Analysis for Remodeling of Hepatic Tissue Structures in 3D During Regeneration

  • Kota KanekoEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1905)


It has been demonstrated that the liver remarkably alter its tissue structures during regeneration, and various types of liver stem or progenitor cells locating in specific areas in the liver tissue contribute to regeneration. Therefore, it is important to analyze the dynamic rearrangement of the liver tissue structures in 3D for better understanding the process and mechanism of liver regeneration. Here we describe a macroscopic analysis method to visualize the whole 3D structure of the vasculatures and the biliary tree, which are dynamically remodeled during regeneration, and a microscopic analysis method to visualize detailed structures at the cellular level, which can compensate what cannot be detected in the macroscopic analysis.

Key words

Liver regeneration Liver pathology 3D tissue structure 3D imaging Ductular reaction Biliary tree 



The experiments to establish these methods were supported in part by Japan Society for the Promotion of Science KAKENHI grants 22118006 (to Dr. Atsushi Miyajima), 24112507 (to Dr. Tohru Itoh), 24590342 (to T.I.), and 26253023 (to A.M.) as well as by CREST from the Japan Science and Technology Agency (to A.M.). K. K. was a research fellow at the Japan Society for the Promotion of Science.


  1. 1.
    Miyajima A, Tanaka M, Itoh T (2014) Stem/progenitor cells in liver development, homeostasis, regeneration, and reprogramming. Cell Stem Cell 14(5):561–574. Scholar
  2. 2.
    Font-Burgada J, Shalapour S, Ramaswamy S, Hsueh B, Rossell D, Umemura A, Taniguchi K, Nakagawa H, Valasek Mark A, Ye L, Kopp Janel L, Sander M, Carter H, Deisseroth K, Verma Inder M, Karin M (2015) Hybrid periportal hepatocytes regenerate the injured liver without giving rise to cancer. Cell 162(4):766–779. Scholar
  3. 3.
    Tanimizu N, Ichinohe N, Yamamoto M, Akiyama H, Nishikawa Y, Mitaka T (2017) Progressive induction of hepatocyte progenitor cells in chronically injured liver. Sci Rep 7:39990. Scholar
  4. 4.
    Wang B, Zhao L, Fish M, Logan CY, Nusse R (2015) Self-renewing diploid Axin2(+) cells fuel homeostatic renewal of the liver. Nature 524(7564):180–185. Scholar
  5. 5.
    Roskams TA, Theise ND, Balabaud C, Bhagat G, Bhathal PS, Bioulac-Sage P, Brunt EM, Crawford JM, Crosby HA, Desmet V, Finegold MJ, Geller SA, Gouw AS, Hytiroglou P, Knisely AS, Kojiro M, Lefkowitch JH, Nakanuma Y, Olynyk JK, Park YN, Portmann B, Saxena R, Scheuer PJ, Strain AJ, Thung SN, Wanless IR, West AB (2004) Nomenclature of the finer branches of the biliary tree: canals, ductules, and ductular reactions in human livers. Hepatology (Baltimore, MD) 39(6):1739–1745. Scholar
  6. 6.
    Kaneko K, Kamimoto K, Miyajima A, Itoh T (2015) Adaptive remodeling of the biliary architecture underlies liver homeostasis. Hepatology (Baltimore, MD) 61(6):2056–2066. Scholar
  7. 7.
    Kamimoto K, Kaneko K, Kok CYY, Okada H, Miyajima A, Itoh T (2016) Heterogeneity and stochastic growth regulation of biliary epithelial cells dictate dynamic epithelial tissue remodeling. eLife 5:e15034CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Nagahama Y, Sone M, Chen X, Okada Y, Yamamoto M, Xin B, Matsuo Y, Komatsu M, Suzuki A, Enomoto K, Nishikawa Y. Contributions of hepatocytes and bile ductular cells in ductular reactions and remodeling of the biliary system after chronic liver injury. Am J Pathol 184(11):3001–3012.
  9. 9.
    Tanimizu N, Kaneko K, Itoh T, Ichinohe N, Ishii M, Mizuguchi T, Hirata K, Miyajima A, Mitaka T (2016) Intrahepatic bile ducts are developed through formation of homogeneous continuous luminal network and its dynamic rearrangement in mice. Hepatology (Baltimore, MD) 64(1):175–188. Scholar
  10. 10.
    Ke M-T, Fujimoto S, Imai T (2013) SeeDB: a simple and morphology-preserving optical clearing agent for neuronal circuit reconstruction. Nat Neurosci 16:1154. Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pathology, School of MedicineUniversity of CaliforniaSan DiegoUSA

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