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Biomaterials, Available online 18 May 2021, Volume 274, 120899 | https://doi.org/10.1016/j.biomaterials.2021.120899 Hepatic patch by stacking patient-specific liver progenitor cell sheets formed on multiscale electrospun fibers promotes regenerative therapy for liver injury

Yohan Kim^a,b,1, Young Won Kim^c,1,2, Seung Bum Lee^d,1, Kyojin Kang^a, Sangtae Yoon^a,b, Dongho Choi^a,b,*, Suk-Hee Park^e,*, Jaemin Jeong^a,b,*

^aDepartment of Surgery, Hanyang University College of Medicine, Seoul, 04763, Republic of Korea
^bHY Indang Center of Regenerative Medicine and Stem Cell Research, Hanyang University, Seoul, 04763, Republic of Korea
^cDigital Manufacturing Process Group, Korea Institute of Industrial Technology, 113-58 Seohaean-ro, Siheungsi, Gyeonggi-do, 15014, Republic of Korea
^dLaboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological & Medical Science, Seoul, 01812, Republic of Korea
^eSchool of Mechanical Engineering, Pusan National University, Busan, 46241, Republic of Korea

¹These authors contributed equally to this study as co-first authors.
²Present address : School of Mechanical Engineering, Purdue University, West Lafayette, IN 47907, USA

^*Corresponding author

Abstract

Recently, use of cell sheets with bio-applicable fabrication materials for transplantation has been an attractive approach for the treatment of patients with liver failure. However, renewable and scalable cell sources for engineered tissue patches remain limited. We previously reported a new type of proliferating bipotent human chemically derived hepatic progenitor cells (hCdHs) developed by small molecule-mediated reprogramming. Here, we developed a patient-specific hepatic cell sheet constructed from liver biopsy-derived hCdHs on a multiscale fibrous scaffold by combining electrospinning and three-dimensional printing. Analysis of biomaterial composition revealed that the high-density electrospun sheet was superior in increasing the functional properties of hCdHs. Furthermore, the hepatic patch assembled by multilayer stacking with alternate cell sheets of hCdHs and human umbilical vein endothelial cells (HUVECs) recapitulated a liver tissue-like structure, with histological and morphological shape and size similar to those of primary human hepatocytes, and exhibited a significant increase in hepatic functions such as albumin secretion and activity of cytochrome P450 during in vitro hepatic differentiation compared with that in hCdH cells cultured in a two-dimensional monolayer. Interestingly, in the hepatic patch, the induction of functional hepatocytes was associated with both the electrospun fibrous-facilitated oncostatin M signaling and selective activation of AKT signaling by HUVECs. Notably, upon transplantation into a mouse model of therapeutic liver repopulation, the hepatic patch effectively repopulated the damaged parenchyma and induced the restoration of liver function with healthy morphology in the lobe and an improved survival rate (>70%) in mice. Overall, these results suggested that liver biopsy-derived hCdHs can be an efficient alternative source for developing hepatic cell sheets and patches with potential clinical applications in tissue engineering to advance liver regeneration.

Keywords : Human hepatocytes, Human chemically derived hepatic progenitors, Electrospun fiber scaffold, Hepatic cell sheet and hepatic patch

논문정보

형식Research article
게재일2021년 05월 (BRIC 등록일 2021-06-10)
연구진국내 연구진
분야 의약학 > 분자세포의학

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