Gadd Victoria L, Ferreira-Gonzalez Sofia, Man Tak Yung, Kilpatrick Alastair M, Aird Rhona E, Smith Ian P, Rodrigo-Torres Daniel, Kurian Dominic, Hallett John M, Ashmore-Harris Candice, Esser Hannah, Ferreira Marisa F, Macmillan Mark T, Lu Wei-Yu, Forbes Stuart J
Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, EH16 4UU, United Kingdom.
Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, EH16 4UU, United Kingdom; Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, EH16 4UU, United Kingdom.
J Hepatol. 2025 Jul;83(1):161-176. doi: 10.1016/j.jhep.2024.12.039. Epub 2025 Jan 2.
BACKGROUND & AIMS: Hepatocyte transplantation has shown promise for genetic diseases of the hepatocytes but to date has shown limited efficacy for non-genetic forms of severe liver injury. Limited cell engraftment and poor function of donor hepatocytes in recipient livers impacts the clinical utility of hepatocyte cell therapy. The mechanisms underpinning this are poorly understood. We explored this in a liver injury model, where predictable levels of injury and hepatocyte senescence were induced in AhCreMdm2 mice through genetic excision of hepatocyte Mdm2.
Freshly isolated mouse or human cryopreserved hepatocytes were delivered via intrasplenic injection into AhCreMdm2 (immune competent and deficient strains) mice. Engraftment kinetics, donor cell engraftment and host liver function were assessed. Paired transcriptomic and proteomic analyses were performed on healthy vs. senescent mouse hepatocytes.
We found inhibition of host hepatocyte proliferation and liver injury is a requirement for donor hepatocyte engraftment and long-term repopulation, improving liver repair and function, but excessive senescence inhibited this process, causing a decline in graft function due to transmission of senescence from host to donor cells. Paired proteomic and transcriptomic analyses of healthy vs. senescent hepatocytes reveal a unique senescent signature associated with paracrine senescence. Modification of the host niche prior to transplantation with the senotherapeutic drug ABT737 improved donor cell proliferative capacity.
The host niche impacts the initial engraftment and long-term function of transplanted hepatocytes. Targeting paracrine senescence may be a way to improve donor hepatocyte function, optimise therapy and guide translation into the clinic.
Hepatocyte transplantation has shown promise for genetic diseases but has limited efficacy for acute and severe liver injury. Poor engraftment and functionality have prevented large-scale clinical application. We show that host senescence provides the required non-competitive niche for donor hepatocytes to repopulate the recipient liver, but can, paradoxically, negatively impact donor function. These findings demonstrate a requirement for a clear understanding of the host niche prior to cell transfusion. This has significant implications not only for hepatocellular therapies, but also when developing and optimising any preclinical and clinical cell therapies.
肝细胞移植在治疗肝细胞遗传性疾病方面已显示出前景，但迄今为止，在治疗非遗传性严重肝损伤方面疗效有限。供体肝细胞在受体肝脏中的植入受限以及功能不佳影响了肝细胞治疗的临床应用。其背后的机制尚不清楚。我们在一个肝损伤模型中对此进行了探索，通过基因敲除AhCreMdm2小鼠肝细胞中的Mdm2来诱导可预测程度的损伤和肝细胞衰老。
将新鲜分离的小鼠或人类冻存肝细胞经脾内注射到AhCreMdm2小鼠（免疫健全和缺陷品系）体内。评估植入动力学、供体细胞植入情况和宿主肝功能。对健康与衰老的小鼠肝细胞进行配对转录组学和蛋白质组学分析。
我们发现抑制宿主肝细胞增殖和肝损伤是供体肝细胞植入和长期再增殖的必要条件，可改善肝修复和功能，但过度衰老会抑制这一过程，由于衰老从宿主细胞传递到供体细胞，导致移植功能下降。对健康与衰老肝细胞进行配对蛋白质组学和转录组学分析，揭示了与旁分泌衰老相关的独特衰老特征。在移植前用衰老治疗药物ABT737修饰宿主微环境可提高供体细胞的增殖能力。
宿主微环境影响移植肝细胞的初始植入和长期功能。靶向旁分泌衰老可能是改善供体肝细胞功能、优化治疗并指导临床转化的一种方法。
肝细胞移植在治疗遗传性疾病方面已显示出前景，但对急性和严重肝损伤的疗效有限。植入不佳和功能不良阻碍了大规模临床应用。我们表明，宿主衰老为供体肝细胞重新填充受体肝脏提供了所需的非竞争性微环境，但矛盾的是，也会对供体功能产生负面影响。这些发现表明，在细胞输注前需要清楚了解宿主微环境。这不仅对肝细胞治疗有重要意义，而且在开发和优化任何临床前和临床细胞治疗时也具有重要意义。
