Therapeutic benefit of mesenchymal stem cells in pregnant rats with angiotensin receptor agonistic autoantibody-induced hypertension: Implications for immunomodulation and cytoprotection

ABSTRACT

Immunomodulation by mesenchymal stem cells (MSCs) is potentially important for maintaining peripheral tolerance. Preeclampsia may be due to maternal immune rejection of the genetically foreign fetus. This study aimed to investigate the biological function of human umbilical cord–derived mesenchymal stem cells (HU-MSCs) for the treatment of angiotensin receptor agonistic autoantibody (AT1-AA)-induced hypertension during pregnancy. HU-MSCs were isolated, cultured, and labeled in vitro. AT1-AA and HU-MSCs were administered to pregnant rats. Green fluorescent protein (GFP)–positive HU-MSCs infused in vivo were identified by immunofluorescence. Systolic blood pressure (SBP) was evaluated. The effects of HU-MSCs on fetal weight, kidney burden, and spiral artery remodeling, as well as on the expression of tumor necrosis factor α (TNF-α), interleukin 10 (IL-10), and heme oxygenase 1 (HO-1), were investigated. The SBP levels in the HU-MSC-treated pregnant hypertension rats decreased by gestational day 19. The reduction in fetal weight was largely ameliorated after HU-MSC treatment. Lesion burden in the kidney was attenuated and spiral artery remodeling was improved in HU-MSC-treated pregnant hypertension rats. However, green fluorescent protein (GFP)–labeled cells were sparingly observed in the kidney and placenta. Intravenous infusion of HU-MSCs into AT1-AA-induced rats significantly downregulated serum TNF-α levels and upregulated IL-10 levels, concomitant with increased placenta and mesometrial triangle (MT) HO-1 expression. Taken together, intravenous infusion of HU-MSCs ameliorates AT1-AA-induced pregnancy hypertension, intrauterine growth retardation, kidney impairment, and spiral artery remodeling impairment. Moreover, the potential benefits of HU-MSCs may be attributable to both an interference with the pathogenic immune response and a paracrine cytoprotective action.

KEYWORDS:

• Angiotensin receptor agonistic autoantibody
• mesenchymal stem cells
• preeclampsia
• spiral artery remodeling

Funding

This work was supported by Shengjing Hospital of China Medcine University Science Foundation (M931 and MA60).

Additional information

Funding

This work was supported by Shengjing Hospital of China Medcine University Science Foundation (M931 and MA60).

Notes on contributors

Dan Zhang

Dan Zhang conducted the study, participated in the data collection, performed most experiments, and wrote the initial draft and revised the manuscripts. Lihua Fu collected the preliminary data, and helped to perform some experiments. Leilei Wang participated in the study design and interpretation of the data. Lihong Yu, Lin Lin, and Lijun Zhang helped to interpret data. Tao Shang studied coordination and participated in the study design. All authors read and approved the final manuscript.

Lijun Zhang

Dan Zhang conducted the study, participated in the data collection, performed most experiments, and wrote the initial draft and revised the manuscripts. Lihua Fu collected the preliminary data, and helped to perform some experiments. Leilei Wang participated in the study design and interpretation of the data. Lihong Yu, Lin Lin, and Lijun Zhang helped to interpret data. Tao Shang studied coordination and participated in the study design. All authors read and approved the final manuscript.