Development of a Culture Sub‐population Induction Model: Signaling Pathways Synergy and Taxanes Production by Taxuscanadensis

Abstract

Cell cultures of Taxus canadensis were subjected to exogenously applied ethylene (ET) hormone and methyl jasmonate (MJ) elicitation in factorial design experiments. Levels of extracellular taxanes, including paclitaxel, were used with principal component analysis for fault detection and real-coded genetic algorithms for parameter optimization to construct a culture sub-population induction model. Culture sub-populations were identified by the model as (1) uninduced, (2) induced to unilateral function of the ET-signaling pathway, and (3) induced to cooperation between jasmonic acid (JA)- and ET-signaling pathways. Comprehensive model results suggested greater rates of cellular induction (resulting in exogenous taxane production) by ET gas as opposed to MJ elicitation. However, cellular induction of ET-signaling pathway genes increased the rate of induction of JA-signaling pathway genes by orders of magnitude. In addition, model results showed that induction of genes leading to extracellular production of the simple taxane 10-deacetylbaccatin III was regulated by the unilateral ET-signaling pathway. However, it was suggested that further processing of this simple taxane to complex taxane structures, such as paclitaxel, required further gene induction by the JA-signaling pathway. Thus, production rate constants of exogenous complex taxanes were predicted to be an order of magnitude lower than that for the simple taxane 10-deacetylbaccatin III. The fraction of the cell culture sub-population displaying unilateral ET-signaling pathway gene induction was found inversely proportional to levels of MJ elicitation. When coupled with simple non-growth product models, levels of all extracellular taxanes were effectively predicted using the culture sub-population induction model.

Genome‐scale model for Clostridium acetobutylicum: Part II. Development of specific proton flux states and numerically determined sub‐systems

“…We refer to this procedure as testing the trained model. Details of the genetic algorithm parameters applied here have been published (Senger et al, 2006).…”

Effect of Methyl Jasmonate on the Growth and Biosynthesis of C13- and C14-Hydroxylated Taxoids in the Cell Culture of Yew (Taxus wallichiana Zucc.) of Different Ages

“…MeJ has been used for the elicitation of yew cell cultures since the 1990s [ 4 , 15 , 16 ]. However, there is evidence that the MeJ effect may be species- and even genotype-specific and vary depending on cell immobilization and culture conditions, possibly due to a cross-talk between MeJ and other signaling pathways [ 17 , 18 , 19 ].…”

Pharmaceutically Active Natural Product Synthesis and Supply via Plant Cell Culture Technology

“…For instance, differences in bulk anthocyanin production in C. roseus cultures were primarily dependent on the percentage of producer cells rather than the production level of each cell, determined by visual identification of the colored pigment, and similar findings were reported regarding paclitaxel accumulation in Taxus cultures using flow cytometry . To predict the effect of different elictors on taxane accumulation, a subpopulation induction model was developed based on the assumption that only certain subpopulations would be stimulated by two different elicitors (methyl jasmonate and ethylene); combined with enzyme kinetics-derived relationships to describe the production rate of paclitaxel and other intermediate taxanes, the model accurately predicted trends of metabolite accumulation under specified elicitation conditions . As subpopulation dynamics have been shown to exert considerable influence on culture behavior as a whole, understanding the basis of these subpopulations is key.…”