Tissue Eng Regen Med.  2021 Apr;18(2):305-313. 10.1007/s13770-020-00327-8.

Generation of Hepatic Progenitor Cells from the Primary Hepatocytes of Nonhuman Primates Using Small Molecules

Affiliations
  • 1Department of Surgery, Hanyang University College of Medicine, Seoul 04763, Republic of Korea
  • 2HY Indang Center of Regenerative Medicine and Stem Cell Research, Hanyang University, Seoul 04763, Republic of Korea
  • 3Hanyang ICT Fusion Medical Research Center, Hanyang University, Seoul 04763, Republic of Korea
  • 4Laboratory of Radiation Exposure and Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science, Seoul 01812, Republic of Korea
  • 5Korea Institute of Toxicology, Daejeon 53212, Republic of Korea
  • 6GenNBio, Inc., Seoul 06193, Republic of Korea

Abstract

BACKGROUND
Since primates have more biological similarities to humans than do other animals, they are a valuable resource in various field of research, including biomedicine, regenerative medicine, and drug discovery. However, there remain limitations to maintenance and expansion of primary hepatocytes derived from nonhuman primates. To overcome these limitations, we developed a novel culture system for primate cells.
METHODS
Primary hepatocytes from Macaca fascicularis (mf-PHs) were isolated from hepatectomized liver. To generate chemically derived hepatic progenitor cells (mf-CdHs), mf-PHs were cultured with reprogramming medium containing A83-01, CHIR99021, and hepatocyte growth factor (HGF). The bi-potent differentiation capacity of mf-CdHs into hepatocytes and biliary epithelial cells was confirmed by treatment with hepatic differentiation medium (HDM) and cholangiocytic differentiation medium (CDM), respectively.
RESULTS
mf-PHs cultured with reprogramming medium showed rapid proliferation capacity in vitro and expressed progenitor-specific markers. Moreover, when cultured in HDM, these progenitor cells stably differentiated into hepatocytelike cells expressing the mature hepatic markers. On the other hand, when cultured in CDM, the differentiated biliary epithelial cells expressed mature cholangiocyte characteristics.
CONCLUSION
The results of the present study demonstrate that we successfully induced the formation of hepatic progenitor cells from mf-PHs by culturing them with a combination of small molecules, including growth factors. These results offer a means of expanding nonhuman primate hepatocytes without genetic manipulation for cellular resource, preclinical applications and regenerative medicine for the liver.

Keyword

Primate; Small molecules; Hepatic progenitors; Reprogramming; Stem cells
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