Mutant astrocytes differentiated from Rett syndrome patients-specific iPSCs have adverse effects on wild-type neurons.

The disease mechanism of Rett syndrome (RTT) is not well understood. Studies in RTT mouse models have suggested a non-cell-autonomous role for astrocytes in RTT pathogenesis. However, it is not clear whether this is also true for human RTT astrocytes. To establish an in vitro human RTT model, we previously generated isogenic induced pluripotent stem cell (iPSC) lines from several RTT patients carrying different disease-causing mutations. Here, we show that these RTT iPSC lines can be efficiently differentiated into astroglial progenitors and glial fibrillary acidic protein-expressing (GFAP(+)) astrocytes that maintain isogenic status, that mutant RTT astrocytes carrying three different RTT mutations and their conditioned media have adverse effects on the morphology and function of wild-type neurons and that the glial effect on neuronal morphology is independent of the intrinsic neuronal deficit in mutant neurons. Moreover, we show that both insulin-like growth factor 1 (IGF-1) and GPE (a peptide containing the first 3 amino acids of IGF-1) are able to partially rescue the neuronal deficits caused by mutant RTT astrocytes. Our findings confirm the critical glial contribution to RTT pathology, reveal potential cellular targets of IGF-1 therapy and further validate patient-specific iPSCs and their derivatives as valuable tools to study RTT disease mechanism.

Arm-mounted optical coherence tomography angiography in extremely low birth weight neonates with retinopathy of prematurity.

PURPOSE: To assess the feasibility of imaging extremely low birth weight infants, defined as infants born weighing less than 1000 g or before 27 weeks of gestational age, with an arm-mounted optical coherence tomography angiography (OCTA) device. METHODS: Cross-sectional case series conducted at a single site in-patient academic center. Subjects included infants who had been born premature and met ROP screening criteria. Birth history such as gestational age and birth weight were collected. Subjects were imaged with OCTA in a supine position during ROP screening and treatment. Segmental errors were manually corrected and FAZ area was calculated from the superficial and deep capillary plexus (SCP, DCP) layers. Main outcomes measures were foveal avascular zone (FAZ) area, ROP stage and treatment. RESULTS: Seven ELBW infants were included with an average gestational age of 25 weeks (range = 23-4/7 to 26 weeks) and average postmenstrual age of 54.7 weeks (range = 43-80 weeks) at the time of imaging. Average birth weight was 615 g (range 500-680 grams). Thirteen eyes had ROP treatment including primary laser, anti-vascular endothelial growth factor injection with delayed laser, and scleral buckle. Six infants were imaged under general anesthesia and one infant was imaged without sedation. Average FAZ area was 0.17 mm2 (range = 0.03 mm2-0.37 mm2) in the SCP and 0.04 mm2 (range 0 mm2-0.09 mm2) in the DCP. FAZ area correlated positively to the ratio of outer retinal layer thickness to inner retinal layer thickness at the foveal center in the SCP and DCP (r2 = 0.48, p = 0.02; r2 = 0.46, p = 0.02) and negatively with inner retinal layer thickness in the SCP (r2 = 0.56, p = 0.008). CONCLUSIONS AND IMPORTANCE: Arm-mounted OCTA was feasible in ELBW infants and provided information about the developing fovea. Measurement of FAZ area and retinal thickness using this modality may be used to study the effects of ELBW, peripheral ROP and ROP treatment on foveal development.