Diversity, Stability, Recursivity, and Rule Generation in Biological System: Intra-inter Dynamics Approach

Basic problems for the construction of a scenario for the Life are discussed. To study the problems in terms of dynamical systems theory, a scheme of intra-inter dynamics is presented. It consists of internal dynamics of a unit, interaction among the units, and the dynamics to change the dynamics itself, for example by replication (and death) of units according to their internal states. Applying the dynamics to cell differentiation, isologous diversification theory is proposed. According to it, orbital instability leads to diversified cell behaviors first. At the next stage, several cell types are formed, first triggered by clustering of oscillations, and then as attracting states of internal dynamics stabilized by the cell-to-cell interaction. At the third stage, the differentiation is determined as a recursive state by cell division. At the last stage, hierarchical differentiation proceeds, with the emergence of stochastic rule for the differentiation to sub-groups, where regulation of the probability for the differentiation provides the diversity and stability of cell society. Relevance of the theory to cell biology is discussed.Comment: 19 pages, Int.J. Mod. Phes. B (in press

Evidence for an interplay between cell cycle progression and the initiation of differentiation between life cycle forms of African trypanosomes

Successful transmission of the African trypanosome between the mammalian host blood-stream and the tsetse fly vector involves dramatic alterations in the parasite's morphology and biochemistry. This differentiation through to the tsetse midgut procyclic form is accompanied by re-entry into a proliferative cell cycle. Using a synchronous differentiation model and a variety of markers diagnostic for progress through both differentiation and the cell cycle, we have investigated the interplay between these two processes. Our results implicate a relationship between the trypanosome cell cycle position and the perception of the differentiation signal and demonstrate that irreversible commitment to the differentiation occurs rapidly after induction. Furthermore, we show that re-entry into the cell cycle in the differentiating population is synchronous, and that once initiated, progress through the differentiation pathway can be uncoupled from progress through the cell cycle

The identification of markers of macrophage differentiation in PMA-stimulated THP-1 Cells and monocyte-derived macrophages

Differentiated macrophages are the resident tissue phagocytes and sentinel cells of the innate immune response. The phenotype of mature tissue macrophages represents the composite of environmental and differentiation-dependent imprinting. Phorbol-12-myristate-13-acetate (PMA) and 1,25-dihydroxyvitamin D3 (VD3) are stimuli commonly used to induce macrophage differentiation in monocytic cell lines but the extent of differentiation in comparison to primary tissue macrophages is unclear. We have compared the phenotype of the promonocytic THP-1 cell line after various protocols of differentiation utilising VD3 and PMA in comparison to primary human monocytes or monocyte-derived macrophages (MDM). Both stimuli induced changes in cell morphology indicative of differentiation but neither showed differentiation comparable to MDM. In contrast, PMA treatment followed by 5 days resting in culture without PMA (PMAr) increased cytoplasmic to nuclear ratio, increased mitochondrial and lysosomal numbers and altered differentiation-dependent cell surface markers in a pattern similar to MDM. Moreover, PMAr cells showed relative resistance to apoptotic stimuli and maintained levels of the differentiation-dependent anti-apoptotic protein Mcl-1 similar to MDM. PMAr cells retained a high phagocytic capacity for latex beads, and expressed a cytokine profile that resembled MDM in response to TLR ligands, in particular with marked TLR2 responses. Moreover, both MDM and PMAr retained marked plasticity to stimulus-directed polarization. These findings suggest a modified PMA differentiation protocol can enhance macrophage differentiation of THP-1 cells and identify increased numbers of mitochondria and lysosomes, resistance to apoptosis and the potency of TLR2 responses as important discriminators of the level of macrophage differentiation for transformed cells

Multi-scale engineering for neuronal cell growth and differentiation

In this paper we investigate the role of micropatterning and molecular coating for cell culture and differentiation of neuronal cells (Neuro2a cell line) on a polydimethylsiloxane substrate. We investigate arrays of micrometric grooves (line and space) capable to guide neurite along their axis. We demonstrate that pattern dimensions play a major role due to the deformation of the cell occasioned by grooves narrower than typical cell dimension. A technological compromise for optimizing cell density, differentiation rate and neurite alignment has been obtained for 20 lm wide grooves which is a dimension comparable with the average cell dimension. This topographical engineered pattern combined with double-wall carbon nanotubes coating enabled us to obtain adherent cell densities in the order of 104 cells/cm2 and a differentiation rate close to 100%

Proliferation tracing with single-cell mass cytometry optimizes generation of stem cell memory-like T cells.

Selective differentiation of naive T cells into multipotent T cells is of great interest clinically for the generation of cell-based cancer immunotherapies. Cellular differentiation depends crucially on division state and time. Here we adapt a dye dilution assay for tracking cell proliferative history through mass cytometry and uncouple division, time and regulatory protein expression in single naive human T cells during their activation and expansion in a complex ex vivo milieu. Using 23 markers, we defined groups of proteins controlled predominantly by division state or time and found that undivided cells account for the majority of phenotypic diversity. We next built a map of cell state changes during naive T-cell expansion. By examining cell signaling on this map, we rationally selected ibrutinib, a BTK and ITK inhibitor, and administered it before T cell activation to direct differentiation toward a T stem cell memory (TSCM)-like phenotype. This method for tracing cell fate across division states and time can be broadly applied for directing cellular differentiation

Cell cycle length, cell size, and proliferation rate in hydra stem cells

We have analyzed the cell cycle parameters of interstitial cells in Hydra oligactis. Three subpopulations of cells with short, medium, and long cell cycles were identified. Short-cycle cells are stem cells; medium-cycle cells are precursors to nematocyte differentiation; long-cycle cells are precursors to gamete differentiation. We have also determined the effect of different cell densities on the population doubling time, cell cycle length, and cell size of interstitial cells. Our results indicate that decreasing the interstitial cell density from 0.35 to 0.1 interstitial cells/epithelial cell (1) shortens the population doubling time from 4 to 1.8 days, (2) increases the [3H]thymidine labeling index from 0.5 to 0.75 and shifts the nuclear DNA distribution from G2 to S phase cells, and (3) decreases the length of G2 in stem cells from 6 to 3 hr. The shortened cell cycle is correlated with a significant decrease in the size of interstitial stem cells. Coincident with the shortened cell cycle and increased growth rate there is an increase in stem cell self-renewal and a decrease in stem cell differentiation