Safety and preliminary efficacy of allogeneic umbilical cord–derived mesenchymal stem cells administered via the hepatic artery in patients with liver cirrhosis: A phase I open-label trial

Abstract

Liver cirrhosis causes substantial morbidity, and options beyond transplantation are limited. Umbilical cord–derived mesenchymal stem cells (UC-MSCs) may support liver repair, but their delivery via the hepatic artery has not been evaluated. This study assessed the safety and exploratory efficacy of allogeneic UC-MSCs infusion in cirrhosis. Twenty patients with liver cirrhosis entered a single-center open-label pilot trial in Hanoi, Vietnam, between 2020 and 2023; 17 completed follow-up and were included in exploratory analyses. All received a single hepatic artery infusion of UC-MSCs at 1 × 10⁶ cells/kg and were assessed at baseline, 3, 6, and 12 months for liver function, Model for End-stage Liver Disease (MELD) and Child–Pugh scores, Chronic Liver Disease Questionnaire (CLDQ), and adverse events. No serious adverse events occurred; mild events were self-limited. Albumin increased at 3 and 6 months (P = 0.048; P = 0.027). Bilirubin, liver enzymes, coagulation, and MELD remained stable. Child–Pugh score decreased transiently at 3 months (P = 0.024). CLDQ increased across most domains, except systemic symptoms. Hepatic artery infusion of UC-MSCs was safe and well tolerated, with observed increases in albumin and in most CLDQ domains, while other parameters remained stable. Findings are exploratory because of the small sample size and lack of a control group and therefore require confirmation in larger, controlled studies.

Graphical Abstract

Keywords

liver cirrhosis umbilical cord–derived mesenchymal stem cells cell therapy hepatic artery infusion Chronic Liver Disease Questionnaire

Introduction

Liver cirrhosis represents the end stage of chronic liver disease. It is characterized by extensive fibrosis, formation of regenerative nodules, disruption of normal hepatic architecture, and progressive loss of liver function. Alcoholic and nonalcoholic fatty liver disease, metabolic dysfunction–associated steatotic liver disease (MASLD), and viral hepatitis (B or C) are the most common causes of liver cirrhosis. The other causes include primary biliary cholangitis, biliary obstruction, and other chronic liver conditions^1,2.

The global burden of liver cirrhosis has risen over recent decades. From 2009 to 2019, cirrhosis-related deaths increased to nearly 1.5 million worldwide, although the age-standardized death rate declined from 20.71 to 18.00 per 100,000 population¹. Liver cirrhosis generally progresses through two stages: compensated cirrhosis and decompensated cirrhosis. Decompensated cirrhosis is associated with severe complications, including bleeding from esophageal variceal rupture, hepatic encephalopathy, and liver failure. Without liver transplantation, patients typically die in the end stage³. However, the scarcity of suitable donor organs presents a major challenge. As an alternative to liver transplantation, stem cell–based therapy has garnered significant interest.

Mesenchymal stem cells (MSCs) can repair injured liver tissue via several mechanisms. These include the modulation of hepatic stellate cell (HSC) activity, differentiation into hepatocyte-like cells, anti-fibrotic effects, and immunomodulatory effects⁴. HSCs are key drivers of liver cirrhosis. When activated by liver injury, they differentiate into myofibroblast-like cells and produce excess extracellular matrix, leading to fibrosis and structural damage⁵. MSCs play a multifaceted role in modulating the activity of HSCs during liver cirrhosis. Previous studies have shown that MSCs can inactivate HSCs⁶ and induce HSC apoptosis through paracrine signaling, involving hepatocyte growth factor (HGF) and nerve growth factor (NGF)⁷. MSCs can alter the expression of specific miRNAs, such as upregulating of miR-455-3p, which regulates genes involved in fibrosis, thereby reducing HSC activation and promoting liver regeneration⁸.

The anti-fibrotic effects of MSCs are primarily paracrine. MSCs secrete a range of growth factors and cytokines, including HGF, interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), and transforming growth factor-β3 (TGF-β3). These factors inhibit HSC activation and reduce collagen production^4,9. MSCs influence the HSC cell cycle by modulating the levels of key regulatory proteins, such as cyclin D1 and p27, leading to cell cycle arrest and reduced proliferation¹⁰. MSCs can also suppress HSC proliferation by upregulating the expression of Notch 1 and downregulating key components of the Wnt/β-catenin pathway, thereby reducing liver fibrosis^4,9. In addition, MSCs can differentiate into hepatocyte-like cells under appropriate conditions⁹. Fang et al.¹¹ also reported that umbilical cord–derived mesenchymal stem cells (UC-MSCs) decrease pro-inflammatory cytokines (IL-6 and TNF-α) and increase anti-inflammatory cytokines (IL-10 and TGF-β) in models of decompensated liver cirrhosis. Preclinical studies have shown that MSCs can ameliorate liver fibrosis and improve liver function^12–14. Bone marrow–derived MSCs reduce liver collagen deposition and exert anti-fibrotic effects in a carbon tetrachloride-induced liver fibrosis model^12,13. UC-MSC administration was also shown to reduce biochemical markers, including total bilirubin (TBIL), gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP), and ameliorate liver cirrhosis in a diethylnitrosamine-induced rat model¹⁴.

Among the early clinical reports of cell therapy for liver cirrhosis, Terai et al.¹⁵ used autologous bone marrow mononuclear cells. In 2012, Zhang et al.¹⁶ reported outcomes of UC-MSCs therapy in patients with decompensated liver cirrhosis. In recent years, the safety and efficacy of UC-MSCs have been reported in various studies^17–19.

Previous clinical studies have examined hepatic artery infusion in chronic liver disease using autologous bone marrow–derived CD34+ cells or bone marrow mononuclear cells^20,21. However, evidence specifically evaluating hepatic arterial delivery of UC-MSC in liver fibrosis or cirrhosis remains limited. Therefore, this phase I study aimed to assess the safety and feasibility of hepatic arterial delivery of UC-MSCs in patients with liver cirrhosis. Exploratory efficacy outcomes were also evaluated.

Materials and methods

Study design, setting, and registration

This study was an open-label, single-arm, phase I clinical trial conducted at Vinmec Times City International Hospital, Hanoi, Vietnam. Patients were enrolled from 1 January 2021 to September 2023. The primary objective of this early-phase trial was to assess the safety and feasibility of UC-MSC therapy in patients with liver cirrhosis. The trial was registered at ClinicalTrials.gov (identifier: NCT05331872; registered on 6 April 2022).

Sample size

As an exploratory phase I pilot study, the sample size was not based on a formal power calculation for efficacy. A target of 20 participants was considered sufficient to generate preliminary safety and feasibility data and to provide variability estimates for planning subsequent phase II/III trials. A total of 20 patients with liver cirrhosis were enrolled and received study treatment.

Eligibility criteria

Inclusion criteria

Participants were eligible if they met all the following criteria:

Age between 18 and 75 years.

Diagnosis of liver cirrhosis due to alcohol use or hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.

Liver dysfunction and portal hypertension were initially assessed using medical history and FibroScan and were confirmed by liver biopsy.

Liver cirrhosis severity was assessed using the Child–Pugh score, with an inclusion threshold of ≤11.

Patients with virus-induced cirrhosis had received antiviral therapy within the previous 3 months and had shown a positive response to treatment (e.g. HBV-DNA below the detection limit).

Patients with alcohol-induced cirrhosis were required to abstain from alcohol for at least 3 months before treatment.

No liver cancer was detected via computed tomography (CT), magnetic resonance imaging (MRI), or Doppler ultrasound.

Expected survival of more than 24 weeks.

Provision of written informed consent.

Exclusion criteria

Participants were excluded if any of the following were present:

Serum creatinine levels above 2 mg/dL.

International normalized ratio (INR) >2.5.

Portal vein thrombosis.

Pregnant or lactating women, or women of childbearing potential not using effective contraception.

Severe comorbid conditions, including decompensated cirrhosis (Child–Pugh score ≥12), severe metabolic disorders, renal failure, significant respiratory disease, cardiovascular disease, severe mental illness, or systemic infection (including tuberculosis).

Advanced complications of cirrhosis, including hepatic encephalopathy, refractory ascites, or gastrointestinal bleeding due to esophageal variceal rupture.

Intervention: UC-MSC source, manufacturing, and quality control

MSCs were isolated from umbilical cords obtained from healthy full-term neonates. All donors underwent comprehensive screening for infectious agents, and all samples tested negative for HIV, cytomegalovirus (CMV), Epstein–Barr virus (EBV), hepatitis A virus (HAV), HBV, HCV, syphilis, and chlamydia prior to cell isolation. Umbilical cord processing and MSC isolation were performed at the Stem Cell Technology Research Laboratory of Vinmec Times City Hospital in compliance with ISO 14644-1 standards. UC-MSCs were expanded under serum-free and animal component–free culture conditions.

At passage 4 (P4), cells at approximately 80% confluency underwent characterization, including surface marker analysis, assessment of karyotype stability, and purity evaluation. At passage 5 (P5), UC-MSCs meeting predefined release criteria were harvested for transplantation at the required cell density, with a viability greater than 70%.

Cell administration via the hepatic artery

Cell infusion was performed in a radiointerventional operating room. The arterial puncture site was the femoral artery. The skin was sterilized with a 10% betadine solution and draped using sterile techniques. Vascular access to the femoral artery was established via the Seldinger technique, and a 5F introducer sheath was placed. Subsequently, a 5F catheter was advanced from the right femoral artery into the proper hepatic artery. After confirming correct catheter position and stability, fluoroscopic guidance was temporarily discontinued, and the stem cells were infused.

Determining the optimal dose and dosing frequency for MSC therapy remains challenging, and published clinical studies report substantial variability in administered cell doses²². Moreover, dosing schedules differ across trials, ranging from single administration to repeated dosing to sustain therapeutic effects^23–25. In this study, we selected a dose of 1 × 10⁶ cells/kg based on prior clinical evidence, indicating that this dose is commonly used and generally well tolerated across multiple indications, including liver diseases^26,27. Cells were infused at a dose of 1 × 10⁶ cells/kg body weight at a rate of 40 mL per hour. A total volume of 20 mL was administered over 30 min.

Outcome evaluation and follow-up

In this clinical trial, outcomes were evaluated at 3, 6, and 12 months after the intervention. The date of first patient enrollment was 1 January 2021.

Primary endpoint: The primary endpoint of this phase I trial was safety, assessed throughout the follow-up period.

Safety assessment: Adverse events (AEs) and serious adverse events (SAEs) were monitored and classified according to Common Terminology Criteria for Adverse Events (CTCAE) v4.03²⁸. The relationship between each AE and the intervention was evaluated according to the National Cancer Institute (NCI) reporting guidelines²⁹. Safety surveillance included events occurring during hospitalization and throughout the study period.

Exploratory outcomes: Exploratory outcome measures included liver function parameters, the Child–Pugh³⁰ and Model for End-stage Liver Disease (MELD)³¹ scoring systems, and overall quality of life, as assessed using the Chronic Liver Disease Questionnaire (CLDQ)³².

Non-invasive assessment of liver fibrosis

Baseline liver fibrosis was additionally assessed using two-dimensional shear wave elastography (2D-SWE) on a GE LOGIQ E9 ultrasound system (GE Healthcare). Liver stiffness was measured quantitatively (in kPa or m/s) and fibrosis stage was categorized according to the METAVIR (F0–F4) framework. Based on published thresholds for LOGIQ E9 shear wave elastography and its comparison with transient elastography, fibrosis stages were defined as follows: F0–F1 < 7.0 kPa, F2 7.1–9.4 kPa, F3 9.5–12.4 kPa, and F4 ≥ 12.5 kPa^33–35.

Statistical analysis

The data were analyzed with RStudio software version 1.4.1106. Descriptive statistics, including frequency, percentage, mean, and standard deviation, were used to describe the characteristics of the study participants and cell administration parameters. A paired t test or the Wilcoxon signed-rank test was used, as appropriate, to compare pre- and post-intervention values.

To assess changes in Child–Pugh score and differences by baseline severity, we fitted a linear mixed-effects model to evaluate longitudinal changes. The model included time (months), baseline Child–Pugh group (5–6 vs ≥7), and their interaction as fixed effects, with participant-specific random effects to account for repeated measures. In addition, linear mixed-effects sensitivity analyses were conducted for both albumin and Child–Pugh score to assess overall longitudinal changes over time. The results are presented in Supplementary Table S1.

In a post hoc exploratory subgroup analysis, patients with available 12-month data were classified as responders if their MELD score decreased by ≥3 points from baseline to month 12. All other patients were classified as non-responders. To further explore heterogeneity of treatment response, separate linear mixed-effects models were fitted for albumin, Child–Pugh score, and bilirubin. Each model included time, responder status, and their interaction as fixed effects, with a participant-specific random intercept to account for within-subject correlation. Because responder status was defined based on 12-month MELD change, this analysis was considered exploratory and hypothesis-generating.

Plots were prepared using GraphPad Prism 9.0 (GraphPad Software, La Jolla, CA, USA). A P value <0.05 was considered statistically significant.

Ethics and informed consent

The study protocol was approved by the Ethics Committee of the Vinmec Healthcare System (Reference No.: 39/2020/QD-VMEC) on 24 December 2020 and was conducted in accordance with the Declaration of Helsinki and applicable Good Clinical Practice principles. No study-related procedures or patient recruitment were conducted before ethics approval. Written informed consent was obtained from all participants prior to any study-related procedures. The first patient was enrolled on 1 January 2021. The trial was registered at ClinicalTrials.gov (identifier: NCT05331872) on 6 April 2022. Trial registration occurred after enrollment had begun and is explicitly reported for transparency in the revised manuscript.

Results

Patient characteristics at baseline

Among the 20 study participants, 17 completed the 12-month follow-up. Three patients were classified as dropouts: one was lost to follow-up at 6 months due to relocation abroad, and two were not assessed at 12 months because of family-related circumstances (Figure 1). The mean age of the 17 patients who completed follow-up was 51.1 ± 10.9 years. The mean weight was 62.5 ± 9.5 kg. The mean duration of liver cirrhosis prior to enrollment was 6.2 ± 5.3 years. Baseline liver stiffness measured by 2D-SWE indicated predominantly advanced fibrosis; METAVIR stage F4 was observed in 11 of 17 patients (64.7%) (Table 1).

Table 1.

Characteristics of the patients with liver cirrhosis before UC-MSC infusion.

Characteristics	Baseline (N = 17)
Age, mean ± SD (years)	51.1 ± 10.9
Weight, mean ± SD (kg)	62.5 ± 9.5
Sex, M:F	14:3
Duration of liver cirrhosis, mean ± SD	6.2 ± 5.3
Ascites, n (%)
No ascites	7 (41.2%)
Grade 1	8 (47.1%)
Grade 2	2 (11.8%)
Esophageal varices, n (%)
No information	4 (23.5%)
Grade 1	2 (11.8%)
Grade 2	4 (23.5%)
Grade 3	7 (41.2%)
Ishak stage, n (%)
Level 4	2 (11.8%)
Level 5	4 (23.5%)
Level 6	11 (64.7%)
MELD score, mean ± SD	11.53 ± 3.97
Child–Pugh score, mean ± SD	6.35 ± 1.73
ALT (U/L), mean ± SD	36.35 ± 13.49
AST (U/L), mean ± SD	44.2 ± 10.8
Bilirubin (µmol/L), mean ± SD	24.13 ± 15.67
Albumin (g/dL), mean ± SD	3.78 ± 0.57
2D-SWE fibrosis stage (METAVIR), n (%)
F2	1 (5.9%)
F3	5 (29.4%)
F4	11 (64.7%)

ALT: alanine aminotransferase; AST: aspartate aminotransferase; BMI: body mass index; F: female; M: male; MELD: Model for End-stage Liver Disease; 2D-SWE: two-dimensional shear wave elastography.

Figure 1.

CONSORT flow diagram of the patient screening process.

The most common cause of liver cirrhosis was HBV, accounting for 58.8% of cases, whereas HCV and alcohol were responsible for 17.6% and 23.5% of cases, respectively. The mean time from cirrhosis diagnosis to UC-MSC treatment was 6.2 ± 5.3 years (range: 1–20 years). Prior to infusion, 10 of 17 patients (58.8%) presented with ascites. A history of gastrointestinal bleeding was documented in one patient.

Esophagoscopy was performed in 15 of 17 patients prior to stem cell infusion to assess the presence and severity of esophageal varices. Among these 15 patients, 2 (11.8%) had grade 1 varices, 4 (23.5%) had grade 2 varices, and 7 (41.2%) had grade 3 varices.

At baseline, the average Child–Pugh score of the study group was 6.35 ± 1.73, ranging from 5 to 11 points. Cirrhosis severity was assessed using the Ishak classification system, with 64.7% of patients at level 6, 23.5% at level 5, and 11.8% at level 4. The mean MELD score was 11.53 ± 3.97 (Table 1).

UC-MSC characterization

UC-MSCs were obtained from the UC-MSC bank of the Vinmec Healthcare System following a three-step screening process: genetic counseling, biological characterization at passage 2 (P2), and genome sequencing of 6794 genes, as previously described³⁶. For clinical administration, UC-MSCs at passage 3 (P3) were expanded to passage 5 (P5) using StemMACS™ MSC Expansion Medium (Miltenyi Biotec). UC-MSCs were released based on predefined criteria for morphology, identity, viability, and sterility. The morphology of the MSCs is shown in Figure 2(a).

Figure 2.

UC-MSC characterization. (a) MSC morphology. (b) Expression of MSC markers by flow cytometry. (c) MSC viability by cell count.

Flow cytometry confirmed compliance with the International Society for Cell & Gene Therapy (ISCT) minimal criteria. UC-MSCs showed high expression of CD73 (99.48 ± 0.55%), CD90 (99.42 ± 0.29%), and CD105 (98.78 ± 0.55%), and low expression of CD45, CD34, CD11b, CD19, and HLA-DR (Human Leukocyte Antigen—DR isotype) (0.28 ± 0.09%) (Figure 2(b)). These results met the predefined release specifications of CD73 ≥95%, CD90 ≥95%, CD105 ≥95%, and CD34, CD45, CD14/CD11b, CD19/CD79a, and HLA-DR ≤2%.

The mean cell viability at release was 91.47 ± 2.23% (Figure 2(c)), which exceeded the predefined acceptance criterion. The UC-MSCs maintained a normal karyotype, indicating genetic stability and suitability for clinical application. Sterility testing confirmed the absence of mycoplasma, bacteria, and fungi, and endotoxin levels were <0.05 EU/mL.

In addition to these release criteria, the immunomodulatory function, metabolic fitness, and secretome profile of the UC-MSC product were characterized in our previous study. Specifically, passage 4 (P4) UC-MSCs suppressed the proliferation of CD4+ and CD8+ T cells, indicating preserved immunomodulatory function. These cells also demonstrated maintained glycolytic activity and spare respiratory capacity, and secreted multiple cytokines, chemokines, and growth factors into the culture supernatant³⁶. Together, these findings provide support for the biological activity of the UC-MSC product used in this study.

Safety of allogeneic UC-MSC administration

No serious AEs were observed within 72 h following UC-MSC infusion. Only mild AEs, including headache (10%), bruising at the arterial puncture site (5%), mild hematoma at the intervention site (10%), and mild liver area pain (15%), were reported. The most common AE was mild pain at the liver biopsy site, reported in 12 of 20 patients (60%). All AEs were classified as grade 1 or 2 according to the CTCAE, were self-limiting, and required no medical intervention. Two patients experienced low-grade fever (37.5°C–38°C) within 2–6 h postinfusion, which resolved spontaneously within 12 h. A detailed summary of AEs occurring within 72 h postinfusion is presented in Table 2.

Table 2.

Frequency of adverse events within 72 h after UC-MSC infusion.

Adverse event	Number (percentage) N (%)	Classification	Resolution	Severity grade	Relationship with intervention
Mild headache	2 (10%)	AE	Symptoms resolve spontaneously without intervention after 4 h	1	Possibly related to the CT intervention
Bruising at the site of arterial intervention	1 (5%)	AE	Symptoms resolve without intervention	1	Definitely related to the CT intervention
Mild pain at the Liver biopsy site	12 (60%)	AE	Symptoms resolve without intervention after 4–6 h	2	Definitely related to the CT intervention
Mild hematoma at the site of intervention	2 (10%)	AE	Symptoms resolve without intervention	2	Definitely related to the CT intervention
Mild pain in the liver area	3 (15%)	AE	Symptoms resolve without intervention after 4–6 h	1	Definitely related to the CT intervention
Total	20 (100%)

Efficacy of allogeneic UC-MSC administration

Changes in serum albumin, bilirubin, INR, prothrombin time (PT), liver enzymes, MELD score, and Child–Pugh score at baseline and after cell infusion are summarized in Table 3. Detailed paired change estimates, 95% confidence intervals (CIs), effect sizes, and results of linear mixed-effects sensitivity analyses for albumin and Child–Pugh score are provided in Supplementary Table S1.

Table 3.

Liver function parameters of the patients over a 12-month follow-up period.

Indicator	Baselinemean ± SDmedian [min, max](N = 17)	3 monthsmean ± SDmedian [min, max](N = 17)	P value relative to baseline	6 monthsmean ± SDmedian [min, max](N = 17)	P value relative to baseline	12 monthsmean ± SDmedian [min, max](N = 17)	P value relative to baseline
Albumin (g/dL)	3.78 ± 0.573.86 [2.37, 4.61]	3.98 ± 0.593.95 [2.60, 5.02]	0.048*	4.03 ± 0.663.90 [2.57, 5.25]	0.027*	3.90 ± 0.583.95 [2.744, 4.94]	0.190
Serum bilirubin (µmol/L)	24.13 ± 15.6720.6 [12.33, 79.3]	22.33 ± 13.6719.0 [5.4, 59.4]	0.249	29.12 ± 20.4119.8 [8.1, 71.9]	0.433	29.42 ± 22.3521.3 [5.0, 90.8]	0.109
PT (percentage)	76.26 ± 12.6978.0 [42.0, 97.2]	74.7 ± 11.1774.5 [42.0, 92.2]	0.351	74.57 ± 13.3376.0 [35.0, 96.2]	0.155	73.2 ± 14.4372.0 [38.0, 106]	0.129
INR	1.23 ± 0.21.2 [1.01, 1.9]	1.29 ± 0.241.24 [1.04, 1.93]	0.517	1.26 ± 0.271.21 [1.05, 2.24]	0.423	1.28 ± 0.241.23 [1.03, 2.04]	0.225
AST (U/L)	44.2 ± 10.846.23 [26.0, 64.1]	44.72 ± 13.8948.5 [23.4, 66.9]	0.834	42.56 ± 15.2547.12 [4.7, 67.1]	0.854	46.1 ± 22.1639.3 [20.0, 111.6]	0.890
ALT (U/L)	36.35 ± 13.4935.0 [19.4, 69.9]	38.61 ± 15.0538.9 [16.9, 61.0]	0.347	37.6 ± 15.5135.6 [8.5, 61.0]	0.782	42.53 ± 16.3240.7 [18.8, 72.1]	0.225
GGT	138.78 ± 138.0854.0 [15.6, 431.0]	125.28 ± 125.8953.0 [13.4, 445.4]	0.346	112.83 ± 111.4352.0 [16.7, 381.7]	0.190	130.38 ± 132.8852.7 [15.7, 394.0]	0.980
MELD score	11.53 ± 3.9711.0 [7.0, 20.0]	10.94 ± 3.4911.0 [6.0, 18.0]	0.501	12.06 ± 4.2611.0 [7.00, 21.0]	0.726	10.71 ± 3.711.0 [6.00, 20.0]	0.238
Child–Pugh score	6.35 ± 1.736.0 [5.0, 11.0]	5.76 ± 1.485.00 [5.00, 11.0]	0.024*	5.88 ± 1.415.0 [5.0, 10.0]	0.088	6.06 ± 1.345.0 [5.0, 9.0]	0.083

P value < 0.05.

Serum albumin increased at 3 and 6 months compared with baseline, with mean changes of +0.192 g/dL (95% CI: 0.008 to 0.376; P = 0.048) and +0.242 g/dL (95% CI: 0.032 to 0.453; P = 0.027), respectively. At 12 months, the increase was smaller and not statistically significant (+0.115 g/dL; 95% CI: −0.063 to 0.294; P = 0.190). TBIL levels decreased at 3 months relative to the baseline, then increased slightly at 6 and 12 months; however, none of these changes were statistically significant. No significant changes were observed in INR, PT, aspartate aminotransferase (AST), alanine aminotransferase (ALT), GGT, or MELD score at any follow-up time point. All measured parameters remained clinically stable at 3, 6, and 12 months.

Child–Pugh score decreased at 3 months compared with baseline (mean change, −0.588 points; 95% CI: −1.135 to −0.041; P = 0.024). Reductions at 6 months (−0.471 points; 95% CI: −1.019 to 0.078; P = 0.088) and 12 months (−0.353 points; 95% CI: −0.757 to 0.051; P = 0.083) were not statistically significant. In the linear mixed-effects sensitivity analysis, Child–Pugh score showed an overall effect of time (P = 0.0489). The largest model-estimated reduction from baseline occurred at 3 months (Δ = −0.588; 95% CI: −1.110 to −0.066; adjusted P = 0.0234). Changes at 6 and 12 months were smaller and not statistically significant (Supplementary Table S1). The individual longitudinal trajectories of MELD and Child–Pugh scores are shown in Figure 3(a) and (b), respectively, illustrating interpatient variability over the 12-month follow-up period.

Figure 3.

(a) Individual longitudinal trajectories of MELD score over 12 months, stratified by response status. (b) Individual longitudinal trajectories of Child–Pugh score over 12 months, stratified by improvement status.

Patient-reported quality of life, assessed using the CLDQ, is presented in Table 4 and Figure 4. The total CLDQ score and all domains except systemic symptoms showed increases at 3, 6, and 12 months postinfusion compared with baseline (P < 0.001). For systemic symptoms, the score decreased at 3 months (from 5.99 ± 0.47 to 5.28 ± 1.07; P = 0.0155), but differences at 6 and 12 months were not statistically significant compared with baseline (P = 0.5807 and P = 0.1901, respectively).

Table 4.

Quality of life (CLDQ) before and after intervention.

Domain	BaselineMean ± SD(N = 17)	After 3 monthsMean ± SD(N = 17)	P value relative to baseline	After 6 monthsMean ± SD(N = 17)	P value relative to baseline	After 12 monthsMean ± SD(N = 17)	P value relative to baseline
Fatigue	3.27 ± 0.78	4.67 ± 0.95	<0.001	5.64 ± 0.93	<0.001	6.38 ± 0.68	<0.001
Activity	3.43 ± 0.96	4.96 ± 1.18	<0.001	5.72 ± 1.12	<0.001	6.31 ± 0.92	<0.001
Emotion	3.27 ± 0.83	4.71 ± 1.02	<0.001	5.63 ± 0.79	<0.001	6.31 ± 0.67	<0.001
Abdominal Symptoms	3.63 ± 0.99	5.18 ± 1.25	<0.001	5.63 ± 1.05	<0.001	6.43 ± 0.71	<0.001
Systemic Symptoms	5.99 ± 0.47	5.28 ± 1.07	0.0155	6.05 ± 0.72	0.5807	6.20 ± 0.55	0.1901
Anxiety	3.08 ± 0.87	4.61 ± 1.00	<0.001	5.60 ± 1.29	<0.001	6.33 ± 0.69	<0.001
Overall	3.33 ± 0.81	4.90 ± 1.02	<0.001	5.71 ± 0.75	<0.001	6.38 ± 0.57	<0.001

Figure 4.

Patients’ overall quality of life before and after the intervention.

Exploratory analyses

At 12 months after UC-MSC infusion, a clinically meaningful improvement in MELD score, defined as a reduction of ≥3 points from baseline, was observed in 3 of 17 patients (17.6%). Given the small number of responders, this analysis is underpowered and should be considered exploratory. Improvement in Child–Pugh class, defined as a change from class C to B or from class B to A, was observed in 2/17 patients (11.8%) (Table 5).

Table 5.

Changes in MELD score and Child–Pugh class from baseline to 12 months.

Response type (baseline vs 12 months)	n	%
MELD score reduction ≥3 points	3	17.6
No MELD score reduction ≥3 points	14	82.4
Child–Pugh class improvement (≥1 class)	2	11.8
No Child–Pugh class improvement	15	88.2

To further explore heterogeneity of treatment response, an exploratory subgroup analysis was conducted according to 12-month MELD response status, with results summarized in Supplementary Table S2. In linear mixed-effects models, albumin showed a significant overall time effect (P = 0.015). In contrast, Child–Pugh score and bilirubin did not show significant time effects (P = 0.062 and P = 0.557, respectively). No significant effect of responder status or time-by-response interaction was observed for albumin, Child–Pugh score, or bilirubin, indicating no clear differences in longitudinal trajectories between MELD responders and non-responders in this exploratory analysis.

To assess whether longitudinal changes differed according to baseline disease severity, patients were stratified into two groups based on baseline Child–Pugh score (5 to 6 vs ≥7). In the mixed-effects model (Table 6), the baseline group effect was not significant, indicating similar adjusted baseline Child–Pugh scores between groups. Overall, Child–Pugh scores tended to decrease over time (P < 0.001). The significant group-by-time interaction (β = 0.13; P < 0.001) suggests different trajectories by baseline severity: patients with Child–Pugh ≥7 showed a smaller decline over time than those with scores of 5–6, which may indicate a slower change in more advanced disease.

Table 6.

Mixed-effects model results for Child–Pugh score by baseline Child–Pugh group.

Fixed effects	Estimate	Standard error	t value	P value
(Intercept)	6.21	0.36	17.08	<0.001
Baseline Child–Pugh group ≥7	−0.03	0.19	−0.15	>0.05
Time (months)	−0.82	0.07	−11.66	<0.001
Baseline Child–Pugh group ≥7 × Time	0.13	0.01	15.02	<0.001
Correlation among fixed effects:
	(Intercept)	Baseline Child–Pugh group ≥7	Time
Baseline Child–Pugh group ≥7	−0.167
Time (months)	−0.737	0.562
Baseline Child–Pugh group ≥7 × Time	0.129	−0.745	−0.753

Discussion

Our findings indicate that intra-arterial administration of UC-MSCs via the hepatic artery is both technically feasible and well tolerated in patients with liver cirrhosis. The procedure was successfully completed in all participants, with no serious AEs observed either during or after the intervention. All AEs were minor and either resolved spontaneously or required only minimal treatment. However, given the small sample size and limited follow-up, rare or delayed AEs cannot be excluded. Larger controlled studies with longer follow-up are needed to better characterize safety and detect rare or late-onset AEs that may not be evident in a small cohort with only 12 months of observation.

The safety of administering UC-MSCs via the hepatic artery in our study aligns with the findings of previous studies. In 2020, Sun et al.³⁷ conducted a meta-analysis of 10 studies evaluating autologous bone marrow–derived stem cell transplantation via the hepatic artery in patients with hepatitis B–related cirrhosis. In this meta-analysis, three studies reported no AEs, while the remaining studies reported only minor AEs. The safety of cell therapy administered via the intravenous route or the portal vein has also been confirmed in various studies^16,38,39. Nevertheless, ongoing safety assessment in larger studies remains essential because rare AEs may not be detected in small samples and may appear only after longer follow-up periods.

Recent reviews have highlighted both the opportunities and key challenges of MSC therapy in end-stage liver disease, including mechanistic heterogeneity and safety considerations. Li et al.⁴⁰ provided a comprehensive synthesis of current evidence and translational barriers in this field. MSCs exert therapeutic benefits in liver cirrhosis through multiple complementary mechanisms, including immunomodulation, anti-fibrotic activity, and potential hepatocytic differentiation^41–43. MSCs modulate immune responses by suppressing pro-inflammatory cytokines and increasing anti-inflammatory mediators, thereby reducing hepatic inflammation⁴⁴. In addition, MSCs display anti-fibrotic properties by inhibiting activation of HSCs and increasing matrix metalloproteinase activity, which promotes extracellular matrix degradation^45–47. Moreover, MSCs release a broad spectrum of paracrine factors that support hepatocyte proliferation, angiogenesis, and tissue repair⁴⁸. Some studies also suggest that MSCs can partially differentiate into hepatocyte-like cells under specific conditions^49,50. The biological behavior of administered MSCs, including persistence, biodistribution, and potential unintended differentiation, supports the need for long-term safety monitoring in future trials.

In addition to the primary safety findings, our exploratory observations suggest possible maintenance with limited and non-sustained changes in liver function parameters following UC-MSCs therapy; however, these findings should be interpreted with caution due to the single-arm design and small sample size. Importantly, because there was no control group or blinding, these changes cannot be directly attributed to UC-MSC therapy and should be viewed as hypothesis-generating rather than confirmatory evidence of efficacy.

The average serum albumin level was higher at 3 months (P = 0.048) and 6 months (P = 0.027) compared with baseline, whereas the increase at 12 months was not statistically significant.

Following cell infusion, average GGT levels showed a slight, non-significant decrease. ALT, AST, INR, PT, and TBIL showed minor fluctuations over time, with no statistically significant changes at any follow-up point. These laboratory findings suggest relative stability of liver synthetic and coagulation function during follow-up, without clear evidence of worsening hepatocellular injury. Given the single-arm design and variability in laboratory values, these results should be interpreted as indicating overall clinical stability rather than definitive evidence of treatment efficacy. Disease severity, as assessed by the MELD and Child–Pugh scores, showed a transient decrease at 3 months, with no sustained statistically significant changes over time, which should be interpreted as an exploratory numerical trend rather than a confirmed treatment effect.

Our findings are broadly consistent with those of previous reports. In 2012, Zhang et al. reported a controlled study including 15 patients treated with UC-MSCs and 15 control patients receiving saline. The researchers reported that during the 1-year follow-up period, the degree of ascites was significantly lower in the cell therapy group than in the control group. Liver function improved, as demonstrated with different indicators, such as increased serum albumin levels, decreased total serum bilirubin levels, and decreased MELD scores¹⁶. Similarly, in their meta-analysis of 11 clinical trials on the use of MSCs for liver cirrhosis in 2023, Lu et al.⁵¹ observed that albumin levels increased significantly at 2 weeks, 1 month, 3 months, and 6 months, whereas the MELD score significantly decreased at 1 month, 2 months, and 6 months in the cell therapy group compared with the control group. Nevertheless, these studies show substantial clinical and methodological heterogeneity, and treatment effects are not consistent across all reports, underscoring the need for adequately powered, high-quality randomized trials to clarify clinical benefit. In addition, future studies should incorporate longer follow-up to evaluate late safety outcomes in patients with cirrhosis.

In their analysis of data from 28 review studies in 2024, Teng et al.⁵² reported that cell therapy improved certain liver function parameters and increased survival compared with control groups.

In our study, the cells were infused via the hepatic artery. Previous studies have used three main delivery routes to the liver: the portal vein, peripheral intravenous infusion, and the hepatic artery^17,18,26.

The administration of cells via peripheral veins is technically simple; however, it has notable limitations. A substantial proportion of MSCs may become trapped in the lungs, reducing delivery to the liver^53,54. In addition, peripheral intravenous infusion carries a risk of venous thromboembolism. Wu et al.⁵⁵ reported two cases of thromboembolism following umbilical cord MSC infusion, whereas Jung et al.⁵⁶ reported two cases of pulmonary embolism induced by adipose tissue–derived stem cell therapy.

Delivery of cells through the portal vein can avoid lung trapping but carries a risk of intra-abdominal bleeding. In a study by Zhou et al.,¹⁷ one patient experienced perihepatic bleeding, two patients developed pleural effusion, and two had abdominal effusion. These risks are particularly relevant in decompensated cirrhosis, where coagulation abnormalities increase susceptibility to both bleeding and thrombotic events⁵⁷. Hepatic arterial delivery of MSCs may reduce pulmonary sequestration compared with intravenous infusion by limiting first pass trapping in the lungs⁵⁸. However, current evidence is insufficient to determine whether this route reduces overall thrombotic risk, and careful periprocedural monitoring and risk mitigation remain warranted regardless of infusion route. In our cohort, no complications such as intra-abdominal bleeding or arterial injury were observed, consistent with prior reports using the hepatic artery approach^26,59.

Growing evidence suggests that allogeneic UC-MSC therapy confers greater clinical benefit in earlier-stage cirrhosis than in advanced disease⁶⁰. Patients with milder cirrhosis (Child–Pugh class A, score ~5–6) have shown larger improvements in liver function and fibrosis-related markers following hepatic arterial UC-MSC infusion, whereas patients with more advanced cirrhosis (Child–Pugh B/C; score ≥7) generally exhibit more modest responses⁶¹. These observations are preliminary and may be influenced by baseline prognosis and confounding factors; therefore, they should be interpreted cautiously. From a mechanistic perspective, early-stage cirrhosis retains greater regenerative capacity and more reversible fibrosis, which may facilitate the therapeutic effects of MSCs. In contrast, advanced cirrhosis is characterized by fixed structural damage and microvascular alterations, which may limit MSC engraftment and therapeutic efficacy^62,63. These findings support the rationale that hepatic artery delivery of UC-MSCs earlier in the disease course may better harness their pro-regenerative, immunomodulatory, and anti-fibrotic effects before end-stage structural and vascular abnormalities constrain treatment response.

In terms of patient-reported quality of life, as measured by the CLDQ, our study observed increases from 3 months onward across most domains, except systemic symptoms. These findings are consistent with those reported by Kanwal et al., who reported that higher baseline health-related quality of life (HRQOL) was associated with a lower risk of mortality. In that study, each 1-point increase in HRQOL was associated with an approximate 4% reduction in mortality risk⁶⁴. However, our study was not designed to evaluate survival or transplant-free survival, and no conclusions regarding mortality benefit can be drawn. Our findings are generally in line with prior bone marrow mesenchymal stem cell (BM-MSC) studies in liver cirrhosis, which have reported acceptable short-term safety and modest changes in liver function parameters. This study adds preliminary clinical evidence supporting the feasibility and safety of hepatic artery infusion of UC-MSCs⁶⁵.

Key limitations of this study warrant consideration. First, the single-arm design and lack of control group prevent causal attribution of observed changes to UC-MSC therapy. Second, the small sample size and heterogeneity in underlying etiologies limit the statistical power and may reduce the generalizability of the findings.

Regarding trial registration, we acknowledge that ClinicalTrials.gov registration (NCT05331872) was completed on 6 April 2022, after enrollment had begun on 1 January 2021. The study protocol was approved by the institutional Ethics Committee on 24 December 2020, prior to patient enrollment, ensuring that all procedures adhered to ethical standards. Study outcomes, follow-up schedule, and primary endpoints were pre-specified and remained unchanged throughout the trial, with no protocol modifications after enrollment. While prospective registration is the recommended standard, this has now been transparently reported in the revised manuscript.

Some participants had viral hepatitis-related cirrhosis and were receiving antiviral therapy, which may have confounded the observed clinical outcomes. We acknowledge that a more homogeneous cohort (e.g. exclusively MASLD- or alcohol-related cirrhosis) could yield more interpretable efficacy results; in a subsequent phase II study, such an approach would be preferable. Therefore, all efficacy-related findings should be interpreted as exploratory observations rather than confirmatory evidence of treatment benefit. In addition, the exploratory responder/non-responder subgroup analyses should be interpreted cautiously because of the limited sample size, particularly the small number of MELD responders, which may have reduced power to detect between-group differences. Finally, given the number of outcomes assessed across multiple time points, some statistically significant findings may reflect chance.

Critically, the 12-month follow-up is insufficient to fully evaluate uncommon late AEs such as tumorigenicity or malignant transformation. Long-term follow-up in larger, controlled studies is required to better assess these risks. Because a dose-escalation design was not included, the optimal dose, dosing interval, and treatment schedule remain unclear. Therefore, repeated dosing strategies or combination therapies may be needed to achieve sustained clinical benefit. Future studies with larger cohorts, longer follow-up, and controlled repeated-dose designs are needed to define the optimal dosing strategy and long-term efficacy of hepatic artery UC-MSC therapy in cirrhosis.

Conclusion

Overall, our findings support the safety profile of UC-MSC therapy for liver cirrhosis via the hepatic arterial route. This study was designed to assess feasibility and safety; therefore, efficacy findings should be interpreted as exploratory. Larger, controlled studies with longer follow-up are needed to better define long-term safety and clarify clinical efficacy. The absence of a control group and the small sample size are key limitations of this study.

Supplemental Material

sj-docx-1-cll-10.1177_09636897261449975 – Supplemental material for Safety and preliminary efficacy of allogeneic umbilical cord–derived mesenchymal stem cells administered via the hepatic artery in patients with liver cirrhosis: A phase I open-label trial

Supplemental material, sj-docx-1-cll-10.1177_09636897261449975 for Safety and preliminary efficacy of allogeneic umbilical cord–derived mesenchymal stem cells administered via the hepatic artery in patients with liver cirrhosis: A phase I open-label trial by Liem Thanh Nguyen, Hoang-Phuong Nguyen, Hang Thi Bui, Quyen Thi Nguyen, Phan Van Nguyen and Hien Thi Thu Ha in Cell Transplantation

Supplemental Material

sj-docx-2-cll-10.1177_09636897261449975 – Supplemental material for Safety and preliminary efficacy of allogeneic umbilical cord–derived mesenchymal stem cells administered via the hepatic artery in patients with liver cirrhosis: A phase I open-label trial

Supplemental material, sj-docx-2-cll-10.1177_09636897261449975 for Safety and preliminary efficacy of allogeneic umbilical cord–derived mesenchymal stem cells administered via the hepatic artery in patients with liver cirrhosis: A phase I open-label trial by Liem Thanh Nguyen, Hoang-Phuong Nguyen, Hang Thi Bui, Quyen Thi Nguyen, Phan Van Nguyen and Hien Thi Thu Ha in Cell Transplantation

Footnotes

Acknowledgements

The authors used ChatGPT (OpenAI) solely for language support during manuscript preparation to improve the clarity, grammar, and organization of the text. No scientific data, results, analyses, or conclusions were generated or modified using artificial intelligence.

ORCID iDs

Liem Thanh Nguyen

Hoang-Phuong Nguyen

Phan Van Nguyen

Ethical Considerations

The study protocol was approved by the Ethics Committee of the Vinmec Healthcare System (Approval No.: 39/2020/QD VMEC; 24 December 2020) and conducted in accordance with the Declaration of Helsinki and applicable ICH-GCP principles.

Consent to participate

Written informed consent was obtained from all participants prior to enrollment after a detailed explanation of the study objectives, procedures, potential risks and benefits, and sample use.

Consent for publication

All participants provided written informed consent for the publication of de-identified data. No individually identifiable information is included in this manuscript.

Author contributions

L.T.N., H-P.N., H.T.B., Q.T.N., P.V.N., and H.T.T.H. participated in the study conceptualization, experimental design, data collection, and data interpretation. H-P.N. performed the data analysis. L.T.N., H-P.N., H.T.B., Q.T.N., P.V.N., and H.T.T.H. contributed to drafting the manuscript. L.T.N. and H.T.B. accessed and verified the underlying data. All authors read and approved the final version of the manuscript.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Hanoi Department of Science and Technology, Vietnam Government, under the project “Research on the Treatment of Liver Cirrhosis by Transplantation of Umbilical Cord–Derived Mesenchymal Stem Cells” (Grant No. 01C-08-ISC 21.29). The funding agency did not have a role in the study design, data collection, management, analysis, interpretation, writing of the report, or the decision to submit the report for publication.

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Prof. Nguyen Thanh Liem and co-authors Hoang-Phuong Nguyen, Hang Bui Thi, Nguyen Thi Quyen, Nguyen Van Phan, and Hien Ha Thi Thu are salaried employees of VinUniversity or the Vinmec Healthcare System. Prof. Liem also serves as Director of the Vinmec Research Institute for Stem Cell and Gene Technology. The authors declare no other financial or personal relationships that could inappropriately influence the work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data availability statements

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Trial registration

ClinicalTrials.gov Identifier: NCT05331872 (registered on 6 April 2022).

Statement of human and animal rights

This article does not contain any studies with human or animal subjects.

Statement of informed consent

There are no human subjects in this article and informed consent is not applicable.

Supplemental material

Supplemental material for this article is available online.

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