Current Perspectives and Progress in Preoperative Portal Vein Embolization with Stem Cell Augmentation (PVESA)

Abstract

Portal vein embolization with stem cell augmentation (PVESA) is an emerging approach for enhancing the growth of the liver segment that will remain after surgery (i.e., future liver remnant, FLR) in patients with liver cancer. Conventional portal vein embolization (PVE) aims to induce preoperative FLR growth, but it has a risk of failure in patients with underlying liver dysfunction and comorbid illnesses. PVESA combines PVE with stem cell therapy to potentially improve FLR size and function more effectively and efficiently. Various types of stem cells can help improve liver growth by secreting paracrine signals for hepatocyte growth or by transforming into hepatocytes. Mesenchymal stem cells (MSCs), unrestricted somatic stem cells, and small hepatocyte-like progenitor cells have been used to augment liver growth in preclinical animal models, while clinical studies have demonstrated the benefit of CD133 + bone marrow-derived MSCs and hematopoietic stem cells. These investigations have shown that PVESA is generally safe and enhances liver growth after PVE. However, optimizing the selection, collection, and application of stem cells remains crucial to maximize benefits and minimize risks. Additionally, advanced stem cell technologies, such as priming, genetic modification, and extracellular vesicle-based therapy, that could further enhance efficacy outcomes should be evaluated. Despite its potential, PVESA requires more investigations, particularly mechanistic studies that involve orthotopic animal models of liver cancer with concomitant liver injury as well as larger human trials.

Keywords: Future liver remnant; Hematopoietic stem cells; Liver hypertrophy; Mesenchymal stem Cells; PVESA; Portal vein embolization; Portal vein ligation.

Fig. 1

Schematic diagram of factors and mechanisms involved in PVE and PVESA. The growth of hepatocytes following PVE is mediated by several cytokines, growth factors, vasoactive substances, and hormones. On the other hand, PVESA enhances the FLR growth achieved with PVE through additional paracrine effects and differentiation. The differentiation of HSCs and SHPCs to hepatocytes has been suggested, but it requires further investigation. Abbreviations: 5-HT, serotonin; EGF, epidermal growth factor; FLR, future liver remnant; HGF, hepatocyte growth factor; HSC, hematopoietic stem cell; IGF-1, insulin-like growth factor 1; IL, interleukin; MMP-9, matrix metalloproteinase 9; MSC, mesenchymal stem cell; NE, norepinephrine; NO, nitric oxide; PGE₂, prostaglandin E₂; PVE, portal vein embolization; PVESA, portal vein embolization with stem cell augmentation; SHPC, small hepatocyte-like progenitor cell; TGF-α, transforming growth factor alpha; TNF-α, tumor necrosis factor alpha; USSC, unrestricted somatic stem cell; VEGF, vascular endothelial growth factor. The figure has been created using Biorender.com

Fig. 2

Imaging before and after PVE. (a) CT with contrast before PVE in a 67-year-old woman with metastatic colorectal cancer (arrowhead, right liver lobe). (b) Direct portography showing normal portal vein anatomy (arrowhead, portal vein). (c) Glue cast in the right portal vein branches demonstrating adequate embolization using an N-butyl-cyanoacrylate-lipiodol mixture. (d) CT imaging 30 days after right PVE showing growth of the left liver (arrowhead, left liver lobe). (e, f) CT volumetry after PVE illustrates an increase in FLR (red, right liver lobe; green, left liver lobe). Abbreviations: CT, computed tomography; FLR, future liver remnant; PVE, portal vein embolization. Images have been adapted from Luz et al., 2017 [30]. The figure has been created using Biorender.com

Fig. 3

Liver growth after PVESA in cirrhotic rats. (a) Ratios of FLR versus total liver weight as well as (b) Ki-67-positive cells among the three groups were significantly different (p < 0.001), with the BMSC-treated group showing the highest values at days 14 and 28 after surgery (*, p < 0.001; BMSCs, bone marrow-derived mesenchymal stem cells; FLR, future liver remnant; LI, labeling index; SO, sham operation). (c/d) Representative immunohistochemistry slides for the BMSC-treated (c) and PVE-only control (d) groups show higher expression of Ki-67 (brown nuclear stains) in the BMSC-treated liver. Images have been adapted from Li et al., 2013 [48]. The figure has been created using Biorender.com

Fig. 4

Liver growth after PVESA in a patient with HCC. (a) Axial helical computed tomography scans before and (b) 14 days after PVE and intraportal autologous CD133 + BMSC application revealed marked growth of segments II and III, marked by white arrows (black arrowhead, dislocated cyanoacrylate-to-iodinized oil particle; black arrow, hepatocellular carcinoma). Images have been adapted with permission from Fürst et al. 2007 [87]. The figure has been created using Biorender.com