv antibodies with a C-terminal random sequence and obtained C-terminal sequences that increased the formation of mRNA-protein conjugates. We also identified unexpected common substitution mutations around the start codon of scFv antibodies, which were inferred to destabilize the mRNA secondary structure. This destabilization causes an increase in protein expression and the efficiency of the formation of mRNA-protein conjugates. We believe these improvements should make the PURE mRNA display more efficient for selecting antibodies for diagnostic and therapeutic applications..
9. Nakayama M, Komiya S, Fujiwara K, Horisawa K, Doi N, In vitro selection of bispecific diabody fragments using covalent bicistronic DNA display., Biochem Biophys Res Commun., 10.1016/j.bbrc.2016.07.113., 478, 2, 606-611, 2016.09.
10. Niikura K, Horisawa K, Doi N, Endosomal escape efficiency of fusogenic B18 and B55 peptides fused with anti-EGFR single chain Fv as estimated by nuclear translocation., J Biochem., 10.1093/jb/mvv083., 159, 1, 123-132, 2016.01.
11. Tokunaga M., Shiheido H., Tabata N., Sakuma-Yonemura Y., Takashima H., Horisawa K., Doi N., Yanagawa H., MIP-2A Is a Novel Target of an Anilinoquinazoline Derivative for Inhibition of Tumour Cell Proliferation, PLOS ONE, 10.1371/journal.pone.0076774, 8, 9, e76774, 2013.09.
12. Wang PC., Horisawa K., Matsumura M., Construction of glomerular epithelial cells in vitro for removal of immune complex, Journal of Artificial Organs, 2, 170-175, 1999.09.