Cell-intrinsic Processes Research Articles

DNA Damage-Mediated Induction of a Chemoresistant Niche

While numerous cell-intrinsic processes are known to play decisive roles in chemotherapeutic response, relatively little is known about the impact of the tumor microenvironment on therapeutic outcome. Here, we use a well-established mouse model of Burkitt's lymphoma to show that paracrine factors in the tumor microenvironment modulate lymphoma cell survival following the administration of genotoxic chemotherapy. Specifically, IL-6 and Timp-1 are released in the thymus in response to DNA damage, creating a "chemo-resistant niche" that promotes the survival of a minimal residual tumor burden and serves as a reservoir for eventual tumor relapse. Notably, IL-6 is released acutely from thymic endothelial cells in a p38-dependent manner following genotoxic stress, and this acute secretory response precedes the gradual induction of senescence in tumor-associated stromal cells. Thus, conventional chemotherapies can induce tumor regression while simultaneously eliciting stress responses that protect subsets of tumor cells in select anatomical locations from drug action.

Molecular and Cellular Control of Dendrite Maturation During Brain Development

Neuronal dendrites are generated during development by a series of processes involving extension and retraction of dendritic branches in a first step, and subsequently stabilisation of existing dendrites through building of synaptic connections. These processes are tightly controlled at any of these time points and control of dendritic development follows individual differentiation stages. This review describes aspects of the maturation process in cerebellar Purkinje cells and spinal motoneurons. Although motoneurons are glutamatergic whereas Purkinje cells are GABAergic and thereby functionally very different, dendritic maturation processes appear to share common mechanisms and processes in both neuronal cell types. Genetically-regulated cell-intrinsic processes control dendritic outgrowth at an early stage, being thereafter supported by local growth factors. In contrast, increasing synaptic input promotes dendritic maturation by limiting overgrowth at a later stage, with Ca2+-dependent signalling involving PKC or CaMKII as the common mode of action. This series of events apparently is common for other neuronal cell types suggesting a generalised concept for intercellular control of neuronal connectivity.

Burst firing is a neural code in an insect auditory system

Various classes of neurons alternate between high-frequency discharges and silent intervals. This phenomenon is called burst firing. To analyze burst activity in an insect system, grasshopper auditory receptor neurons were recorded in vivo for several distinct stimulus types. The experimental data show that both burst probability and burst characteristics are strongly influenced by temporal modulations of the acoustic stimulus. The tendency to burst, hence, is not only determined by cell-intrinsic processes, but also by their interaction with the stimulus time course. We study this interaction quantitatively and observe that bursts containing a certain number of spikes occur shortly after stimulus deflections of specific intensity and duration. Our findings suggest a sparse neural code where information about the stimulus is represented by the number of spikes per burst, irrespective of the detailed interspike-interval structure within a burst. This compact representation cannot be interpreted as a firing-rate code. An information-theoretical analysis reveals that the number of spikes per burst reliably conveys information about the amplitude and duration of sound transients, whereas their time of occurrence is reflected by the burst onset time. The investigated neurons encode almost half of the total transmitted information in burst activity.

Peroxiredoxin II functions as a signal terminator for H2O2‐activated phospholipase D1

Phospholipase D1 (PLD1) is a signal-transduction regulated enzyme which regulates several cell intrinsic processes including activation of NAPDH oxidase, which elevates intracellular H2O2. Several proteins have been reported to interact with PLD1 in resting cells. We sought to identify proteins that interact with PLD1 after phorbol 12-myristate 13-acetate (PMA) stimulation. A novel interaction with peroxiredoxin II (PrxII), an enzyme that eliminates cellular H2O2, which is a known stimulator of PLD1, was identified by PLD1-affinity pull-down and MS. PMA stimulation was confirmed to promote physical interaction between PLD1 and PrxII and to cause PLD1 and PrxII to colocalize subcellularly. Functional significance of the interaction was suggested by the observation that over-expression of PrxII specifically reduces the response of PLD1 to stimulation by H2O2. These results indicate that PrxII may have a signal-terminating role for PLD1 by being recruited to sites containing activated PLD1 after cellular stimulation involving production of H2O2.

The biology and engineering of stem-cell control.

There is significant interest in studying stem cells, both to elucidate their basic biological functions during development and adulthood as well as to learn how to utilize them as new sources of specialized cells for tissue repair. Whether the motivation is basic biology or biomedical application, however, progress will hinge upon learning how to better control stem-cell function at a quantitative and molecular level. There are several major challenges within the field, including the identification of new signals and conditions that regulate and influence cell function, and the application of this information towards the design of stem-cell bioprocesses and therapies. Both of these efforts can significantly benefit from the synthesis of biological data into quantitative and increasingly mechanistic models that not only describe, but also predict, how a stem cell's environment can control its fate. This review will briefly summarize the history and current state of the stem-cell biology field, but will then focus on the development of predictive models for stem-cell control. Early models formulated on the assumption that cell fate was decided by stochastic, cell-intrinsic processes have gradually evolved into hybrid deterministic-stochastic models with increasingly finer molecular resolution that accounts for environmental regulation. As our understanding of cellular control mechanisms expands from the cell surface and towards the nucleus, these efforts may culminate in the development of a stem-cell culture programme, or a series of signals to provide to the cells as a function of time to guide them along a desired developmental trajectory.

Leukemia inhibitory factor (LIF) concentration modulates embryonic stem cell self-renewal and differentiation independently of proliferation

A major limitation of the widespread use of stem cells in a variety of biotechnological applications is the relatively low level of knowledge about how to maintain these cells in vitro without losing the long-term multilineage growth properties required for their clinical utility. An experimental and theoretical framework for predicting and controlling the outcome of stem cell stimulation by exogenous cytokines would thus be useful. An emerging theme from recent hematopoietic stem cell (HSC)-expansion studies is that a net gain in HSC numbers requires the maintenance of critical signaling ligand(s) above a threshold level. These ligand-receptor complex thresholds can be maintained, for example, by high concentrations of soluble cytokines or by cytokine presentation on cell surfaces. According to such a model, when the relevant ligand-receptor interaction falls below this threshold level, the probability of a differentiation response is increased; otherwise, self-renewal is favored. Taking advantage of the ability of the cytokine leukemia inhibitory factor (LIF) to maintain embryonic stem (ES) cell pluripotentiality at high concentrations, we are testing this model by investigating critical parameters in the control of ES cell responses. We have developed quantitative assays of ES cell differentiation by measuring cell-surface alkaline phosphatase activity, cell-surface stage specific embryonic antigen (SSEA)-1 expression, and the ability of ES cells to form embryoid bodies. Examination of ES cell responses over a range of LIF concentrations shows that LIF supplementation has little effect on ES cell-growth rate but significantly alters the probability of a cell undergoing a self-renewal vs. a differentiation division. In vitro culture parameters such as inoculum cell density, medium exchange, as well as cell-intrinsic processes such as autocrine secretion are shown to affect this decision. In addition to yielding new information on stem cell regulation by exogenous factors, these studies provide important clues about culture of these cells and should stimulate further investigations into the mechanistic basis of stem cell differentiation control.