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Acute liver failure is a rapidly progressing, life-threatening condition most commonly caused by an overdose of acetaminophen (paracetamol). The antidote, N-acetylcysteine (NAC), has limited efficacy when liver injury is established. If acute liver damage is severe, liver failure can rapidly develop with associated high mortality rates. We have previously demonstrated that alternatively, activated macrophages are a potential therapeutic option to reverse acute liver injury in pre-clinical models. In this paper, we present data using cryopreserved human alternatively activated macrophages (hAAMs)-which represent a potential, rapidly available treatment suitable for use in the acute setting. In a mouse model of APAP-induced injury, peripherally injected cryopreserved hAAMs reduced liver necrosis, modulated inflammatory responses, and enhanced liver regeneration. hAAMs were effective even when administered after the therapeutic window for NAC. This cell therapy approach represents a potential treatment for APAP overdose when NAC is ineffective because liver injury is established., Competing Interests: Competing interests: S.J.F. and P.J.S.L. are founders of Resolution Therapeutics, which is developing a macrophage cell therapy product to treat patients at risk of liver decompensation; A.M.K. is a consultant to Resolution Therapeutics. The remaining authors declare no competing interests., (© 2025. The Author(s).)

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 was induced in AhCreMdm2 fl/fl mice through genetic excision of hepatocyte Mdm2., Methods: Freshly isolated mouse, or human cryopreserved hepatocytes were delivered via intrasplenic injection into AhCreMdm2 fl/fl (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., Results: 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 graft function decline due to transmission of senescence from host to donor cells. Paired proteomic and transcriptomic analysis 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., Conclusions: 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 clinics., Impact and Implications: Hepatocyte transplantation has shown promise for genetic diseases but has limited efficacy for acute and severe liver injury. Poor engraftment and functionality inhibit wide-spread clinical application. We show that host senescence provides a 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 pre-clinical and clinical cell therapies., Competing Interests: Declaration of Competing Interest S.J.F is a founder and scientific advisor of Resolution Therapeutics Ltd. S.F-G and S.J.F are founders and scientific advisors of SensiBile (both not related to this study)., (Copyright © 2025 The Author(s). Published by Elsevier B.V. All rights reserved.)