Instructional materials that control cellular activity through synthetic Notch receptors.

The field of regenerative engineering relies primarily on the dual technical platforms of cell selection/conditioning and biomaterial fabrication to support directed cell differentiation. As the field has matured, an appreciation for the influence of biomaterials on cell behaviors has resulted in engineered matrices that meet biomechanical and biochemical demands of target pathologies. Yet, despite advances in methods to produce designer matrices, regenerative engineers remain unable to reliably orchestrate behaviors of therapeutic cells in situ. Here, we present a platform named MATRIX whereby cellular responses to biomaterials can be custom defined by combining engineered materials with cells expressing cognate synthetic biology control modules. Such privileged channels of material-to-cell communication can activate synthetic Notch receptors and govern activities as diverse as transcriptome engineering, inflammation attenuation, and pluripotent stem cell differentiation, all in response to materials decorated with otherwise bioinert ligands. Further, we show that engineered cellular behaviors are confined to programmed biomaterial surfaces, highlighting the potential to use this platform to spatially organize cellular responses to bulk, soluble factors. This integrated approach of co-engineering cells and biomaterials for orthogonal interactions opens new avenues for reproducible control of cell-based therapies and tissue replacements.

Perinatal vs genetic programming of serotonin states associated with anxiety.

Large numbers of women undergo antidepressant treatment during pregnancy; however, long-term consequences for their offspring remain largely unknown. Rodents exposed to serotonin transporter (SERT)-inhibiting antidepressants during development show changes in adult emotion-like behavior. These changes have been equated with behavioral alterations arising from genetic reductions in SERT. Both models are highly relevant to humans yet they vary in their time frames of SERT disruption. We find that anxiety-related behavior and, importantly, underlying serotonin neurotransmission diverge between the two models. In mice, constitutive loss of SERT causes life-long increases in anxiety-related behavior and hyperserotonemia. Conversely, early exposure to the antidepressant escitalopram (ESC; Lexapro) results in decreased anxiety-related behavior beginning in adolescence, which is associated with adult serotonin system hypofunction in the ventral hippocampus. Adult behavioral changes resulting from early fluoxetine (Prozac) exposure were different from those of ESC and, although somewhat similar to SERT deficiency, were not associated with changes in hippocampal serotonin transmission in late adulthood. These findings reveal dissimilarities in adult behavior and neurotransmission arising from developmental exposure to different widely prescribed antidepressants that are not recapitulated by genetic SERT insufficiency. Moreover, they support a pivotal role for serotonergic modulation of anxiety-related behavior.