Published online Jun 26, 2026. doi: 10.4252/wjsc.116526
Revised: December 31, 2025
Accepted: March 25, 2026
Published online: June 26, 2026
Processing time: 208 Days and 23.4 Hours
Preeclampsia (PE) is a serious complication in pregnancy. It is one of the primary causes of maternal and perinatal mortality. Human amniotic epithelial cells (hAECs) and mesenchymal stem cells (MSCs) derived from human umbilical cord blood (hucbMSCs) are both perinatal stem cells, capable of expressing characteristic stem cell surface markers. MSC-derived exosomes (MSCs-exos) exhibit functional properties comparable to those of MSCs, while offering advantages such as greater biological stability and the ability to circumvent potential complications associated with MSC-based therapy. This study utilized hAEC-derived exosomes (hAECs-exos) and hucbMSC-derived exosomes (hucbMSCs-exos) to treat preeclamptic rats and investigate their therapeutic effects.
To investigate the therapeutic effects of hAECs-exos and hucbMSCs-exos on PE in rats.
Thirty-two pregnant rats were divided into four groups (normal pregnancy, PE, and two exosome-treated groups; n = 8). The PE model was induced by L-arginine methyl ester. From gestation day 12, the treatment groups received hAECs-exos or hucbMSCs-exos for 7 days, while controls received normal saline. Blood pressure, urinary protein, fetal/placental weight, and tissue analyses were performed. Quantitative data are expressed as the mean ± SD. Differences among multiple groups were analyzed by one-way analysis of variance (ANOVA), followed by the LSD-t test for pairwise comparisons. A P value < 0.05 was considered statistically significant.
Compared to the normal pregnancy group, rats in the PE group exhibited significantly elevated blood pressure and 24-hour urinary protein levels, indicating successful model establishment. Furthermore, the PE group showed significantly increased levels of interleukin-6, tumor necrosis factor-α, soluble fms-like tyrosine kinase-1, and malondialdehyde, along with decreased fetal/placental weight, levels of interleukin-10, placental growth factor, vascular endothelial growth factor, superoxide dismutase, and placental CD31 expression (P < 0.05). Treatment with both exosomes significantly reversed all these alterations compared to the PE group (P < 0.05). Histological analysis further confirmed that the treatments markedly alleviated renal and placental pathological damage induced by PE.
This study demonstrates that both hAECs-exos and hucbMSCs-exos have therapeutic effects in rats with PE, po
Core Tip: Preeclampsia (PE) is a serious obstetric syndrome, and effective therapeutic options are required urgently. This study demonstrates that exosomes derived from human amniotic epithelial cells and umbilical cord mesenchymal stem cells can function as innovative cell-free agents. Treatment with these exosomes effectively ameliorated key pathological features, including hypertension, proteinuria, and placental damage, in a rat model of PE. The underlying mechanisms involve multi-target modulation of angiogenic and inflammatory pathways. These findings highlight the clinical translation potential of exosomes derived from human amniotic epithelial cells and umbilical cord mesenchymal stem cells as novel therapeutic strategies for PE.
- Citation: Han LY, Zhang WZ, Zhang Y, Zhong W, Sun JL, Shen J. Therapeutic effects of human amniotic epithelial cell-derived and umbilical cord blood mesenchymal stem cell-derived exosomes on preeclamptic rats. World J Stem Cells 2026; 18(6): 116526
- URL: https://www.wjgnet.com/1948-0210/full/v18/i6/116526.htm
- DOI: https://dx.doi.org/10.4252/wjsc.116526
Preeclampsia (PE) is a prevalent and severe pregnancy complication characterized by hypertension and proteinuria occurring after 20 weeks of gestation. Left uncontrolled, it can advance to multiple organ dysfunction, contributing significantly to maternal and perinatal mortality rates[1]. PE affects an estimated 2%-8% of pregnant women globally[2]. The precise pathogenesis of PE remains incompletely understood. Current understanding implicates impaired tropho
Human amniotic epithelial cells (hAECs) and mesenchymal stem cells (MSCs) derived from human umbilical cord blood (hucbMSCs) are perinatal stem cell types. hAECs express key stem cell surface markers, suggesting the retention of stem cell properties[5]. hAECs exhibit immunomodulatory features, anti-inflammatory effects, and paracrine functions by secreting diverse cytokines that facilitate tissue repair, cell proliferation, migration, angiogenesis, and antioxidant, anti
Exosomes are small extracellular vesicles ranging from 30 nm to 150 nm in diameter, released by cells across diverse organs and tissues, ubiquitous in organisms[11]. Laden with bioactive molecules such as RNAs, proteins and lipids, exosomes mediate intercellular signaling through multiple pathways, eliciting effects such as promoting angiogenesis, inhibiting apoptosis and inflammation, and combating fibrosis. MSC-derived exosomes (MSCs-exos) mirror the functions of MSCs but offer advantages such as enhanced stability, reduced immunogenicity, decreased pulmonary retention, blood-brain barrier penetrance, and circumvention of potential MSC-related issues such as chromosomal abnormalities, tumorigenesis, thrombosis, and immune rejection[12,13]. Consequently, leveraging exosomes in clinical settings emerges as an optimal strategy for managing diverse ailments.
In this study, hAEC-derived exosomes (hAECs-exos) and hucbMSC-derived exosomes (hucbMSCs-exos) were administered to preeclamptic rats. The efficacy of these exosomes was evaluated through the assessment of pertinent biomarkers, and their underlying mechanisms of action were initially investigated. The ultimate goal was to establish a theoretical framework and empirical groundwork for the clinical management of hypertensive disorders during preg
Exosomes from hAECs and hubcMSCs were obtained from Liaoning Shengjing Stem Cell Technology Co. Ltd.
Sixteen healthy male Sprague-Dawley rats, aged 8-10 weeks and weighing 250 ± 20 g, along with 32 healthy female rats weighing 220 ± 20 g, were obtained from Beijing Huafukang Bioscience Co. Ltd. The animals were provided with an animal quality certificate number No. 110322230100948264 and an animal use license number SCXK (Beijing) 2019-0008. They underwent a 1-week acclimatization period in an environment maintained at 18-22 °C, relative humidity of 50%-70%, and a 12-hour light-dark cycle, with ad libitum access to food and water. This experimental protocol was approved by the Animal Medical Research Ethics Committee branch of the hospital (Ethics number: No. 2024-19).
L-arginine methyl ester (L-NAME) (Sigma, WI, United States), total protein assay kit (Nanjing Jiancheng Bioengineering Institute, Nanjing, Jiangsu Province, China), enzyme-linked immunosorbent assay (ELISA) kit (Shanghai Keaibo Biotechnology, Shanghai, China), hematoxylin and eosin (HE) staining kit (Shanghai Beyotime Biotechnology, Shanghai, China), immunohistochemistry hypersensitive SP kit (Fuzhou Maixin Biotechnology Development, Fuzhou, Fujian Province, China), CD31 antibody (Abcam, United Kingdom), BP-201A noninvasive animal blood pressure monitor (Beijing Ruan
Isolation, culture, and identification of hAECs: The cleaned amniotic membrane tissue was placed in phosphate buf
hAECs were harvested and adjusted to a density of 106 cells/mL. Subsequently, 1 mL of the cell suspension was processed. Following a wash with cold PBS, the cells were resuspended in 100 μL PBS. A 5-μL aliquot of monoclonal antibody was introduced, with a control group devoid of antibodies serving as the negative control. The cells were incubated at 4 °C in darkness for 30 minutes, followed by three washes with cold PBS. Flow cytometry was used to assess expression of CD29, CD31, CD34, CD90, CD105, HLA-DR and SSEA-4. The differentiation potential was evaluated using human adipose-derived MSC-specific adipogenic, osteogenic and chondrogenic induction media.
Isolation, culture and identification of hucbMSCs: Umbilical cord blood samples were diluted with PBS at a 1:1 ratio, followed by isolation of mononuclear cells (MNCs) through gradient density centrifugation using Ficoll-Paque (density = 1.077 g/mL). Subsequently, 20 mL diluted blood was layered onto an equal volume of Ficoll-Paque in a 50-mL centrifuge tube and centrifuged at 600 × g for 20 minutes at room temperature. The resulting MNC layer was carefully transferred to a new sterile 50-mL centrifuge tube. After a wash with PBS, the isolated MNCs were resuspended in StemMACS™ MSC expansion medium supplemented with 10% autologous serum and seeded in a six-well plate. The plate was incubated at 37 °C in a humidified atmosphere with 5% CO2. The medium was replaced after 1 day to eliminate nonadherent cells. Upon observation of fibroblast-like cell colonies reaching 80%-90% confluence, adherent cells were detached using trypsin solution, and the cells were passaged continuously until reaching P3.
hucbMSCs were harvested and adjusted to a density of 106 cells/mL. One milliliter of the cell suspension was removed, washed with cold PBS, and resuspended in 100 μL PBS. Five μL monoclonal antibody was added, and a group without antibody was designated as the negative control. The cells were incubated at 4 °C in the dark for 30 minutes, followed by three washes with cold PBS. A flow cytometer was used to assess expression of CD11b, CD34, CD45, CD73, CD90 and CD105. The differentiation potential was evaluated by exposing the cells to hAECMSC-specific adipogenic, osteogenic and chondrogenic induction media.
Extraction of exosomes: hAECs and hucbMSCs were cultured in T75 flasks until reaching 80% confluence. The cells were washed twice with PBS and incubated in Dulbecco’s modified Eagle’s medium/F12 in a CO2 incubator at 37 °C with 5% CO2 and saturated humidity. After 48 hours, the supernatant was harvested and subjected to sequential centrifugation steps at 300 × g for 5 minutes, 200 × g for 15 minutes, and 13000 × g for 35 minutes at 4 °C. The supernatant was filtered through a 0.22-μm sterile filter, and processed via ultrafiltration with discard of the lower liquid phase. Following resuspension in PBS, the sample underwent centrifugation at 150000 × g for 3 hours at 4 °C. The supernatant was discarded, and the precipitate was collected. The concentration of hAECs-exos and hucbMSCs-exos was determined using a BCA protein quantification kit, while the Exo count was assessed through nanoparticle tracking analysis (NTA). The samples were stored at -80 °C.
Transmission electron microscopy: Transmission electron microscopy (TEM) was set to the operational state. Ten microliters of purified hAECs-exos and hucbMSCs-exos were transferred onto copper grids, allowed to settle for 5 minutes, and filter paper was used to remove excess liquid at the grid edge. Phosphotungstic acid (10 μL) was applied to the grids, followed by drying and imaging at 80-120 kV.
NTA: The concentration of exosomes were determined by a nanoparticle tracking analyzer. The system was calibrated with 100 nm polystyrene microspheres prior to measurement. Purified exosomes were appropriately diluted in 1 × PBS buffer and introduced into the sample chamber for analysis.
Western blotting: Proteins (30 μg) were separated using sodium-dodecyl sulfate gel electrophoresis at 80 V followed by 120 V. The proteins were transferred from the separation gel to a polyvinylidene difluoride (PVDF) membrane at a constant current of 200 mA. The PVDF membrane was incubated in a blocking solution containing 5% nonfat milk powder at room temperature for 2 hours. The PVDF membrane was sectioned based on the molecular weights of the proteins and immersed in a diluted primary antibody hybridization solution (CD9 antibody 1:100, CD63 antibody 1:100, and CD81 antibody 1:100) for overnight incubation at 4 °C. The membrane underwent five washes with Tris-buffered saline-Tween for 5 minutes each. Horseradish-peroxidase-labeled secondary antibody (diluted 1:10000 with 5% bovine serum albumin) was applied, and the membrane was incubated at room temperature for 1 hour. The PVDF membrane was washed five times with Tris-buffered saline-Tween for 5 minutes each. A mixture of ECL luminescent solutions A and B at a 1:1 ratio was applied to the PVDF membrane, followed by imaging using a chemiluminescence imaging system.
Establishment and grouping of PE models: After 1 week of adaptive feeding, female and male rats were housed together at a 2:1 ratio at 17:00. The presence of a milky white gelatinous substance in the vaginal canal of female rats before 08:00 the following morning was indicative of a vaginal plug, confirming pregnancy and designating that day as gestational day (GD). The pregnant rats were randomly assigned to four groups of eight: Normal pregnancy (NP), PE, hAECs-exos treatment, and hucbMSCs-exos treatment. On GD5, the PE, hAECs-exos and hucbMSCs-exos groups received intraperitoneal injections of 1 mL L-NAME at 150 mg/kg for 7 consecutive days, while the NP group received 1 mL normal saline. On GD12, 6 hours post-L-NAME injection, the hAECs-exos and hucbMSCs-exos groups were intravenously administered 1 mg/kg hAECs-exos and hucbMSCs-exos, respectively, for 7 consecutive days. In parallel, the NP and PE groups were given 1 mL normal saline.
Measurement of blood pressure in rats: Rats’ blood pressure was noninvasively monitored on GD 4, 8, 11, 15 and 18, with three measurements obtained during each session in a calm state, followed by calculation of the mean value.
Determination of 24-hour urinary protein in rats: From 08:00 on GD4 to 08:00 the following day, metabolic cages were used to collect 24-hour urine samples from rats in each experimental group. The urine volume was quantified, and the urine protein concentration was determined using the Coomassie Brilliant Blue method.
Specimen collection and processing: Delivery was via cesarean section at GD19, and fetal mouse and placental weights were recorded. Subsequently, 5 mL blood was extracted from the inferior vena cava, and the upper-layer serum(1.5 mL) was isolated by centrifugation, which was then preserved at -80 °C. Portions of placental and kidney tissues were allo
HE staining of kidney and placental tissues: The kidney and placenta tissues from each group of rats were fixed, embedded in paraffin, sectioned, and subjected to HE staining to assess morphological alterations.
ELISA detection: ELISA kits were used to quantify interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, and soluble fms-like tyrosine kinase (sFlt)-1 levels in rat serum. Placental tissue weighing 100 mg was homogenized in 0.9 mL normal saline using an ultrasonic cell crusher. Following centrifugation at 300 rpm for 10 minutes, the resulting supernatant was analyzed using ELISA kits to determine placental growth factor (PLGF), vascular endothelial growth factor (VEGF), supe
Immunohistochemical detection: Immunohistochemistry was used to assess CD31 expression in rat placental tissues across all experimental groups. Tissue samples were examined microscopically, processed with Image-J software, and the proportion of positively stained cells was quantified.
Statistical analysis was conducted utilizing SPSS 26 software. Measurement data were presented as mean ± SD. One-way analysis of variance was used to assess variances among multiple groups, with post hoc least significant difference t tests utilized for pairwise group comparisons. Statistical significance was defined as P < 0.05.
Under microscopic examination, primary amniotic epithelial cells exhibited a consistent morphology and were organized in a characteristic cobblestone pattern. Subsequent cultivation in adipogenic, osteogenic and chondrogenic differentiation media demonstrated the capacity of hAECs to manifest lipid droplets, calcium nodules, and acid mucopolysaccharides, indicative of their potential for adipogenic, osteogenic and chondrogenic differentiation (Figure 1). Flow cytometry of P1 hAECs indicated positive expression of CD29, CD90, CD105 and SSEA-4, and negative expression of CD31, CD34 and HLA-DR (Figure 2).
Under microscopic examination, hucbMSCs exhibited consistent morphology. Subsequent culture in adipogenic, osteoge
TEM showed that hAECs-exos had round or oval vesicles with a saucer-like shape (Figure 5). NTA indicated that 97.3% of the cells had a diameter distribution of 121.3 ± 71.9 (full width at half maximum) nm, consistent with typical exosome size. Western blotting confirmed the presence of exosome-specific markers CD9, CD63 and CD81 on the surface.
TEM showed the saucer-like morphology of hucbMSCs-exos (Figure 6). NTA revealed that 97.3% of the cell diameters were around 126.4 ± 80 (full width at half maximum) nm, consistent with typical exosome size. Western blot analysis confirmed the presence of exosome surface markers CD9, CD63, and CD81 on the membrane of hucbMSCs-exos.
On GD4, there were no significant differences in systolic blood pressure among the four rat groups (Table 1 and Figure 7A) (P > 0.05). Following L-NAME intraperitoneal injection on GD8 and GD11, systolic blood pressure in the PE, hAECs-exos and hucbMSCs-exos groups significantly exceeded that in the NP group (P < 0.05), confirming successful establishment of the PE rat model. Throughout gestation, blood pressure in the PE group exhibited a progressive rise. Subsequent to exosome intervention, on GD15 and GD18, systolic blood pressure in the hAECs-exos and hucbMSCs-exos groups significantly decreased compared to that in the PE group (P < 0.05). There was no significant disparity between the two treatment cohorts (P > 0.05).
| Group | GD4 | GD8 | GD11 | GD15 | GD18 |
| NP | 111.75 ± 1.83 | 112.50 ± 3.42 | 114.50 ± 3.30 | 112.25 ± 4.95 | 113.00 ± 4.44 |
| PE | 112.63 ± 1.30 | 137.25 ± 2.44a | 143.00 ± 2.27a | 151.38 ± 3.74a | 155.38 ± 6.95a |
| hAECs-exos | 113.00 ± 3.96 | 139.25 ± 3.15a | 149.13 ± 3.91a | 130.88 ± 3.40a,b | 121.50 ± 4.14a,b |
| hucbMSCs-exos | 110.88 ± 2.42 | 138.25 ± 4.23a | 146.5 ± 4.66a | 128.38 ± 3.89a,b | 120.25 ± 4.98a,b |
On GD4, there were no significant differences in 24-hour urinary protein levels among the four groups of rats (P > 0.05) (Table 2 and Figure 7B). Following intraperitoneal L-NAME injection, rats in the GD8, GD11, PE, hAECs-exos and hucbMSCs-exos groups exhibited significantly elevated 24-hour urinary protein levels compared to the NP group (P < 0.05). In the PE group, urinary protein levels continued to rise with advancing gestational age. Subsequent exosome administration led to a significant reduction in 24-hour urinary protein levels in the hAECs-exos and hucbMSCs-exos groups compared to the PE group on GD15 and GD18 (P < 0.05). Importantly, no significant difference was observed between the two treatment groups (P > 0.05).
All fetal mice in the NP group exhibited normal development (Figure 8A). In contrast, within the PE group, one pregnant mouse experienced a miscarriage, leading to halted embryo development (Figure 8B), along with the observation of limb malformations, congestion, and edema in multiple fetal mice (Figure 8C). Fetal mice in the hAECs-exos and hucbMSCs-exos groups displayed larger sizes compared to those in the PE group, with significant improvements noted in limb malformations and congestion (Figure 8D and E). There was a significant reduction in the weights of fetal mice and placentas in the PE group compared to the NP group (P < 0.05) (Table 3). Conversely, the weight of fetal mice and placentas in the hAECs-exos and hucbMSCs-exos groups was increased compared to in the PE group (P < 0.05).
Histological examination of kidney sections revealed no pathological alterations in the NP group, demonstrating normal morphology with intact glomerular and tubular structures. Conversely, the PE group exhibited disrupted kidney tissue architecture characterized by enlarged glomeruli, epithelial cell exfoliation, narrowed tubular lumens, epithelial cell edema, and vacuolization. Remarkably, rats treated with hAECs-exos and hucbMSCs-exos showed significantly reduced renal damage compared to the PE group (Figure 9). Similarly, placental HE staining indicated that the NP group main
Compared to the NP group, the serum levels of IL-6, TNF-α, and sFlt-1 in the PE group exhibited a significant increase, while IL-10 levels decreased significantly (P < 0.05) (Table 4 and Figure 11). Conversely, in comparison to the PE group, the hAECs-exos and hucbMSCs-exos groups demonstrated decreased levels of IL-6, TNF-α, and sFlt-1 in serum, along with an increase in IL-10 levels (P < 0.05). There was no significant disparity observed between the two treatment groups (P > 0.05).
| Cytokine | NP | PE | hAECs-exos | hucbMSCs-exos |
| IL-6 (pg/mL) | 93.18 ± 9.75 | 149.26 ± 13.71a | 120.15 ± 16.20a,b | 124.64 ± 9.73a,b |
| IL-10 (pg/mL) | 2.30 ± 0.58 | 0.87 ± 0.18a | 1.58 ± 0.39a,b | 1.41 ± 0.53a,b |
| TNF-α (pg/mL) | 7.30 ± 1.01 | 11.20 ± 1.48a | 8.96 ± 1.23a,b | 9.43 ± 1.95a,b |
| sFlt-1 (ng/mL) | 0.22 ± 0.05 | 0.43 ± 0.10a | 0.33 ± 0.09a,b | 0.32 ± 0.12a,b |
In comparison to the NP group, placental levels of PLGF, VEGF and SOD were notably reduced, while MDA levels were significantly elevated in the PE group (Table 5 and Figure 12) (P < 0.05). Conversely, the placental levels of PLGF, VEGF and SOD were elevated, and MDA levels were decreased in the hAECs-exos and hucbMSCs-exos groups compared to the PE group (P < 0.05). There was no significant difference observed between the two treatment groups (P > 0.05).
Immunohistochemical staining of placental tissue was used to assess CD31 endothelial cell expression. A notable reduction in the percentage of CD31-positive cells in the placental tissue of rats in the PE group compared to the NP group was observed (P < 0.05). Conversely, a significant increase in CD31-positive cells was evident in the placental tissue of rats in the hAECs-exos and hucbMSCs-exos groups compared to the PE group (P < 0.05) (Table 6 and Figure 13). No significant difference was observed between the two treatment cohorts (P > 0.05).
PE is a prevalent complication in pregnancy, posing significant risks to both maternal and fetal health[14]. Abnormal placental development and dysfunction are currently recognized as primary factors contributing to PE. The existing therapeutic approaches for PE primarily aim to manage hypertension, extend gestation, and facilitate timely delivery; however, these strategies do not offer a definitive solution. Consequently, there is an urgent demand for the development of a safe and efficacious treatment modality to ameliorate clinical manifestations and adverse pregnancy outcomes asso
In this study, L-NAME was utilized to induce a rat model of PE, and the therapeutic efficacy and underlying mecha
VEGF regulates the invasive capacity of trophoblasts, promotes placental angiogenesis, enhances vascular permeabi
During a normal pregnancy, the differentiation balance between T helper 1 (Th1) and Th2 cells is tightly maintained. In the first trimester of pregnancy, T helper cells are predominantly differentiated into pro-inflammatory Th1 cells, which secrete TNF-α and interferon-γ. These cytokines facilitate the invasion of placental trophoblasts and vascular remodeling. Subsequently, the differentiation of T helper cells shifts toward an anti-inflammatory Th2 phenotype, with the secretion of IL-10 and IL-4. These anti-inflammatory cytokines help neutralize pro-inflammatory cytokines and inhibit the activation of Th17 and Th1 cells[21]. In the context of PE, the body exhibits immune imbalance, characterized by in
During normal pregnancy, maternal oxidation and antioxidant systems maintain equilibrium, whereas the placental antioxidant defense is compromised in individuals with PE[27]. MDA is a byproduct of cell membrane lipid peroxidation due to increased free radicals during oxidative stress, disrupting cell membrane permeability and integrity, thereby affecting cellular functions. SOD is a crucial antioxidant enzyme that scavenges free radicals, protects cells from oxidative damage, and exhibits anti-inflammatory properties[28]. Studies indicate decreased SOD levels and increased MDA levels in PE patients[29]. Treatment of PE rats with exosomes resulted in decreased MDA expression and increased SOD expression in placental tissue, suggesting that hAECs-exos and hucbMSCs-exos can mitigate oxidative stress responses, thereby alleviating vascular and tissue damage and ameliorating PE symptoms.
This study compared the therapeutic effects of hAECs-exos with hucbMSCs-exos in a PE rat model, and indicated no significant difference in therapeutic efficacy. Both exosome types ameliorated clinical symptoms and pregnancy outcomes in PE rats, attenuated oxidative stress and inflammatory responses, and mitigated kidney and placental tissue damage. However, as compared with hucbMSCs, hAECs offer distinct advantages[30]: Easy procurement from postpartum medical waste without invasive procedures, ethical concerns; wide availability; simple isolation and culture procedures for rapid cell expansion; low major histocompatibility complex-1 expression; absence of major histocompatibility com
This study had the following limitations and shortcomings: (1) Existing studies have summarized established PE models[32], but it is generally acknowledged that a single model can hardly encompass the full spectrum of the patho
In summary, both hAECs-exos and hucbMSCs-exos demonstrate notable therapeutic efficacy in PE rats, offering a novel avenue for investigating noncellular treatment modalities. Nonetheless, a comprehensive investigation into the precise molecular mechanisms and cellular signaling pathways underlying their therapeutic actions is warranted.
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