Key Takeaways & Executive Findings
- •• SS-USCs exhibit superior tissue repair and antioxidant capabilities compared to RS-USCs, as revealed by multi-omics analyses. • SS-USCs-derived exosomes (SS-USCs-Exo) significantly inhibit ferroptosis and alleviate severe fatty liver ischemia-reperfusion injury in vivo and in vitro. • The therapeutic mechanism involves the delivery of GPX4 protein via exosomes, which suppresses ferroptosis and enhances cellular viability. • SS-USCs are identified as the most suitable cell subtype for treating severe fatty liver IRI, offering a promising strategy to expand the donor liver pool.
Abstract
Background Severe hepatic steatosis can exacerbate Ischemia–reperfusion injury (IRI), potentially leading to early graft dysfunction and primary non-function. In this study, we investigated the heterogeneity of different subpopulations of Urine-derived stem cells (USCs) to explore the most suitable cell subtype for treating severe steatotic liver IRI. Methods This study utilized scRNA-seq and Bulk RNA-seq to investigate the transcriptional heterogeneity between Spindle-shaped USCs (SS-USCs) and Rice-shaped USCs (RS-USCs). Additionally, rat fatty Liver transplantation (LT) model, mouse fatty liver IRI model, and Steatotic Hepatocyte Hypoxia-Reoxygenation (SHP-HR) model were constructed. Extracellular vesicles derived from SS-USCs and RS-USCs were isolated and subjected to mass spectrometry analysis. The therapeutic effects of Spindle-shaped USCs Exosomes (SS-USCs-Exo) and Rice-shaped USCs Exosomes (RS-USCs-Exo) were explored, elucidating their potential mechanisms in inhibiting ferroptosis and alleviating IRI. Results Multiple omics analyses confirmed that SS-USCs possess strong tissue repair and antioxidant capabilities, while RS-USCs have the potential to differentiate towards specific directions such as the kidney, nervous system, and skeletal system, particularly showing great application potential in renal system reconstruction. Further experiments demonstrated in vivo and in vitro models confirming that SS-USCs and SS-USCs-Exo significantly inhibit ferroptosis and alleviate severe fatty liver IRI, whereas the effects of RS-USCs/RS-USCs-Exo are less pronounced. Analysis comparing the proteomic differences between SS-USCs-Exo and RS-USCs-Exo revealed that SS-USCs-Exo primarily inhibit ferroptosis and improve cellular viability by secreting exosomes containing Glutathione Peroxidase 4 (GPX4) protein. This highlights the most suitable cell subtype for treating severe fatty liver IRI. Conclusions SS-USCs possess strong tissue repair and antioxidant capabilities, primarily alleviating ferroptosis in the donor liver of fatty liver through the presence of GPX4 protein in their exosomes. This highlights SS-USCs as the most appropriate cell subtype for treating severe fatty liver IRI.
1. Introduction
The management and outcomes for individuals suffering from terminal liver disease are critically influenced by the prevalent scarcity of suitable donor organs, representing a significant barrier in the realm of liver transplants [1]. To address this issue, the use of marginal donor livers has increased significantly in recent years. Marginal donor livers mainly refer to fatty livers, elderly donor livers, donor livers with a history of viral infection, and donor livers with prolonged ischemic times, with a significant proportion of fatty liver donors [2–4]. Nonetheless, more than 60% of livers with severe steatosis are often removed. IRI in the liver may be worsened by severe hepatic steatosis, resulting in early graft malfunction and primary non-function [5]. Therefore, reducing IRI in severely steatotic donor livers holds significant importance in expanding the donor liver pool for transplantation.
USCs, sourced from urine, are increasingly recognized for their multiple advantages including non-invasive collection, ease of access, and minimal costs [6]. These cells demonstrate a robust capacity for self-renewal and the ability to differentiate into various cell lineages, positioning them as a valuable resource for tissue and organ regeneration. Recent research has advanced substantially, with USCs now being capable of differentiating into neuron-like cells, indicating potential applications in neuroscience [7, 8]. Furthermore, their utility in the field of regenerative medicine and tissue engineering is expanding. Current applications involve the use of USCs for the reconstruction of diverse tissues such as skin, bone, and cartilage, thereby opening new avenues for therapeutic interventions.
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Shangheng Shi, Cunle Zhu, Shangxuan Shi, Xinqiang Li, Imran Muhammad, Qingguo Xu, Xinwei Li, Ziyin Zhao, Huan Liu, Guangming Fu, Meiying Song, Xijian Huang, Feng Wang, Jinzhen Cai (2026). Human spindle-shaped urine-derived stem cell exosomes alleviate severe fatty liver ischemia–reperfusion injury by inhibiting ferroptosis via GPX4. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-025-04202-y
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Frequently Asked Questions
What are urine-derived stem cells (USCs) and why are they advantageous?
Urine-derived stem cells (USCs) are stem cells isolated from urine, offering advantages such as non-invasive collection, easy accessibility, and low cost. They exhibit self-renewal and multi-lineage differentiation potential, making them valuable for regenerative medicine.
How do spindle-shaped USCs (SS-USCs) differ from rice-shaped USCs (RS-USCs)?
SS-USCs possess strong tissue repair and antioxidant capabilities, while RS-USCs have potential to differentiate towards kidney, nervous system, and skeletal system lineages. SS-USCs are more effective in inhibiting ferroptosis and alleviating severe fatty liver ischemia-reperfusion injury.
What is the mechanism by which SS-USCs alleviate fatty liver ischemia-reperfusion injury?
SS-USCs secrete exosomes containing GPX4 protein, which inhibits ferroptosis in hepatocytes, thereby reducing ischemia-reperfusion injury and improving cellular viability.
What models were used in this study?
The study utilized rat fatty liver transplantation (LT) model, mouse fatty liver IRI model, and steatotic hepatocyte hypoxia-reoxygenation (SHP-HR) model to evaluate the therapeutic effects of SS-USCs and their exosomes.
What is the clinical significance of this research?
This research identifies SS-USCs as the most suitable cell subtype for treating severe fatty liver IRI, potentially expanding the donor liver pool by enabling the use of severely steatotic livers that are currently discarded.
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