Modulation of PRL-1 in placental MSCs: A novel therapeutic strategy for hepatic fibrosis: Editorial on “Modulation of phosphatase of regenerating liver-1 within placental mesenchymal stem cells instigates the transition between epithelial-to-mesenchymal transition and mesenchymal-to-epithelial transition subsequent to hepatic fibrosis”

Hepatic fibrosis, a pathological consequence of chronic liver injury, remains a significant global health burden, affecting millions worldwide and frequently leading to cirrhosis and hepatocellular carcinoma. Despite substantial advances in understanding the pathophysiology mechanisms, effective anti-fibrotic strategies remain limited. Current treatments primarily focus on addressing underlying etiologies, such as viral hepatitis or metabolic disorders, while therapies that directly target the fibrogenic process are still warranted.

Epithelial-mesenchymal transition (EMT) and its reverse process, mesenchymal-epithelial transition (MET), are pivotal in the fibrosis progression and resolution, respectively [1]. EMT is characterized by epithelial cells acquiring mesenchymal properties, enhancing motility and fibrogenic activity, whereas MET facilitates the restoration of epithelial features and tissue repair. In this context, the study by Kim et al. [2] sheds light on the role of phosphatase of regenerating liver-1 (PRL-1) in regulating EMT/MET dynamics within placental mesenchymal stem cells (MSCs), offering a promising therapeutic avenue for hepatic fibrosis therapy.

PRL-1, a member of the protein tyrosine phosphatase family, has been recognized for its role in cell proliferation, migration, and invasion [3,4]. While its oncogenic potential has been well-documented, emerging evidence suggests a critical role for PRL-1 in fibrotic diseases. Kim et al. [2] demonstrate that PRL-1 expression is significantly upregulated during EMT, contributing to the fibrogenic phenotype in hepatic stellate cells. Conversely, PRL-1 suppression promotes MET, leading to fibrosis resolution. This dual role of PRL-1 highlights its potential as a therapeutic target in hepatic fibrosis. Mechanistically, Kim et al. [2] elucidate the regulatory role of PRL-1 in TGF-β/Smad and Wnt/β-catenin signaling, two pivotal pathways governing fibrosis progression and resolution [5]. TGF-β is a well-established pro-fibrotic cytokine that drives EMT, while Wnt/β-catenin signaling regulates cellular plasticity and tissue homeostasis [6]. By modulating PRL-1, the authors propose a novel strategy for regulating these pathways, offering a potential breakthrough in fibrosis management.

Placental MSCs have been increasingly recognized for their regenerative potential, immunomodulatory properties, and ease of isolation. Compared to other MSC sources, placental MSCs exhibit superior proliferative capacity and lower immunogenicity, making them ideal for therapeutic applications [7,8]. In a significant advancement, Kim et al. [2] engineer placental MSCs to either overexpress or silence PRL-1, demonstrating that PRL-1 modulation critically influences MSC therapeutic efficacy in hepatic fibrosis. PRL- 1-overexpressing MSCs exacerbate fibrosis by promoting EMT, whereas PRL-1-silenced MSCs induce MET, facilitating fibrosis resolution. These findings highlight the potential of engineered MSC therapy tailored to specific fibrotic conditions. Moreover, the authors underscore the safety and feasibility of PRL-1-engineered MSCs, addressing ethical concerns associated with alternative stem cell sources and paving the way for future clinical translation.

While this study presents compelling evidence supporting PRL-1-modulated MSC therapy, several mechanistic and translational hurdles remain. The authors demonstrate that recombinant PRL-1 treatment in naïve PD-MSCs leads to increased BMP7 mRNA and protein levels, suggesting a dual regulatory mechanism of BMP7 by PRL-1 at both the transcriptional and post-translational levels. However, the precise pathways through which PRL-1 exerts this regulation remain unclear. At the transcriptional level, PRL-1 may enhance BMP7 expression by directly regulating its promoter activity or interacting with transcriptional regulators. Chromatin immunoprecipitation and luciferase reporter assays may be conducted to determine whether PRL-1 directly binds to BMP7 regulatory elements or modulates its transcription levels via other factors. For the post-translational level, PRL-1 may stabilize BMP7 protein by inhibiting its degradation via either the ubiquitin-proteasome system or the autophagy-lysosomal pathway. Alternatively, PRL-1 may also enhance BMP7 translation efficiency via RNA-binding proteins. The specific degradation pathway involved should be identified through protein stability assays and rescue studies. A comprehensive understanding of PRL-1’s potential dual role in BMP7 regulation will refine its potential as a therapeutic target in hepatic fibrosis and may broaden its application to other fibrotic disorders.

Additionally, before PRL-1-engineered MSCs can be considered for clinical use, potential safety risks and translational challenges need to be carefully evaluated. One of the concerns is long-term safety, as the study relies on short-term assessments (≤5 weeks post-transplantation), leaving uncertainties about the durability of therapeutic effects and the possibility of late-onset complications. Given PRL-1’s known oncogenic potential in other contexts, extended follow-up studies are essential to assess tumorigenicity, immune rejection, and systemic off-target effects [9]. Lack of rigorous long-term safety evaluations may lead to unintended fibrogenic activation, aberrant proliferation, or immune-mediated complications. To address these concerns, future studies should incorporate in vivo imaging, molecular tracking, and immunological profiling to monitor the behavior of transplanted MSCs and detect any emerging risks.

Furthermore, the absence of dose-response data for PRL-1-engineered MSCs remains a hurdle for clinical application. Systematic dose optimization is essential to identify minimal effective doses and mitigate safety risks while maximizing therapeutic efficacy. Excessive PRL-1 activity may result in uncontrolled EMT dynamics, potentially disrupting normal tissue function. The effectiveness of PRL-1 may also vary depending on the disease context. To optimize its therapeutic potential, future research should explore controlled delivery methods, such as inducible expression systems or spatiotemporal regulation, allowing for precise modulation of PRL-1 activity based on fibrosis severity.

Although the biliary duct ligation model provides useful insights into cholestatic fibrosis, it does not fully represent the varied causes and progression patterns of human hepatic fibrosis. As is known, most clinical fibrosis cases arise from viral hepatitis, non-alcoholic steatohepatitis (NASH), and metabolic dysfunction-associated liver fibrosis, each with distinct inflammatory and fibrotic mechanisms [10]. To improve clinical relevance, future investigations should evaluate PRL-1-engineered MSCs in a broader range of preclinical models, including NASH-induced fibrosis models, genetically modified fibrosis models, and humanized liver models. Patient-derived liver organoids could also provide a more human-relevant system to evaluate therapeutic potential and help to bridge the gap between animal studies and clinical application.

Another challenge is the lack of direct comparison between PRL-1-modulated MSC therapy and other existing anti-fibrotic treatments. The study evaluates PRL-1-engineered MSCs only against naïve MSCs, without considering how they measure up to alternative cell therapies, exosome-based approaches, or pharmacological treatments. Emerging strategies, including TGF-β and Wnt pathway inhibitors, small-molecule epigenetic modulators, and extracellular vesicle-based therapies, have shown promise in fibrosis treatment [11]. Without a head-to-head comparison, it remains unclear whether PRL-1-engineered MSCs offer a clear therapeutic advantage over these options. A broader evaluation across different modalities would help establish their true potential.

Hepatic fibrosis is a complex and multifaceted condition, making it unlikely that a single therapy targeting one pathway will be fully sufficient. The integration of PRL-1 modulation with existing anti-fibrotic treatments could offer a more effective approach. Targeting TGF-β or Wnt pathways, both key drivers of fibrosis, alongside PRL-1 could enhance EMT/MET reprogramming and promote fibrosis resolution. Additionally, using MSC-derived exosomes as a delivery system for PRL-1 could help regulate its effects more precisely, potentially reducing risks associated with direct MSC transplantation. Future studies should explore these combination strategies to improve the clinical applicability of PRL-1-based therapies.

This study provides strong evidence that PRL-1 modulation in placental MSCs influences EMT/MET dynamics, presenting a promising approach for treating hepatic fibrosis. By clarifying PRL-1’s role in fibrosis progression, it deepens our understanding of disease mechanisms and highlights engineered MSCs as a potential therapeutic option for liver diseases. As personalized medicine advances, PRL-1-targeted MSC therapy could contribute to more precise anti-fibrotic treatments. However, key challenges, including long-term safety, dose optimization, and broader validation, should be addressed before clinical translation. Tackling these issues will be essential to bringing PRL-1-modulated MSC therapy closer to clinical use and improving patient outcomes.

Abbreviations

ECM

extracellular matrix

EMT

epithelial-mesenchymal transition

MET

mesenchymal-epithelial transition

MSCs

mesenchymal stem cells

NASH

non-alcoholic steatohepatitis

PRL-1

phosphatase of regenerating liver-1

TGF-β

transforming growth factor-beta