Stem cell-derived hepatocyte therapy using versatile biomimetic nanozyme incorporated nanofiber-reinforced decellularized extracellular matrix hydrogels for the treatment of acute liver failure

Yuanyuan Jin; Jiabin Zhang; Yanteng Xu; Ke Yi; Fenfang Li; Huicong Zhou; Haixia Wang; Hon Fai Chan; Yeh-Hsing Lao; Shixian Lv; Yu Tao; Mingqiang Li

doi:10.1016/j.bioactmat.2023.05.001

Stem cell-derived hepatocyte therapy using versatile biomimetic nanozyme incorporated nanofiber-reinforced decellularized extracellular matrix hydrogels for the treatment of acute liver failure

Bioact Mater. 2023 May 18:28:112-131. doi: 10.1016/j.bioactmat.2023.05.001. eCollection 2023 Oct.

Authors

Yuanyuan Jin^{1

2}, Jiabin Zhang^{1

2}, Yanteng Xu^{1

2}, Ke Yi¹, Fenfang Li¹, Huicong Zhou^{1

3}, Haixia Wang¹, Hon Fai Chan⁴, Yeh-Hsing Lao⁵, Shixian Lv³, Yu Tao¹, Mingqiang Li^{1

2}

Affiliations

¹ Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China.
² Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630, China.
³ School of Materials Science and Engineering, Peking University, Beijing, 100871, China.
⁴ Institute for Tissue Engineering and Regenerative Medicine, School of Biomedical Science, The Chinese University of Hong Kong, 999077, Hong Kong, China.
⁵ Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, 14214, USA.

Abstract

Reactive oxygen species (ROS)-associated oxidative stress, inflammation storm, and massive hepatocyte necrosis are the typical manifestations of acute liver failure (ALF), therefore specific therapeutic interventions are essential for the devastating disease. Here, we developed a platform consisting of versatile biomimetic copper oxide nanozymes (Cu NZs)-loaded PLGA nanofibers (Cu NZs@PLGA nanofibers) and decellularized extracellular matrix (dECM) hydrogels for delivery of human adipose-derived mesenchymal stem/stromal cells-derived hepatocyte-like cells (hADMSCs-derived HLCs) (HLCs/Cu NZs@fiber/dECM). Cu NZs@PLGA nanofibers could conspicuously scavenge excessive ROS at the early stage of ALF, and reduce the massive accumulation of pro-inflammatory cytokines, herein efficiently preventing the deterioration of hepatocytes necrosis. Moreover, Cu NZs@PLGA nanofibers also exhibited a cytoprotection effect on the transplanted HLCs. Meanwhile, HLCs with hepatic-specific biofunctions and anti-inflammatory activity acted as a promising alternative cell source for ALF therapy. The dECM hydrogels further provided the desirable 3D environment and favorably improved the hepatic functions of HLCs. In addition, the pro-angiogenesis activity of Cu NZs@PLGA nanofibers also facilitated the integration of the whole implant with the host liver. Hence, HLCs/Cu NZs@fiber/dECM performed excellent synergistic therapeutic efficacy on ALF mice. This strategy using Cu NZs@PLGA nanofiber-reinforced dECM hydrogels for HLCs in situ delivery is a promising approach for ALF therapy and shows great potential for clinical translation.

Keywords: Acute liver failure; Electrospun nanofiber; Hepatocyte-like cells; Human adipose-derived mesenchymal stem/stromal cells; Nanozyme.