Glucocorticoid and hypothermia exposure of neural stem cells during proliferation alters their differentiation potential

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 1-25-Glucocorticoid Actions & HPA Axis
Basic
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-8
Luisa Fernanda Gonzalez*1, Derrick Tint2, Selma Feldman Witchel1, Paula Monaghan-Nichols2 and Donald Benedict DeFranco2
1Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, 2University of Pittsburgh School of Medicine, Pittsburgh, PA
Background: Corrective or palliative surgery with cardiopulmonary bypass (CPB) and hypothermic circulatory arrest are utilized to treat infants with complex congenital heart disease (CHD). Glucocorticoids (GC), typically dexamethasone (Dex) or methylprednisolone (MP), are used to attenuate the ischemic injury and inflammatory responses in infants undergoing CPB (1). With improved survival rate among infants with CHD, greater attention is being directed to the quality of life of survivors. Impaired neurologic development after surgical repair of CHD remains is a major common adverse outcome. Yet, no consistent improvements in long-term neurodevelopmental outcomes have been achieved. Although neurogenesis occurs mainly in utero, peri-operative steroid exposure might protect the CNS or, alternatively, might have deleterious effects on gliogenesis since gliogenesis continues during postnatal human brain development along with the formation of myelin and synapses.  To evaluate the effect of GCs on neuronal development, we developed an in vitro model system of murine cerebral cortical neural stem cells (NSC) that adopt distinct differentiation fates as they mature in culture. The in vivo temporal order of neuron, astrocyte, and oligodendrocyte production is preserved in the neurosphere cultures. 

Results: We have examined the impact of GCs or hypothermia (HT) on cell fate specification, using NSCs exposed to Dex or HT only during their proliferative phase and then withdrawn from hormone or changed to normothermia upon the initiation of differentiation. The number and type of cells produced from each lineage were examined following 5-14 days of differentiation using indirect immunofluorescence to detect markers of neurons (neuron specific class III beta-tubulin) and glia, (glial fibrillary acidic protein). Preliminary results showed that GC treatment during proliferation alters the fate of NSCs leading to enhancement of neurogenesis at a time when untreated cells were mainly adopting a glial identity. Furthermore, Dex alters neurogenic fate as evidenced by the increased production of bipolar neurons and decreased multi-polar neurons generated upon differentiation of early passage progenitors. Hypothermia alone did not lead to these changes in neurogenic fate.

Conclusion: Future studies will include more detailed analysis of GC effects on genes responsible for triggering gliogenesis and examination of hormone effects on NSCs with distinct cell fates.

(1) Graham EM, et al. J Thorac Cardiovasc Surg. 2011;142:1523

Nothing to Disclose: LFG, DT, SFW, PM, DBD

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH Grant RO1 DK078394 to DBD;  NIH Grant T32 DK007729-16