New insights into mammalian signaling pathways using microfluidic pulsatile inputs and mathematical modeling

Abstract

Temporally modulated input mimics physiology. This chemical communication strategy filters the biochemical noise through entrainment and phase-locking. Under laboratory conditions, it also expands the observability space for downstream responses. A combined approach involving microfluidic pulsatile stimulation and mathematical modeling has led to deciphering of hidden/unknown temporal motifs in several mammalian signaling pathways and has provided mechanistic insights, including how these motifs combine to form distinct band-pass filters and govern fate regulation under dynamic microenvironment. This approach can be utilized to understand signaling circuit architectures and to gain mechanistic insights for several other signaling systems. Potential applications include synthetic biology and biotechnology, in developing pharmaceutical interventions, and in developing lab-on-chip models.

System Identification Using Compressed Sensing Reveals Signaling-Decoding System by Gene Expression

“…Recently, fluorescence resonance energy transfer probes, optogenetics, and microfluidic devices have been developed to achieve observation and time control of ERK phosphorylation temporal patterns. These methods allow us to focus on quantitative relationships between various ERK phosphorylation temporal patterns and phenotypes such as cell differentiation (Albeck et al, 2013; Aoki et al, 2013; Doupé and Perrimon, 2014; Ryu et al, 2015; Sumit et al, 2017; Toettcher et al, 2013; Zhang et al, 2014). Although the relationship between signal transduction and phenotype has been extensively studied, it remains unclear how the signaling molecules quantitatively regulate the downstream gene expressions over a longer time scale, leading to cell fate decisions.…”

“…Thus, how the distinct patterns of signaling molecules are decoded by LP gene expression is critical for understanding the unknown mechanism underlying cell differentiation in PC12 cells. Decoding the combinations and temporal patterns of signaling molecules by downstream gene expression is a general mechanism underlying various cellular functions (Behar and Hoffmann, 2010; Purvis and Lahav, 2013; Sumit et al, 2017).…”

PiFlow: A Biocompatible Low-Cost Programmable Dynamic Flow Pumping System Utilizing a Raspberry Pi Zero and Commercial Piezoelectric Pumps

“…The ability to create dynamic flow waveforms has been crucial in many in vitro physiological studies such as those investigating effects of blood [36][37][38] and lymphatic shear stress 39,40 . Several systems have recently demonstrated the ability to control flow dynamically or through valving techniques to create temporal concentration profiles 18,[41][42][43][44][45][46][47][48] . While each of them is powerful for certain applications, we believe that the flexibility MICCS provides allows researchers to more easily accomplish such tasks.…”

Gene expression patterns in synchronized islet populations

“…It has been shown in multiple cells types that the frequency, amplitude, and phase of [Ca 2+ ]i oscillations offers specificity and robustness to signal transduction pathways. [21][22][23][24][25][26] Some of the functions encoded by [Ca 2+ ]i signatures include cellular proliferation and differentiation, morphogenesis, contraction, and secretion. 23 Moreover, expression levels of several genes were found to be dependent on the oscillation frequency of [Ca 2+ ]i .…”

“…23 Moreover, expression levels of several genes were found to be dependent on the oscillation frequency of [Ca 2+ ]i . 24,26 In one study performed with T-cells, oscillations in [Ca 2+ ]i activated NFAT and NF-kB more efficiently than a constant [Ca 2+ ]i level. 27,28 In another study with B-lymphocytes, the activation of NFAT was highest when only select values of [Ca 2+ ]i oscillation frequencies were present.…”