CD177+ Neutrophils: New Drivers of Liver Regeneration

Liver resection remains the main curative option for many patients with primary and secondary liver malignancies, including hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and colorectal liver metastases. However, a substantial proportion of patients are not eligible for surgery due to insufficient future liver remnant (FLR) for sustained postoperative liver function. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) was developed just over a decade ago to address this specific problem and to overcome the limitations of traditional hypertrophy-induced strategies, such as perioperative portal vein embolization (PVE) and “classic” two-stage hepatectomy. By combining right portal vein ligation with in situ parenchymal transection, ALPPS induces a remarkably rapid increase in FLR volume, enabling patients within advanced liver malignancies and marginal FLR to undergo potentially curative resection within just a few days [1]. The initial multicenter ALPPS registry analysis reported higher perioperative morbidity and mortality in elder patients, but confirmed improved resectability [2]. For liver surgeons and oncologists, ALPPS represents a challenging clinical trade-off: it can offer a surgical opportunity for patients who would otherwise be inoperable, yet it does so with a narrow safety margin. Given persistent debate over the biological basis and safety profile of ALPPS, mechanistic studies are essential for understanding why the procedure succeeds in some patients yet fails in others.

In this issue, Yan et al. [3] provide novel insights into the mechanistic landscape of the ALPPS-induced regenerative niche. Using paired FLR samples from patients undergoing ALPPS, they integrate single-cell RNA sequencing, spatial transcriptomics, and multiplex immunostaining with complementary experiments in a 3D liver organoid model and in a mouse ALPPS model. This comprehensive approach moves beyond a hepatocyte-centered view of regeneration and instead highlights the coordinated interactions among liver immune cells, stromal populations, and the extracellular matrix (ECM). Their analyses identify CD177+ neutrophils as a dominant, metabolically active, and functionally specialized subset that expands within the FLR after ALPPS and emerges as a central orchestrator of the regenerative response (Fig. 1).

Figure 1.

CD177+ neutrophils play a key role in driving liver regeneration. Following associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), circulating CD177+ neutrophils interact with endothelial cells via CD177-CD31 to facilitate their transmigration into the liver. Within the regenerating liver, infiltrated CD177+ neutrophils secrete abundant matrix metalloproteinase 9 (MMP9), which promotes extracellular matrix degradation and converts inactive pro-hepatocyte growth factor (pro-HGF) into active HGF. The resulting increase in active HGF enhances hepatocyte proliferation, ultimately accelerating liver regeneration.

A key conceptual contribution of this work [3] is the reframing of the role of neutrophils in liver regeneration. Traditionally viewed as short-lived, cytotoxic cells that amplify liver injury or combat infection, neutrophils are now recognized as highly plastic and capable of promoting liver repair [4]. Yan et al. [3] extend this paradigm by demonstrating that the CD177+ neutrophil subset adopts a pro-regenerative program characterized by metabolic re-wiring, ECM remodeling, and growth factor activation, even though liver CD177+ neutrophils have also been implicated in promoting biliary atresia via producing neutrophil extracellular traps (NETs) [5]. Their data show a shift of CD177+ neutrophils from a pro-inflammatory to a pro-regenerative state during ALPPS-induced liver regeneration [3], providing a concrete cellular explanation for the “two faces” of neutrophils in liver diseases: the same lineage can exacerbate injury or support regeneration, depending on disease stage and microenvironment.

Mechanistically, Yan et al. [3] demonstrate that CD177+ neutrophils lie at the crossroads of several key regenerative pathways. Matrix metalloproteinases (MMPs), particularly MMP9, are crucial regulators of ECM turnover, capable of liberating latent growth factor from the matrix and reshaping the physical and biochemical landscape of the regenerative lobule [6]. Yan et al. connect the proteolytic activity of MMP9, produced predominantly by CD177+ neutrophils, to the activation of hepatocyte growth factor (HGF), a central driver of liver regeneration that is normally stored in the ECM [7]. Although neutrophils have previously been recognized as a potential source of HGF [7], their study underscores the specific contribution of CD177+ neutrophils to ECM-remodeling-enabled HGF activation through MMP9 secretion, which in turn promotes hepatocyte proliferation and ultimately supports liver regeneration [3].

CD177 is a glycosylphosphatidylinositol-anchored surface protein expressed on human neutrophils across various inflammatory settings and is best known as a counter-receptor for platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) on endothelial cells, thereby facilitating neutrophil transendothelial migration [8]. In this context, CD177 primarily enables the entry of pro-regenerative neutrophils into liver tissue. Supporting this model, Yan et al. [3] report that CD177 deficiency in mice results in reduced MMP9 production and attenuated ALPPS-induced liver regeneration, likely reflecting an impaired capacity of pro-regenerative neutrophils to transmigrate through the endothelium. Nevertheless, the molecular cues and microenvironmental signals that shape the distinctive genetic program of CD177+ pro-regenerative neutrophils remain to be elucidated.

In conclusion, Yan et al. [3] significantly advanced our understanding of how innate immune cells, and neutrophils in particular, interact with the core regenerative machinery of the liver. By defining a functionally specialized CD177+ neutrophil subset that links ECM remodeling to HGF activation, they introduce a previously unrecognized cellular component into the landscape of liver regenerative biology. Their findings provide a compelling rationale for leveraging neutrophils as therapeutic targets to improve outcomes following major hepatectomy. As we aim to extend curative-intent surgery to more patients with advanced liver cancers while reducing the risk of post-hepatectomy liver failure, strategies that enhance the trafficking of CD177+ neutrophils to the FLR or reprogram neutrophils toward a pro-regenerative state capable of driving MMP9-dependent HGF activation represent promising avenues for preclinical investigation.

Important limitations, however, must be considered before drawing clinical inferences. The human single-cell omics data were generated from a relatively small cohort of ALPPS patients [3], and although Yan et al. [3] strengthen these conclusions with extensive immunostaining, independent validation in larger, more diverse, multi-center cohorts will be essential. In addition, neutrophil proteases and MMP9-mediated ECM degradation are inherently double-edged: while they can release growth factors and facilitate tissue remodeling, they have also been implicated in sinusoidal injury, parenchymal hemorrhage, and necrosis in the remnant liver after extensive hepatectomy [6, 9]. Thus, any therapeutic approach targeting CD177+ neutrophils or enhancing MMP9 activity will require careful calibration of timing, magnitude, and patient selection to maximize regenerative benefit while minimizing the risk of exacerbating liver injury.