Placental histological findings in COVID-19 term, preterm and metabolic disorders pregnancy

Objective. In the last two years COVID-19 infection has represented a true unknown in the management of pregnancies with maternal COVID-19 positivity. However, it has not represented a serious complication, indeed it has rarely caused premature rupture of the membrane, fetal thrombosis or postnatal complications. Materials and Methods. Our retrospective cohort study included placental samples from 350 patients from San Pietro Fatebenefratelli Hospital collected in a period of 4 months. Inclusion criteria were COVID-19 positivity during childbirth or in the previous two months but also a pregnancy without previous COVID-19 infection. Anamnestic data were carried out for the histological study on each placenta. 59% of patients were COVID-19 positive (15% of these had other associated disorders like gestational diabetes, hypertension, fetal death, preterm birth) 26.5% were preterm and the 14,5% were high-risk pregnancy with COVID-19 negativity. Results. The most frequently represented lesion in a COVID-19 placenta was a mild chronic deciduitis, usually absent in placentas with normal outcome. The same deciduitis was observed in gestational diabetes placentas, although less frequently. Other rare findings were patchy fibrinoid necrosis of capsular decidua, chronic villitis, umbilical cord thrombosis. Severe lesions were rare. Conclusions. COVID-19 does not seem to have a severe impact on the health of the placenta except in rare cases in which predisposing factors coexist and determine a more serious involvement of the fetus and its appendages. COVID-19 determines a constant but mild chronic placental inflammation, that is balanced by the maternal capacity to maintain homeostasis stemming the external injuries.

FEATURES OF IMMUNOHISTOCHEMICAL MARKERS OF STEM CELLS CD-117, CD-44 IN FEMALE PLACENTAS ON THE BACKGROUND OF CHRONIC STRESS.

Background. Placenta is a subject of interest to a wide range of scientists because it is rich in stem cells and their precursors. A stem cell is a cell that has the ability to self-repair and can differentiate into offspring (daughter cells) of one or more germ layers. In recent years, scientists have obtained new data of stem cells regenerative potential. However, only isolated publications about placental stem cells are available. Therefore, our studies about placental stem cells are important for discovery of structural and molecular mechanisms, their changes under the influence of chronic stress. Objective(s): to study the features of immunohistochemical markers of pluripotent stem cells and their morphological features. Materials and methods. We examined 80 women placentas with chronic stress in comparison with control using general histological and immunohistochemical methods in the following groups: group 1 - women placentas with physiological course of pregnancy in term 38-40 weeks, group 2 - women placentas with miscarriage, group 3 - women placentas with chronic stress due to internal irradiation (4.5 Bq/kg and more), group 4 - women placentas which had COVID-19 during pregnancy. Results. There was a significant increase of stem cell markers expression in the three study groups with a significant predominance in groups 3 and 4. It was also determined the different direction of their active factors. Conclusions. The general changes of all structures of the placental barrier are detected as a result of chronic stress due to various factors: micro detachment of the decidual membrane (significant increase in cases in the studied groups);malperfusion in the structures of the maternal placental barrier;in the placenta stem cells of the three study groups in comparison with the control were found stress markers. Thus, chronic stress due to various factors causes the same type of changes in placental structures, but they have different degrees of expression - with internal irradiation doses >= 4.8 Bq/kg, these changes are most expressive.Copyright © 2022 Authors. All rights reserved.

Mesenchymal stromal cells as treatment for acute respiratory distress syndrome. Case Reports following hematopoietic cell transplantation and a review.

Acute respiratory distress syndrome (ARDS) is a life-threatening lung disease. It may occur during the pancytopenia phase following allogeneic hematopoietic cell transplantation (HCT). ARDS is rare following HCT. Mesenchymal stromal cells (MSCs) have strong anti-inflammatory effect and first home to the lung following intravenous infusion. MSCs are safe to infuse and have almost no side effects. During the Covid-19 pandemic many patients died from ARDS. Subsequently MSCs were evaluated as a therapy for Covid-19 induced ARDS. We report three patients, who were treated with MSCs for ARDS following HCT. Two were treated with MSCs derived from the bone marrow (BM). The third patient was treated with MSCs obtained from the placenta, so-called decidua stromal cells (DSCs). In the first patient, the pulmonary infiltrates cleared after infusion of BM-MSCs, but he died from multiorgan failure. The second patient treated with BM-MSCs died of aspergillus infection. The patient treated with DSCs had a dramatic response and survived. He is alive after 7 years with a Karnofsky score of 100%. We also reviewed experimental and clinical studies using MSCs or DSCs for ARDS. Several positive reports are using MSCs for sepsis and ARDS in experimental animals. In man, two prospective randomized placebo-controlled studies used adipose and BM-MSCs, respectively. No difference in outcome was seen compared to placebo. Some pilot studies used MSCs for Covid-19 ARDS. Positive results were achieved using umbilical cord and DSCs however, optimal source of MSCs remains to be elucidated using randomized trials.

Potential and challenges of placenta-derived decidua stromal cell therapy in inflammation-associated disorders.

Decidual stromal cells (DSCs) isolated from maternal part of placenta, like mesenchymal stromal cells (MSCs), are able to inhibit alloreactivity in-vitro but in a superior way which makes them an attractive alternative for anti-inflammatory therapies. In alloreactivity, when a strong immune response is developed against alloantigens, DSCs develop an anti-inflammatory environment, both through cell-to-cell contact and soluble factors, to prevent the adverse effects of alloantigens. In alloreactivity-associated inflammation, proinflammatory cytokines can be released and then involved in the up-regulation of inflammatory reactions which is one of the main causes of inflammatory related disorders. According to the preclinical and clinical studies, DSCs could be promising alternatives for the treatment of inflammatory-related diseases for which no definitive and successful treatment has been found yet. Here we first present the DSCs functions in creating the anti-inflammatory environment, their immunomodulatory effects, and their advantages over MSCs. Then, preclinical and clinical studies using DSCs for treatment of inflammatory disease including: graft-versus-host-disease (GVHD) after allogeneic hematopoi-etic stem cell transplantation (Allo-HSCT), COVID-19-associated Acute Respiratory Distress Syndrome (ARDS) and in particular, Infertility-related disorders, are presented. Finally, the challenges of using DSCs in clinical settings will be described.

Single-cell RNA sequencing reveals immunological rewiring at the maternal-fetal interface following asymptomatic/mild SARS-CoV-2 infection.

While severe coronavirus 2019 (COVID-19) is associated with immune activation at the maternal-fetal interface, responses to asymptomatic/mild severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy remain unknown. Here, we assess immunological adaptations in blood and term decidua in response to asymptomatic/mild disease in pregnant women. We report attenuated antigen presentation and type I interferon (IFN) signaling pathways, loss of tissue-resident decidual macrophages, and upregulated cytokine/chemokine signaling in monocyte-derived decidual macrophages. Furthermore, we describe increased frequencies of activated tissue-resident T cells and decreased abundance of regulatory T cells with infection while frequencies of cytotoxic CD4/CD8 T cells are increased in the blood. In contrast to decidual macrophages, type I IFN signaling is higher in decidual T cells. Finally, infection leads to a narrowing of T cell receptor diversity in both blood and decidua. Collectively, these observations indicate that asymptomatic/mild COVID-19 during pregnancy results in remodeling of the immunological landscape of the maternal-fetal interface, with a potential for long-term adverse outcomes for the offspring.

Human placental biology at single-cell resolution: a contemporaneous review.

Single-cell technologies capture cellular heterogeneity to focus on previously poorly described subpopulations of cells. Work by our laboratory and many others has metagenomically characterised a low biomass intrauterine microbial community, alongside microbial transcripts, antigens and metabolites, but the functional importance of low biomass microbial communities in placental immuno-microenvironments is still being elucidated. Given their hypothesised role in modulating inflammation and immune ontogeny to enable tolerance of beneficial microbes while warding off pathogens, there is a need for single-cell resolution. Herein, we summarise the potential for mechanistic understanding of these and other key fundamental early developmental processes by applying single-cell approaches.

Conquering the cytokine storm in COVID-19-induced ARDS using placenta-derived decidua stromal cells.

Acute respiratory distress syndrome (ARDS) is the most common cause of death in COVID-19 patients. The cytokine storm is the main driver of the severity and magnitude of ARDS. Placenta-derived decidua stromal cells (DSCs) have a stronger immunosuppressive effect than other sources of mesenchymal stromal cells. Safety and efficacy study included 10 patients with a median age of 50 (range 14-68) years with COVID-19-induced ARDS. DSCs were administered 1-2 times at a dose of 1 × 106 /kg. End points were safety and efficacy by survival, oxygenation and effects on levels of cytokines. Oxygenation levels increased from a median of 80.5% (range 69-88) to 95% (range 78-99) (p = 0.012), and pulmonary infiltrates disappeared in all patients. Levels of IL-6 decreased from a median of 69.3 (range 35.0-253.4) to 11 (range 4.0-38.3) pg/ml (p = 0.018), and CRP decreased from 69 (range 5-169) to 6 (range 2-31) mg/ml (p = 0.028). Two patients died, one of a myocardial infarction and the other of multiple organ failure, diagnosed before the DSC therapy. The other patients recovered and left the intensive care unit (ICU) within a median of 6 (range 3-12) days. DSC therapy is safe and capable of improving oxygenation, decreasing inflammatory cytokine level and clearing pulmonary infiltrates in patients with COVID-19.

SARS-CoV-2 colonization of maternal and fetal cells of the human placenta promotes alteration of local renin-angiotensin system.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection appears to increase the risk of adverse pregnancy outcomes, such as pre-eclampsia in pregnant women. The mechanism(s) by which this occurs remains unclear. METHODS: We investigated the pathophysiology of SARS-CoV-2 at maternal-fetal interface in pregnant women who tested positive for the virus using RNA in situ hybridization (viral RNA), immunohistochemistry, and hematoxylin and eosin staining. To investigate whether viral infection alters the renin angiotensin system (RAS) in placenta, which controls blood pressure, we treated human trophoblasts with recombinant spike protein or a live modified virus with a vesicular stomatitis viral backbone expressing spike protein (VSV-S). FINDINGS: Viral colonization was highest in maternal decidua, fetal trophoblasts, Hofbauer cells, and in placentas delivered prematurely. We localized SARS-CoV-2 to cells expressing angiotensin-converting enzyme 2 (ACE2) and demonstrate that infected placentas had significantly reduced ACE2. In response to both spike protein and VSV-S, cellular ACE2 decreased although angiotensin II receptor type 1 (AT1R) increased with concomitant increase in soluble fms-like tyrosine kinase-1 (sFlt1). Viral infection decreased pro-angiogenic factors, AT2R, and placental growth factor, which competitively binds to sFlt1. Sera from infected pregnant women had elevated levels of sFlt1 and angiotensin II type 1-receptor autoantibodies prior to delivery, both signatory markers of pre-eclampsia. CONCLUSIONS: SARS-CoV-2 colonizes ACE2-expressing maternal and fetal cells in the placenta. Infection in pregnant women correlates with alteration of placental RAS. As RAS regulates blood pressure, SARS-CoV-2 infection may thus increase adverse hemodynamic outcomes, such as pre-eclampsia in pregnant women. FUNDING: NIH/NICHD grants R01 HD091218 and 3R01HD091218-04S1 (RADx-UP Supplement).

Current Status and Future Prospects of Perinatal Stem Cells.

The placenta is a temporary organ that is discarded after birth and is one of the most promising sources of various cells and tissues for use in regenerative medicine and tissue engineering, both in experimental and clinical settings. The placenta has unique, intrinsic features because it plays many roles during gestation: it is formed by cells from two individuals (mother and fetus), contributes to the development and growth of an allogeneic fetus, and has two independent and interacting circulatory systems. Different stem and progenitor cell types can be isolated from the different perinatal tissues making them particularly interesting candidates for use in cell therapy and regenerative medicine. The primary source of perinatal stem cells is cord blood. Cord blood has been a well-known source of hematopoietic stem/progenitor cells since 1974. Biobanked cord blood has been used to treat different hematological and immunological disorders for over 30 years. Other perinatal tissues that are routinely discarded as medical waste contain non-hematopoietic cells with potential therapeutic value. Indeed, in advanced perinatal cell therapy trials, mesenchymal stromal cells are the most commonly used. Here, we review one by one the different perinatal tissues and the different perinatal stem cells isolated with their phenotypical characteristics and the preclinical uses of these cells in numerous pathologies. An overview of clinical applications of perinatal derived cells is also described with special emphasis on the clinical trials being carried out to treat COVID19 pneumonia. Furthermore, we describe the use of new technologies in the field of perinatal stem cells and the future directions and challenges of this fascinating and rapidly progressing field of perinatal cells and regenerative medicine.

Expression of severe acute respiratory syndrome coronavirus 2 cell entry genes, angiotensin-converting enzyme 2 and transmembrane protease serine 2, in the placenta across gestation and at the maternal-fetal interface in pregnancies complicated by preterm birth or preeclampsia.

BACKGROUND: Although there is some evidence that severe acute respiratory syndrome coronavirus 2 can invade the human placenta, limited data exist on the gestational age-dependent expression profile of the severe acute respiratory syndrome coronavirus 2 cell entry mediators, angiotensin-converting enzyme 2 and transmembrane protease serine 2, at the human maternal-fetal interface. There is also no information as to whether the expression of these mediators is altered in pregnancies complicated by preeclampsia or preterm birth. This is important because the expression of decidual and placental angiotensin-converting enzyme 2 and transmembrane protease serine 2 across gestation may affect the susceptibility of pregnancies to vertical transmission of severe acute respiratory syndrome coronavirus 2. OBJECTIVE: This study aimed to investigate the expression pattern of specific severe acute respiratory syndrome coronavirus 2 cell entry genes, angiotensin-converting enzyme 2 and transmembrane protease serine 2, in the placenta across human pregnancy and in paired samples of decidua and placenta in pregnancies complicated by preterm birth or preeclampsia compared with those in term uncomplicated pregnancies. STUDY DESIGN: In this study, 2 separate cohorts of patients, totaling 87 pregnancies, were included. The first cohort was composed of placentae from first- (7-9 weeks), second- (16-18 weeks), and third-trimester preterm (26-31 weeks) and third-trimester term (38-41 weeks) pregnancies (n=5/group), whereas the second independent cohort included matched decidua and placentae from pregnancies from term uncomplicated pregnancies (37-41 weeks' gestation; n=14) and pregnancies complicated by preterm birth (26-37 weeks' gestation; n=11) or preeclampsia (25-37 weeks' gestation; n=42). Samples were subjected to quantitative polymerase chain reaction and next-generation sequencing or RNA sequencing for next-generation RNA sequencing for angiotensin-converting enzyme 2 and transmembrane protease serine 2 mRNA expression quantification, respectively. RESULTS: In the first cohort, angiotensin-converting enzyme 2 and transmembrane protease serine 2, exhibited a gestational age-dependent expression profile, that is, angiotensin-converting enzyme 2 and transmembrane protease serine 2 mRNA was higher (P<.05) in the first-trimester placenta than in second-trimester, preterm birth, and term placentae (P<.05) and exhibited a negative correlation with gestational age (P<.05). In the second cohort, RNA sequencing demonstrated very low or undetectable expression levels of angiotensin-converting enzyme 2 in preterm birth, preeclampsia, and term decidua and in placentae from late gestation. In contrast, transmembrane protease serine 2 was expressed in both decidual and placental samples but did not change in pregnancies complicated by either preterm birth or preeclampsia. CONCLUSION: The increased expression of these severe acute respiratory syndrome coronavirus 2 cell entry-associated genes in the placenta in the first trimester of pregnancy compared with those in later stages of pregnancy suggests the possibility of differential susceptibility to placental entry to severe acute respiratory syndrome coronavirus 2 across pregnancy. Even though there is some evidence of increased rates of preterm birth associated with severe acute respiratory syndrome coronavirus 2 infection, we found no increase in mRNA expression of angiotensin-converting enzyme 2 or transmembrane protease serine 2 at the maternal-fetal interface.