Academic Postdoctoral Fellow Shanghai Institute of Biochemistry and Cell Biology (SIBCB), China
Abstract: Successful cell engraftment requires navigation through confined microenvironments, yet the underlying adaptive mechanisms remain elusive. Here, we identify a mechano-induced autonomous reprogramming state critical for hepatocyte engraftment during transplantation. Hepatic sinusoidal confinement triggers transplanted hepatocytes (Tx-Heps) to adopt a conserved reprogramming state, characterized by liver progenitor genes activation. This transcriptional reprogramming correlate with stress resistance and enhanced cell fitness, facilitating Tx-Heps to survive distal capillaries entrapment and accelerate engraftment. Lineage tracing reveals most Tx-Heps undergo this reprogramming. Importantly, mechanical confinement emerged as a key inducer of transplantation reprogramming, with Arid1a identified as a downstream regulator. Hepatocyte-specific ablation of Arid1a suppressed reprogramming and led to transplantation failure, highlighting the role of transplantation reprogramming in successful engraftment. Furthermore, we developed a norepinephrine/dopamine-based pharmacological strategy that amplifies confinement-induced reprogramming, achieving a 4.3-fold engraftment improvement. Our findings provide novel insights into the influence of mechanical factors on cell fate reprogramming and suggest strategies for improving transplantation outcomes through mechanopriming and molecular modulation.
Funding Source: This project was supported by the “Strategic Priority Research Program” of the Chinese Academy of Sciences (XDA16020201, XDB38040400), the National Key Research and Development Project (2020YFA0112503, 2022YFA1004800)
