The Human Fetal and Adult Stem Cell Secretome Can Exert Cardioprotective Paracrine Effects against Cardiotoxicity and Oxidative Stress from Cancer Treatment.

Cardiovascular side effects are major shortcomings of cancer treatments causing cardiotoxicity and late-onset cardiomyopathy. While doxorubicin (Dox) has been reported as an effective chemotherapy agent, unspecific impairment in cardiomyocyte mitochondria activity has been documented. We demonstrated that the human fetal amniotic fluid-stem cell (hAFS) secretome, namely the secreted paracrine factors within the hAFS-conditioned medium (hAFS-CM), exerts pro-survival effects on Dox-exposed cardiomyocytes. Here, we provide a detailed comparison of the cardioprotective potential of hAFS-CM over the secretome of mesenchymal stromal cells from adipose tissue (hMSC-CM). hAFS and hMSC were preconditioned under hypoxia to enrich their secretome. The cardioprotective effects of hAFS/hMSC-CM were evaluated on murine neonatal ventricular cardiomyocytes (mNVCM) and on their fibroblast counterpart (mNVFib), and their long-term paracrine effects were investigated in a mouse model of Dox-induced cardiomyopathy. Both secretomes significantly contributed to preserving mitochondrial metabolism within Dox-injured cardiac cells. hAFS-CM and hMSC-CM inhibited body weight loss, improved myocardial function, reduced lipid peroxidation and counteracted the impairment of mitochondrial complex I activity, oxygen consumption, and ATP synthesis induced by Dox. The hAFS and hMSC secretomes can be exploited for inhibiting cardiotoxic detrimental side effects of Dox during cancer therapy, thus ensuring cardioprotection via combinatorial paracrine therapy in association with standard oncological treatments.

Reactivating endogenous mechanisms of cardiac regeneration via paracrine boosting using the human amniotic fluid stem cell secretome.

BACKGROUND: The adult mammalian heart retains residual regenerative capability via endogenous cardiac progenitor cell (CPC) activation and cardiomyocyte proliferation. We previously reported the paracrine cardioprotective capacity of human amniotic fluid-derived stem cells (hAFS) following ischemia or cardiotoxicity. Here we analyse the potential of hAFS secretome fractions for cardiac regeneration and future clinical translation. METHODS: hAFS were isolated from amniotic fluid leftover samples from prenatal screening. hAFS conditioned medium (hAFS-CM) was obtained following hypoxic preconditioning. Anti-apoptotic, angiogenic and proliferative effects were evaluated on rodent neonatal cardiomyocytes (r/mNVCM), human endothelial colony forming cells (hECFC) and human CPC. Mice undergoing myocardial infarction (MI) were treated with hAFS-CM, hAFS-extracellular vesicles (hAFS-EV), or EV-depleted hAFS-CM (hAFS-DM) by single intra-myocardial administration and evaluated in the short and long term. RESULTS: hAFS-CM improved mNVCM survival under oxidative and hypoxic damage, induced Ca2+-dependent angiogenesis in hECFC and triggered hCPC and rNVCM proliferation. hAFS-CM treatment after MI counteracted scarring, supported cardiac function, angiogenesis and cardiomyocyte cell cycle progression in the long term. hAFS-DM had no effect. hAFS-CM and hAFS-EV equally induced epicardium WT1+ CPC reactivation. Although no CPC cardiovascular differentiation was observed, our data suggests contribution to local angiogenesis by paracrine modulation. hAFS-EV alone were able to recapitulate all the beneficial effects exerted by hAFS-CM, except for stimulation of vessel formation. CONCLUSIONS: hAFS-CM and hAFS-EV can improve cardiac repair and trigger cardiac regeneration via paracrine modulation of endogenous mechanisms. While both formulations are effective in sustaining myocardial renewal, hAFS-CM retains higher pro-angiogenic potential, while hAFS-EV particularly enhances cardiac function.

Fetal surgery: an overview.

In utero fetal surgery interventions are currently considered in selected cases of congenital diaphragmatic hernia, cystic pulmonary abnormalities, amniotic band sequence, selected congenital heart abnormalities, myelomeningocele, sacrococcygeal teratoma, obstructive uropathy, and complications of twin pregnancy. Randomized controlled trials have demonstrated an advantage for open fetal surgery of myelomeningocele and for fetoscopic selective laser coagulation of placental vessels in twin-to-twin transfusion syndrome. The evidence for other fetal surgery interventions, such as tracheal occlusion in congenital diaphragmatic hernia, excision of lung lesions, fetal balloon cardiac valvuloplasty, and vesicoamniotic shunting for obstructive uropathy, is more limited. Conditions amenable to intrauterine surgical treatment are rare; the mother may consider termination of pregnancy as an option for many of them; treatment can be lifesaving but in itself carries risks to both the infant (preterm premature rupture of the membranes, preterm delivery) and the mother. This makes conducting prospective or randomized trials difficult and explains the relative lack of good-quality evidence in this field. Moreover, there is scanty information on long-term outcomes. It is recommended that fetal surgery procedures be performed in centers with extensive facilities and expertise. The aims of this review were to describe the main fetal surgery procedures and their evidence-based results and to provide generalist obstetricians with an overview of current indications for fetal surgery.

Maternal periconceptional factors affect the risk of spina bifida-affected pregnancies: an Italian case-control study.

PURPOSE: Neural tube defects, including spina bifida and anencephaly, are the second most common birth defects with an incidence in Italy of 0.4-1/1,000. Information on factors playing a role in the pathogenesis of spina bifida is based on populations with different exposures, lifestyle, social and cultural habits compared to Italian people. Our objective was to fill this gap by using data from a case-control interview study carried out at the G. Gaslini Children's Hospital, Genoa, from 2000 to 2008. METHODS: We surveyed questionnaires from 133 case mothers and 273 control women providing information on periconceptional risk factors. Univariate and multivariate logistic regression analyses were used to estimate risks by odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: Univariate results suggest that birth order, low maternal educational level, age, smoking habits, alcohol consumption, high caffeine intake, lack of folate supplementation, low and high calorie diet, occasional consumption of fruit and vegetables, high emotional stress, and environmental pollution are associated with an increased spina bifida risk. Nevertheless, high caffeine intake (OR = 10.82; 95% CI, 3.78-31), low calorie diet (OR = 5.15; 95%CI, 1.79-14), occasional consumption of fruit and vegetables (OR = 3.38; 95% CI, 1.67-6.82), alcohol consumption (OR = 3.05; 95% CI, 1.24-7.50) and, above all, lack of folate supplementation at any time of pregnancy (OR = 20.54; 95% CI, 5.41-77) mainly determined spina bifida risk in the multivariate analysis. CONCLUSION: Our findings point out that a common underlying mechanism, a disturbed folate/homocysteine metabolism, may be causative for the burden of spina bifida in the Italian population.

Association between birth weight and first-trimester free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A.

STUDY OBJECTIVE: To assess the relationship between first-trimester maternal serum PAPP-A and free beta-hCG and birth weight. DESIGN: Observational study. SETTING: Teaching hospital. PATIENT(S): Singleton pregnancies (n = 1,630) at 10-14 weeks of gestation. INTERVENTION(S): Fluorimetric immunoassays for maternal serum pregnancy-associated plasma protein A (PAPP-A) and free beta-hCG. MAIN OUTCOME MEASURE(S): Customized birth weight percentiles, calculated taking into account maternal height, weight, ethnic origin, parity, smoking status, and fetal gender. RESULT(S): There was a significant positive correlation between birth weight and PAPP-A, but not free beta-hCG levels. Maternal serum levels of PAPP-A were significantly lower in small-for-gestation (SGA) newborns than in control subjects and were significantly higher in large-for-gestation (LGA) newborns than in control subjects. Maternal serum free beta-hCG levels were lower in pregnancies complicated by pre-eclampsia than in normotensive ones. Multivariable analysis found PAPP-A to be an independent predictor of absolute birth weight, SGA, and LGA. Free beta-hCG was found to be an independent predictor of gestational hypertension and pre-eclampsia. Neither of the two markers was associated with preterm delivery. CONCLUSION(S): Maternal serum PAPP-A levels in the late first trimester of pregnancy are associated with subsequent fetal growth (including both physiologic variation and abnormal growth), and decreased free beta-hCG is more predictive of hypertensive disorders of pregnancy.

Correlation between first-trimester uterine artery Doppler indices and maternal serum free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A.

OBJECTIVE: To assess the correlation between first-trimester uterine artery Doppler measurements and maternal serum levels of free beta-hCG and pregnancy-associated plasma protein A (PAPP-A). DESIGN: Observational study. SETTING: Teaching hospital. PATIENT(S): Four hundred thirty-three women at 10-14 weeks of gestation. INTERVENTION(S): Doppler ultrasound of the uterine arteries. Fluorimetric immunoassays for free beta-hCG and PAPP-A. MAIN OUTCOME MEASURE(S): Uterine artery mean resistance index (RI), pulsatility index (PI), and number of early diastolic notches. Maternal serum levels of free beta-hCG and PAPP-A. RESULT(S): There were 401 uncomplicated pregnancies. In this group, free beta-hCG and PAPP-A did not significantly correlate with uterine artery RI or PI (r values between -0.089 and 0.029, all nonsignificant). Free beta-hCG and PAPP-A levels did not significantly change with the number of notches. Uterine artery resistance and PAPP-A levels were independently correlated with birth weight. CONCLUSION(S): Preliminary evidence suggests that first-trimester uterine artery Doppler measurements do not correlate with maternal serum levels of free beta-hCG and PAPP-A. This may allow their combined use in multivariate screening for pregnancy complications.

Early vaginal bleeding and first-trimester markers for Down syndrome.

OBJECTIVES: To assess the effect of early vaginal bleeding on first-trimester markers for Down syndrome. METHODS: A retrospective study was conducted on 2330 normal singleton fetuses who underwent first-trimester combined screening for Down syndrome based on ultrasound and maternal serum markers. Fetal nuchal translucency (NT), maternal serum pregnancy-associated plasma protein A (PAPP-A), free beta-hCG and the false-positive rate of the test were compared between pregnancies with (n = 253) and without (n = 2077) a history of early vaginal bleeding. RESULTS: The mean +/- SD log(10) MoM for NT, PAPP-A and free beta-hCG was -0.024 +/- 0.101, 0.007 +/- 0.244, 0.047 +/- 0.273 and -0.011 +/- 0.108, -0.006 +/- 0.223, 0.008 +/- 0.264 in pregnancies with and without a history of early vaginal bleeding, with a p value of 0.07, 0.40 and 0.03 respectively. The false-positive rate was 2.4% and 3.6% (p = 0.33). CONCLUSIONS: An earlier episode of vaginal bleeding is associated with an increase in maternal serum free beta-hCG levels at first-trimester combined screening for Down syndrome. However, this phenomenon is unlikely to significantly affect the false-positive rate of the test.