Wnt inhibition promotes vascular specification of embryonic cardiac progenitors.

Several studies have demonstrated a multiphasic role for Wnt signaling during embryonic cardiogenesis and developed protocols that enrich for cardiac derivatives during in vitro differentiation of human pluripotent stem cells (hPSCs). However, few studies have investigated the role of Wnt signaling in the specification of cardiac progenitor cells (CPCs) toward downstream fates. Using transgenic mice and hPSCs, we tracked endothelial cells (ECs) that originated from CPCs expressing NKX2.5. Analysis of EC-fated CPCs at discrete phenotypic milestones during hPSC differentiation identified reduced Wnt activity as a hallmark of EC specification, and the enforced activation or inhibition of Wnt reduced or increased, respectively, the degree of vascular commitment within the CPC population during both hPSC differentiation and mouse embryogenesis. Wnt5a, which has been shown to exert an inhibitory influence on Wnt signaling during cardiac development, was dynamically expressed during vascular commitment of hPSC-derived CPCs, and ectopic Wnt5a promoted vascular specification of hPSC-derived and mouse embryonic CPCs.

Diminished ovarian reserve is the predominant risk factor for gonadotropin-releasing hormone antagonist failure resulting in breakthrough luteinizing hormone surges in in vitro fertilization cycles.

OBJECTIVE: To identify risk factors for breakthrough LH surge despite GnRH antagonist (GnRH-ant) suppression in IVF cycles. DESIGN: Case-control study. SETTING: Academic medical center. PATIENT(S): All patients undergoing IVF from August 2004 through July 2012 in whom GnRH-ant pituitary suppression (0.25 mg/d) was used in a flexible protocol. INTERVENTION(S): GnRH-ant-based IVF. MAIN OUTCOME MEASURE(S): Breakthrough LH surges as evidenced by an increase in LH (minimum 2.5-fold increase from baseline above a threshold of 17 mIU/mL) associated with a decrease in E2, and free fluid on ultrasound. RESULT(S): Breakthrough LH surges despite GnRH-ant administration occurred in 37 (0.34%) of the 10,809 antagonist cycles during the study period. Compared with all patients remaining suppressed, patients with breakthrough surges were significantly older and had significantly increased FSH and decreased antral follicle counts. Compared with age-matched controls (allocation ratio, 1:50), significant differences in ovarian reserve remained evident. CONCLUSION(S): The occurrence of a breakthrough LH surge despite GnRH-ant treatment is a reassuringly rare event. However, patients with diminished ovarian reserve are at risk for this outcome despite GnRH-ant down-regulation. Further studies are needed to determine whether these patients can be prospectively identified and whether they may benefit from higher doses of GnRH-ant.