Recombinant human soluble thrombomodulin as an anticoagulation therapy improves recurrent miscarriage and fetal growth restriction due to placental insufficiency – The leading cause of preeclampsia

Sano, Tsuyoshi; Daimon, Atsushi; Nunode, Misa; Nagayasu, Yoko; Okamoto, Aikou; Fujita, Daisuke; Hayashi, Masami; Ohmichi, Masahide

doi:10.1016/j.placenta.2018.03.006

Cited by 14 publications

(10 citation statements)

References 32 publications

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“…15 Restoring TM levels may be a new and, as solulin cannot cross the placental barrier, safe therapy for placental defects associated with excess platelet activation and placental inflammasome activation, as observed in PE. 10,[16][17][18] However, our data do not support the converse hypothesis that the placental defects observed in TM-null embryos are mechanistically linked to NLRP3 inflammasome activation. Whether platelet-dependent placental inflammasome activation may be a contributing factor to pregnancy complications in less severe cases of thrombophilia, such as those observed in pregnancies of homozygous factor V Leiden carriers, 15 remains to be established.…”

Section: Resultscontrasting

confidence: 99%

Placental thromboinflammation impairs embryonic survival by reducing placental thrombomodulin expression

Kohli

Singh

Gupta

et al. 2021

Blood

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Excess platelet-activation by extracellular vesicles (EVs) results in trophoblast inflammasome activation, IL-1β activation, preeclampsia (PE) and partial embryonic lethality. Furthermore, embryonic thrombomodulin (TM) deficiency, which causes embryonic lethality hallmarked by impaired trophoblast proliferation, has been linked with maternal platelet-activation. Hence, we hypothesized that placental TM loss, platelet-activation, and embryonic lethality are mechanistically linked to trophoblast inflammasome activation. Here, we uncover a unidirectional interaction of placental inflammasome activation and reduced placental TM-expression: while inflammasome inhibition did not rescue TM-null embryos from lethality, the inflammasome-dependent cytokine IL-1β reduced trophoblast TM expression and impaired pregnancy outcome. Likewise, EVs known to induce placental inflammasome activation, reduced trophoblast TM expression and proliferation. Trophoblast TM expression correlated negatively with IL-1β expression and positively with platelet numbers and trophoblast proliferation in human PE placentae, implying translational relevance. Soluble TM treatment or placental TM restoration ameliorated the EV-induced PE-like phenotype in mice, preventing placental thrombo-inflammation and embryonic death. Collectively, the lethality of TM-null embryos is not a consequence of placental NLRP3 inflammasome activation. Conversely, EV-induced placental inflammasome activation reduces placental TM expression, which promotes placental and embryonic demise. These data identify a new function of placental TM in PE and suggest that soluble TM limits thrombo-inflammatory pregnancy complications.

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Section: Resultscontrasting

confidence: 99%

Placental thromboinflammation impairs embryonic survival by reducing placental thrombomodulin expression

Kohli

Singh

Gupta

et al. 2021

Blood

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“…In this regard, a previous study has shown that rhTM has excellent bioavailability (74–108%) by subcutaneous injection and that rhTM administered by the subcutaneous route has a longer half-life than that delivered by intravenous injection (16–28 h vs. 5–7 h) [ 26 ]. In addition, the subcutaneous administration of rhTM has been very effective in several experimental disease models, including recurrent miscarriage, chronic kidney vascular injury, radiation-induced intestinal damage, necrotizing enterocolitis, and ventilator-induced lung injury [ 47 , 48 , 49 , 50 , 51 ]. Overall, these previous findings, together with the beneficial effect observed in our model, suggest the potential application of rhTM for the chronic treatment of DM.…”

Section: Discussionmentioning

confidence: 99%

Protective Role of Recombinant Human Thrombomodulin in Diabetes Mellitus

Okano

Takeshita

Yasuma

et al. 2021

Cells

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Diabetes mellitus is a global threat to human health. The ultimate cause of diabetes mellitus is insufficient insulin production and secretion associated with reduced pancreatic β-cell mass. Apoptosis is an important and well-recognized mechanism of the progressive loss of functional β-cells. However, there are currently no available antiapoptotic drugs for diabetes mellitus. This study evaluated whether recombinant human thrombomodulin can inhibit β-cell apoptosis and improve glucose intolerance in a diabetes mouse model. A streptozotocin-induced diabetes mouse model was prepared and treated with thrombomodulin or saline three times per week for eight weeks. The glucose tolerance and apoptosis of β-cells were evaluated. Diabetic mice treated with recombinant human thrombomodulin showed significantly improved glucose tolerance, increased insulin secretion, decreased pancreatic islet areas of apoptotic β-cells, and enhanced proportion of regulatory T cells and tolerogenic dendritic cells in the spleen compared to counterpart diseased mice treated with saline. Non-diabetic mice showed no changes. This study shows that recombinant human thrombomodulin, a drug currently used to treat patients with coagulopathy in Japan, ameliorates glucose intolerance by protecting pancreatic islet β-cells from apoptosis and modulating the immune response in diabetic mice. This observation points to recombinant human thrombomodulin as a promising antiapoptotic drug for diabetes mellitus.

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“…The reduced expression of sFlt1 in the placenta and serum may be one of the main factors that ameliorate the preeclampsia phenotypes, including fetal growth restriction. Indeed, the treatment with pravastatin or thrombomodulin enhances fetal growth in the models 9,18 . However, sFlt1 may not be involved in the fetal resorption because sFlt1 transgenic mice models do not exhibit fetal loss 16,17 .…”

Section: Discussionmentioning

confidence: 99%

“…No Substantial Effects of PSC-EP Injection on the Angiogenic Factor Balance in DBA/2-Mated CBA/J Females DBA/2-mated CBA/J females have the abnormal expression of angiogenic (Vegfa and Plgf) 10 and anti-angiogenic (sFlt1) factors 18 , and exhibit angiogenic factor imbalance. Further, transplanted BM-or PB-derived EPCs, or mesenchymal stem cells (MSCs) frequently release humoral factors that may modulate angiogenesis.…”

Section: Robust Establishment Of Fetomaternal Vasculature By Psc-epsmentioning

confidence: 99%

“…The DBA/2-mated CBA/J model has also been useful for exploring effective treatments for recurrent miscarriage. With the model, several groups invented treatments, such as statins 9 , thrombomodulin 18 , or the complement component 3 (C3) inhibitor 11 , to protect the pregnancy. Our group has shown that intravenous (IV) injection of bone marrow (BM)-derived endothelial progenitor cells (EPCs) reduced the fetal resorption rate in the same mouse model 19 .…”

Section: Introductionmentioning

confidence: 99%

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Intravenously Injected Pluripotent Stem Cell–derived Cells Form Fetomaternal Vasculature and Prevent Miscarriage in Mouse

et al. 2020

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Miscarriage is the most common complication of pregnancy, and about 1% of pregnant women suffer a recurrence. Using a widely used mouse miscarriage model, we previously showed that intravenous injection of bone marrow (BM)-derived endothelial progenitor cells (EPCs) may prevent miscarriage. However, preparing enough BM-derived EPCs to treat a patient might be problematic. Here, we demonstrated the generation of mouse pluripotent stem cells (PSCs), propagation of sufficient PSC-derived cells with endothelial potential (PSC-EPs), and intravenous injection of the PSC-EPs into the mouse miscarriage model. We found that the injection prevented miscarriage. Three-dimensional reconstruction images of the decidua after tissue cleaning revealed robust fetomaternal neovascularization induced by the PSC-EP injection. Additionally, the injected PSC-EPs directly formed spiral arteries. These findings suggest that intravenous injection of PSC-EPs could become a promising remedy for recurrent miscarriage.

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Recombinant human soluble thrombomodulin as an anticoagulation therapy improves recurrent miscarriage and fetal growth restriction due to placental insufficiency – The leading cause of preeclampsia

Cited by 14 publications

References 32 publications

Placental thromboinflammation impairs embryonic survival by reducing placental thrombomodulin expression

Placental thromboinflammation impairs embryonic survival by reducing placental thrombomodulin expression

Protective Role of Recombinant Human Thrombomodulin in Diabetes Mellitus

Intravenously Injected Pluripotent Stem Cell–derived Cells Form Fetomaternal Vasculature and Prevent Miscarriage in Mouse

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