Extremely preterm born individuals at < 28 postconceptional weeks (PCW) are at high risk for encephalopathy of prematurity and life-long neuropsychiatric conditions. Clinical studies and animal models of preterm brain injury suggest that encephalopathy of prematurity is strongly associated with exposure to hypoxia and/or inflammation in the perinatal period. Histologic examination of postmortem brain tissue from children born preterm demonstrates decreased numbers of cortical GABA-ergic interneurons in the cerebral cortex. However, the cellular and molecular mechanisms underlying the decreased numbers of GABA-ergic interneurons in the cerebral cortex of extremely preterm individuals remain unclear. Here, we developed a dual, complementary human cellular model to study hypoxia-induced interneuronopathies using human forebrain assembloids (hFA) derived from human induced pluripotent stem cells (hiPSCs) and ex vivo human prenatal cerebral cortex at mid-gestation. The hFA are generated through the integration of region-specific neural organoids containing either dorsal forebrain (excitatory) glutamatergic neurons or ventral forebrain (inhibitory) GABA-ergic interneurons. We discover a substantial reduction in migration of cortical interneurons during exposure to hypoxic stress in both hFA and ex vivo human prenatal cerebral cortex. Next, we identify that this migration defect is restored by supplementation of hypoxic cell culture media with exogenous adrenomedullin (ADM), a peptide hormone member of the calcitonin gene related peptide (CGRP) family. Lastly, we demonstrate that the rescue is mediated through increased activity of the PKA molecular pathway and increased pCREB-dependent expression of GABA receptors. Overall, these findings provide important insights into the cellular mechanisms possibly contributing to cortical interneuron depletion in preterm infants, and pinpoint novel therapeutic molecular pathways with translational potential for hypoxic encephalopathy of prematurity.
Gastrointestinal (GI) maturation is a key determinant of survival for extremely preterm infants. The enteric nervous system (ENS) controls GI motility, and immature GI motility limits enteral feeding and causes severe health complications.1 Due to the significant challenges in obtaining and studying human fetal tissue, little is known about when the human ENS becomes mature enough to carry out vital functions. Here we define the progressive anatomical maturation of the human fetal ENS and analyze GI motility in the second trimester of in utero development. We identify substantial structural changes in the ENS including the emergence of striped neuronal cytoarchitecture and a shift in the representation of excitatory and inhibitory neurons. We further analyze and pharmacologically manipulate GI motility in freshly collected human fetal intestines, which, to our knowledge, is a first functional analysis of intact human fetal organs ex vivo. We find that the ENS influences GI motility beginning at 21 postconceptional weeks (PCW), the earliest reported evidence of neurogenic GI motility. Our study provides unprecedented insight into human fetal ENS development, foundational knowledge which facilitates comparisons with common animal models to advance translational disease investigations and testing of pharmacological agents to enhance GI motility in prematurity.
Immature gastrointestinal motility impedes preterm infant survival. The enteric nervous system controls gastrointestinal motility, yet it is unknown when the human enteric nervous system matures enough to carry out vital functions. Here we demonstrate that the second trimester human fetal enteric nervous system takes on a striped organization akin to the embryonic mouse. Further, we perform ex vivo functional assays of human fetal tissue and find that human fetal gastrointestinal motility matures in a similar progression to embryonic mouse gastrointestinal motility. Together, this provides critical knowledge, which facilitates comparisons with common animal models to advance translational disease investigations and testing of pharmacological agents to enhance gastrointestinal motility in prematurity.
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