Glucocorticoids promote neural progenitor cell proliferation derived from human induced pluripotent stem cells

Abstract

Glucocorticoids (GCs) are frequently used for treating and preventing chronic lung disease and circulatory dysfunction in premature infants. However, there is growing concern about the detrimental effects of systemic GC administration on neurodevelopment. The first choice of GCs to minimize the adverse effects on the developing brain is still under debate. We investigated the effect of commonly used GCs such as dexamethasone (DEX), betamethasone (BET) and hydrocortisone (HDC) on the proliferation of human-induced pluripotent stem cell (iPSC)-derived neuronal progenitor cells (NPCs). In this study, NPCs were treated with various concentrations of GCs and subjected to cell proliferation assays. Furthermore, we quantified the number of microtubule-associated protein 2 (MAP2) positive neurons in NPCs by immunostaining. All GCs promoted NPC proliferation in a dose-dependent manner. We also confirmed that MAP2-positive neurons in NPCs increased upon GC treatment. However, differential effects of GCs on MAP2 positive neurons were observed when we treated NPCs with H2O2. The total numbers of NPCs increased upon any GC treatment even under oxidative conditions but the numbers of MAP2 positive neurons increased only by HDC treatment. GCs promoted human iPSCs–derived NPC proliferation and the differential effects of GCs became apparent under oxidative stress. Our results may support HDC as the preferred choice over DEX and BET to prevent adverse effects on the developing human brain.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-3-527) contains supplementary material, which is available to authorized users.

Effects of antenatal glucocorticoids on the developing brain

“…The timing of neurogenesis and gliogenesis are tightly controlled and regulated such that neurogenesis occurs before birth in humans, followed by the subsequent formation of oligodendrocytes and astrocytes 48–52 . Human and mice NSPCs express GR from early developmental stages and have been shown to respond to GC stimulation in-vitro indicating that the developing brain is poised to respond to premature GC administration and activate downstream signaling 33,53 . Since GCs have been shown to have anti-proliferative effects on NSPCs 51,54 , GC exposure is likely to have effects on neurogenesis and gliogenesis.…”

Human Codon Usage: The Genetic Basis of Pathogen Latency

“…In this experimentally validated perspective, it assumes a crucial importance the fact that pathogen (re)activation is mostly associated with immunosuppressive treatments, 70 71 72 73 74 75 76 77 that is, with treatments that in general implicate administration of glucocorticoids. As a matter of fact, it is well known that glucocorticosteroids can induce cell proliferation 78 79 80 81 82 83 84 85 86 87 88 89 90 91 so that, consequently, it can induce proliferation-associated tRNA changes and favor pathogen protein expression and (re)activation. Therefore, in a clinical context, the present study might also help understand the pathogen (re)activation phenomenon in infected fetuses and newborns (i.e., in organisms growing rapidly) 7 and pregnancy, 17 as well as in subjects treated with glucocorticoids following, for example, transplant procedures.…”

Modeling gene x environment interactions in PTSD using glucocorticoid-induced transcriptomics in human neurons

“…Even here, the biological relevance is high, as increased glucocorticoid signaling during fetal development has been linked to psychiatric disorders 37,38 . Towards this, glucocorticoid treatment increases the proliferation of hiPSC-derived neural progenitor cells 39 , and impairs neuronal differentiation and maturation in hiPSC-derived neurons 15,40 and primary mouse neurons 41 . It follows from these observations that if hiPSC-derived neurons represent a fetal-like pre-trauma state, then patient-derived PBMCs represent an adult state, post-trauma and disease onset.…”