Research ArticleExperimental Studies
Open Access

Adipose-derived Stem Cell Sheets Induce Angiogenesis and Hepatic Stellate Cell Activation

YUKI WATANABE, TOSHIO KOKURYO, SHUNSUKE ONOE, JUNPEI YAMAGUCHI, MASAKI SUNAGAWA, TAISUKE BABA, SHOJI KAWAKATSU, NOBUYUKI WATANABE, TAKASHI MIZUNO and TOMOKI EBATA
In Vivo November 2025, 39 (6) 3106-3115; DOI: https://doi.org/10.21873/invivo.14112

Abstract

Background/Aim: Despite advances in critical care, postoperative liver failure remains a substantial complication of liver resection, with high mortality rates. Adipose-derived stem cells (ADSCs) have demonstrated potential in various regenerative applications; however, their precise mechanisms in liver repair remain unclear. This study investigated the effects of ADSC sheets on the vascular and cellular responses in a mouse model of partial hepatectomy.

Materials and Methods: Human ADSCs were cultured with magnetic nanoparticle-containing liposomes and formed multilayered cell sheets. Following partial hepatectomy in BALB/c nude mice, ADSC or collagen control sheets were attached to liver resection sites. Immunohistochemical analysis assessed angiogenesis (CD31), hepatic stellate cell activation (α-SMA), and cellular origin. Mice were sacrificed on postoperative days 4 and 7. Statistical analysis was conducted using Bonferroni’s method (p<0.05).

Results: Compared to cell-free collagen sheets (control), ADSC sheets demonstrated significantly enhanced neovascularization, with higher CD31 expression on postoperative days 4 and 7. Immunohistochemical analysis revealed that these CD31-positive cells were predominantly of mouse origin, rather than differentiated from transplanted human ADSCs, indicating host cell migration into the sheets. Additionally, ADSC sheets significantly increased α-SMA expression compared to that with collagen sheets, with expression levels progressively increasing from day 4 to 7, suggesting continuous activation of hepatic stellate cells. These findings indicate that ADSC sheets induce angiogenesis and hepatic stellate cell activation during liver regeneration, likely through paracrine mechanisms that recruit host cells, rather than through direct differentiation of transplanted ADSCs.

Conclusion: This study lays the groundwork for the clinical application of ADSC sheets, demonstrating their potential to enhance liver regeneration after hepatectomy by promoting host cell-mediated angiogenesis and hepatic stellate cell activation.

Keywords:

Introduction

Postoperative liver failure is one of the most severe complications of liver resection, with a reported incidence of 1.2-32% after hepatectomy (1-3). In 2010, the International Study Group of Liver Surgery defined post-hepatectomy liver failure as postoperative acquired deterioration in the ability of the liver to maintain its synthetic, excretory, and detoxifying functions, which are characterized by an increased international normalized ratio and concomitant hyperbilirubinemia on or after postoperative day 5, and differentiated the severity of post-hepatectomy liver failure into three grades from A to C (2). Among these grades, Grade C represents the most severe form with the highest mortality risk. Reissfelder et al. reported that Grade C liver failure occurred in 13 of 65 patients who developed post-hepatectomy liver failure, with 7 of these patients (53.8%) experiencing perioperative death (4). Conventional treatments primarily focus on supportive care, including nutritional support, management of coagulopathy, and prevention of complications, such as infection and encephalopathy. Therefore, effective prevention and treatment strategies are urgently needed.

Adipose-derived stem cells (ADSCs) are mesenchymal stem cells present in adipose tissue. They have gained substantial attention in regenerative medicine and research has progressed in many fields, including bone, skin, ligament, liver, nerve, and cardiac muscle regeneration (5-7). Compared to bone marrow-derived stem cells, ADSCs are characterized by their superior multipotent differentiation ability and immunosuppressive effects (8). Additionally, they can be easily and minimally invasively harvested in large quantities from the subcutaneous fat and other adipose tissues.

ADSCs promote liver regeneration (9-10). Our laboratory has been conducting research on liver regeneration using ADSCs in an ischemia-reperfusion model (11). In this model, we clamped the rat hepatoduodenal ligament for 15 min to block portal vein blood flow and then performed 70% hepatectomy. After releasing the clamp, 2×106 ADSCs were injected into the penile veins. ADSCs were detected in the liver and we reported a significant increase in the liver regeneration rate in the ADSC group compared with that in the control group on day 2.

Furthermore, to directly apply these effects to organ defect sites, we developed a novel technique to rapidly create multilayered ADSC sheets using magnetic nanoparticles (12). Human ADSCs were magnetized by incorporating magnetic nanoparticle-containing liposomes (MCLs) and mixed with a culture medium containing biocollagen. An external magnetic force was used to aggregate the ADSCs and form sheets. Our laboratory has been studying the application of these sheets in a rat model of a pancreatic fistula. We previously reported that sheet formation prevents cell loss, reduces intraperitoneal amylase levels, and is effective in preventing pancreatic fistulas.

This study aimed to investigate the preventive effects of ADSC sheets on postoperative liver failure and their mechanism of action using a mouse partial hepatectomy model.

Materials and Methods

Cell culture. Human ADSC lines (PT-5006) were obtained from Lonza Walkersville Inc. (Lonza, Walkersville, MD, USA). ADSCs were cultured in Mesen Pro (Thermo Fisher Scientific, Waltham, MA, USA) at 37°C in a humidified atmosphere with 5% CO2.

Creation of the ADSC sheets. The ADSCs were cultured with MCLs in Dulbecco’s Modified Eagle’s Medium (DMEM) supplemented with 10% fetal bovine serum and antibiotics (100 U/ml of penicillin G and 100 mg/ml of streptomycin) at 37.8°C and 5% CO2. When the cells reached confluence, the attached ADSCs were resected in medium similar to that described above at a concentration of 2×103 cells/cm2. The MCL-labeled ADSC suspension (5×105 cells in 50 ml) was mixed with an extracellular matrix (ECM) precursor solution comprising 75 ml of DMEM and 25 ml of atelocollagen (KOKEN, Tokyo, Japan) solution. The mixture (150 ml) was added to each well of a 24-well ultra-low attachment plate, in which cloning rings (diameter, 5 mm; height, 10 mm; Asahi Glass Co. Ltd, Tokyo, Japan) were placed at the center of each well. The magnets were immediately placed under the wells. Magnetized ADSCs formed multilayered cell sheets after approximately 3 h of incubation.

Histology. Mouse liver specimens were immediately fixed in neutral-buffered formalin and embedded in paraffin. Samples were dehydrated using a graded ethanol series and embedded in paraffin. Sections (6-mm thick) were mounted on glass slides and stained with hematoxylin and eosin.

Immunohistochemistry. Formalin-fixed and paraffin-embedded tissues were sliced into 3.5-μm thick sections, deparaffinized and rehydrated. The tissues were heated in Target Retrieval Solution (pH6.0; Dako, Osaka, Japan), and endogenous peroxidase activity was blocked with 3% H2O2 in methanol at room temperature for 15 min. After using the Protein Block Serum free (Dako) at room temperature, the tissues were incubated with anti- CD31, α-SMA, human lamin B1, and mouse lamin B1 (Sigma-Aldrich) at 4°C overnight. The tissues were then incubated with a secondary antibody conjugated to HRP-labeled polymer (EnVision+ system, anti-rabbit; Dako) for 60 min at room temperature. The reaction products were visualized using diaminobenzidine and the nuclei were counterstained with hematoxylin.

CD31, α-SMA, human lamin B1, and mouse lamin B1-positive cells were analyzed in five randomly selected high-power fields.

Animal studies. All animal experiments were conducted in compliance with the guidelines of the Institute for Laboratory Animal Research at Nagoya University Graduate School of Medicine. BALB/c nude mice (8 weeks old and weighing 20-25 g) were purchased from SLC (Nagoya, Japan) and housed in temperature- and humidity-controlled environments under a 12-h light-dark cycle. The animals had ad libitum access to water and food.

Procedure of partial hepatectomy. The mice were anesthetized with isoflurane. The liver was exposed via upper abdominal midline laparotomy. Partial hepatectomy (5-mm diameter) was performed in the left liver lobe. After the partial resection of the liver, an ADSC or collagen sheet was attached to the resection surface (Figure 1A). The mice were sacrificed on postoperative days 4 and 7. During laparotomy, the liver tissue was collected from each mouse.

Figure 1.
Figure 1.
Figure 1.

Grafting of ADSC sheets onto the liver defect site and analysis of angiogenesis. (A) Representative macroscopic images of the liver defect site after partial hepatectomy and attachment to the ADSC sheets. (B) Histological images of ADSC and collagen sheets attached to the liver defect site (H&E staining). Brown particles within the ADSC sheets represent magnetic nanoparticle-containing liposome (MCLs). Arrowheads indicate angiogenesis in the ADSC sheets. (C) Representative immunohistochemical staining of CD31 in ADSC and collagen sheets. Graphs show the relative CD31 expression in both sheets (*p<0.01). ADSC, Adipose-derived stem cells.

Statistical analysis. All data are presented as means± standard error. Differences were analyzed using Bonferroni’s method. Differences were considered statistically significant at p<0.05.

Results

Grafting of ADSC sheets to the liver defect after partial hepatectomy. We investigated two groups of mice with partial hepatectomy: one with human-derived multilayered ADSC sheets attached to the liver resection site, and the other with cell-free collagen sheets attached to the same site as a control. Mice were sacrificed on postoperative day 4 or 7, and the liver tissues were harvested for examination. Both sheets remained attached to the liver defect at the same site 7 days after the operation.

The effect of ADSC sheets on angiogenesis. Collagen sheets were prepared without cells; consequently, few cellular components were observed within the sheets (Figure 1B). In contrast, the ADSC sheets contained abundant cellular components. Histologically, almost no hepatocyte necrosis or inflammatory cell infiltration was identified in either the ADSC or collagen sheets. The brown foreign materials visible within the ADSC sheets represent MCLs used for sheet preparation. No neovascularization was observed in the collagen sheets. However, in the ADSC sheet, many cells containing MCLs were observed and significant neovascularization was detected. At higher magnification, blood cells were clearly identified within these newly formed vessels, confirming functional vascularization.

CD31 expression on ADSC sheets. We examined CD31 expression in both sheet types and found significantly higher levels of this endothelial cell marker in ADSC sheets than those in the collagen sheets (Figure 1C), indicating enhanced vascularization in the ADSC group.

Migration of mouse CD31- expressing cells. These findings suggested that ADSCs promote angiogenesis. To confirm whether CD31-expressing cells differentiated from human ADSC, we stained ADSC sheets using CD31 and human lamin B1 antibodies. Unexpectedly, the localization of CD31 and human lamin B1 did not coincide, suggesting that CD31-expressing cells were not of human origin (Figure 2A).

Figure 2.
Figure 2.

Origin of endothelial cells in ADSC sheets. (A) Double immunofluorescence images of CD31 (red) and human lamin B1 (green) of ADSC sheets. The nuclei were stained using DAPI. (B) Double immunofluorescence images of human lamin B1 and mouse lamin B1 in ADSC sheets. The nuclei were stained using DAPI. ADSC, Adipose-derived stem cells.

To determine whether the endothelial cells observed in the ADSC sheets were of human or mouse origin, we stained the ADSC sheets with human or mouse lamin B1. The sheets contained a mixture of ADSCs and mouse cells, indicating migration of mouse cells into the sheets (Figure 2B). However, we were not observed the ADSC migration into the mouse liver.

Activation of hepatic stellate cells on ADSC sheets. The neovascularization observed in ADSC sheets was primarily facilitated by host-derived endothelial cells. We next investigated whether ADSC sheets influenced other cellular components involved in liver regeneration, particularly hepatic stellate cells. Compared with the collagen sheet group, the ADSC sheet group demonstrated significantly increased expression of α-SMA, a marker of hepatic stellate cells (Figure 3A). This suggests that the stellate cells were activated on the ADSC sheets. Furthermore, α-SMA was highly expressed in ADSC sheets on postoperative day 7, in comparison with day 4 (Figure 3B). The increasing number of α-SMA-positive cells indicated that the activation of hepatic stellate cells on the ADSC sheets was continuously promoted over time.

Figure 3.
Figure 3.
Figure 3.

Activation of hepatic stellate cells in ADSC sheets. (A) Immunohistochemical images of α-SMA in ADSC and collagen sheets. Nuclei were stained using DAPI. Graphs showed relative α-SMA expression in both sheets (*p<0.01). (B) Immunohistochemical images of α-SMA in ADSC sheets between postoperative day 4 and 7. Graphs showed relative α-SMA expression at postoperative day 4 and 7 (*p<0.01). ADSC, Adipose-derived stem cells.

Discussion

Liver regeneration is an effective therapeutic approach for liver diseases due to the liver’s inherent regenerative capacity. However, extensive liver defects often exceed its natural healing abilities, therefore innovative treatment strategies are required. Cell sheet engineering has demonstrated efficacy in various tissue regeneration. However, the therapeutic potential of ADSC sheets for liver defect, particularly their effects on angiogenesis and cellular activation, remains insufficiently understood.

This study demonstrated that ADSC sheets grafted onto liver defects promoted angiogenesis and stellate cell activation in a mouse partial hepatectomy model.

Histological analysis revealed that ADSC sheets significantly promoted neovascularization compared to that with collagen sheets. The expression of CD31, an endothelial cell marker, was significantly higher in the ADSC sheets than that in the collagen sheets. These findings suggest that the ADSC sheets promote angiogenesis, which is crucial for liver regeneration. Notably, immunohistochemical staining showed that the localization of CD31 and human lamin B1 did not coincide, indicating that the CD31-positive cells were not derived from transplanted human ADSCs. Angiogenesis occurs through migration of mouse cells.

In addition, our study demonstrated that ADSC sheets significantly increased the activation of hepatic stellate cells compared to that with collagen sheets. Hepatic stellate cells, also known as Ito cells, store vitamin A and reside in the space of Disse between the hepatocytes and sinusoidal endothelial cells in the liver (13). Hepatic stellate cells play a crucial role in liver regeneration when activated during liver injury (14, 15). These cells secrete various growth factors and cytokines that stimulate hepatocyte proliferation. The activation of hepatic stellate cells increases the secretion of IL-8, known as a promoter of angiogenesis (16). Hepatic stellate cell activation can be induced by various stimuli, including small extracellular vesicles. The activation increased IL-8 secretion through NF-κB nuclear translocation, which subsequently promotes cell migration (16). This supports our findings that ADSC sheets promote liver regeneration by activating stellate cells and enhancing the local cytokine microenvironment.

The enhanced regeneration by ADSC sheets may involve multiple factors. ADSCs secrete various growth factors and cytokines, such as hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and interleukin-6 (IL-6), which promote liver regeneration (17, 18). We have previously reported that ADSCs increased fibroblast growth factor 2 (FGF2) production, which effectively prevents mouse pancreatic fistulas through enhanced tissue repair capacity (12). The paracrine effects of ADSCs and the migration of host cells into sheets may play significant roles in their regenerative potential. Additionally, ECM components in ADSC sheets, such as collagen, may provide a favorable microenvironment for cell migration and angiogenesis.

To further enhance these therapeutic effects, various preconditions have been explored to optimize ADSC function. Among these approaches, deferoxamine (DFO), a hypoxia-mimetic agent, is an effective precondition for ADSCs. Ji et al. demonstrated that DFO-preconditioned ADSCs showed superior therapeutic efficacy compared with that of naive ADSCs In their mouse model of systemic inflammation (19).

Although our partial hepatectomy mouse provides valuable findings regarding liver regeneration mechanisms, it cannot completely recapitulate the complex pathogenesis of postoperative liver failure in humans.

Clinical postoperative liver failure usually occurs in patients whose regenerative capacity has been compromised by diseases, such as liver dysfunction, cirrhosis, steatosis, or viral hepatitis. In contrast, healthy young mice with normal liver function were used in our study. This may overestimate the regenerative potential and therapeutic efficacy of ADSC sheets.

Furthermore, species-specific differences in liver regeneration between mice and humans have been revealed. Zhao et al. reported substantial differences in gene expression between mice and humans by studies of acetaminophen-induced liver injury (20). This demonstrated the complexity of translating murine findings to clinical applications.

To address these issues, alternative experimental models that precisely reflect clinical conditions have been developed, including hepatectomy with ischemia-reperfusion injury and chemical-induced liver injury models. Additionally, to overcome species-specific differences between rodents and humans, experimental models using pigs with liver physiological function similar to humans have been developed (21, 22). Future studies using these animal models would provide more clinically relevant evidence for the therapeutic potential of ADSC sheets in postoperative liver failure.

Conclusion

This study suggested that ADSC sheets promote the recruitment of host endothelial progenitor cells through paracrine factors rather than the direct differentiation of transplanted ADSCs into endothelial cells. This is consistent with previous studies reporting that the paracrine effects of ADSCs play a significant role in their regenerative potential (23). Therefore, ADSC sheets represent a promising therapeutic strategy for treating postoperative liver failure. Future studies with longer follow-up periods are required to assess the long-term benefits and potential adverse effects of the clinical application of the drug.

Footnotes

  • Authors’ Contributions

    Yuki Watanabe, Toshio Kokuryo, Shunsuke Onoe and Tomoki Ebata conceived and designed the study. Junpei Yamaguchi, Masaki Sunagawa, and Taisuke Baba performed the experiments and acquired data. Takashi Mizuno, Nobuyuki Watanabe, and Shoji Kawakatsu analyzed the data. Yuki Watanabe, Toshio Kokuryo and Shunsuke Onoe wrote the manuscript. All the Authors have read and approved the final version of the manuscript.

  • Conflicts of Interest

    The Authors declare no competing interest in relation to this study.

  • Funding

    This study was supported by JSPS KAKENHI (grant number: 19K09118).

  • Artificial Intelligence (AI) Disclosure

    During the preparation of this manuscript, a large language model (Claude) was used solely for language editing and stylistic improvements in select paragraphs. No sections involving the generation, analysis, or interpretation of research data were produced by generative AI. All scientific content was created and verified by the authors. Furthermore, no figures or visual data were generated or modified using generative AI or machine learning-based image enhancement tools.

  • Received July 27, 2025.
  • Revision received September 16, 2025.
  • Accepted September 24, 2025.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Adipose-derived Stem Cell Sheets Induce Angiogenesis and Hepatic Stellate Cell Activation
YUKI WATANABE, TOSHIO KOKURYO, SHUNSUKE ONOE, JUNPEI YAMAGUCHI, MASAKI SUNAGAWA, TAISUKE BABA, SHOJI KAWAKATSU, NOBUYUKI WATANABE, TAKASHI MIZUNO, TOMOKI EBATA
In Vivo Nov 2025, 39 (6) 3106-3115; DOI: 10.21873/invivo.14112
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