Evocation of regrowth phenomena in anuran limbs by electrical stimulation of the nerve supply

Bodemer, Charles W.

doi:10.1002/ar.1091480303

Cited by 22 publications

(8 citation statements)

References 25 publications

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“…By regulation of apoptotic remodeling and downstream activity of genes such as Wnt11 [277], the physiological gradient determines the anatomy of the organs built after injury. In vertebrates, where electric fields were long ago implicated in limb regeneration [278][279][280][281][282][283][284][285], recent experiments showed that driving proton and sodium fluxes can force complete tail [286,287] or limb [288] regeneration in a range of non-regenerative conditions. The mechanisms involve guidance of innervation into the stump, activation of blastema genes such as MSX1, Notch, Delta, BMP2, and BMP4, and induction of cell proliferation in the wound mesenchyme.…”

Section: Spatio-temporal Gradients Of V Mem Are Instructive Cues Mainmentioning

confidence: 99%

Cancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem

Moore

Walker

Levin

2017

Converg. Sci. Phys. Oncol.

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TOPICAL REVIEWCancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem IntroductionCancer is well-recognized not only as an extremely pernicious medical problem, but also as a group of phenomena deeply connected to the fundamental questions of evolution, multicellularity, pattern (disregulation, and the interplay between the genome and the environment [1,2]. Two fundamental paradigms currently divide the field. One is that cancer results from disorders of genetics: cancer cells are fundamentally broken due to genomic mutation or instability, and their clonal progeny form tumors and metastases. This view is sometimes called the SMT, somatic mutation theory [3][4][5]. A competing perspective is that of cancer as a circuit disease-a disorder of the complex biophysical, transcriptional, and epigenetic dynamics that regulate cellular state and the ability of cells to cooperate in vivo [6][7][8]. Under this view (sometimes called the tissue organization field theory or TOFT, [9,10]), cancer is akin to a traffic jam [11]-the problem is not a permanent discrete alteration within a founder cell and all of its clonal descendants, but an undesirable stable attractor in the complex network of controls that normally guides anatomical homeostasis [12].The relative merits of the two models have been discussed extensively [10,[13][14][15][16][17] AbstractThe current paradigm views cancer as arising clonally from a degradation of genetic information in single cells. A complementary perspective, originating at the dawn of modern developmental biology, is that cancer is the result of a system disorder of algorithms that normally orchestrate individual cell activities toward specific anatomical structures and away from tumorigenesis. A view of cancer as a disease of geometry focuses on the pathways that allow cells to cooperate to build and maintain large-scale anatomical patterning. Cancer may result when cells stop maintaining higher-order structures and reduce the boundary of their computational selves to a single-cell level, reverting to a unicellular lifestyle in which the rest of the organism is merely part of the environment at the expense of which all living things survive. While this view has been widely discussed, little progress has been made in providing a quantitative, mechanistic framework within which this perspective's specific and unique implications for treatment strategies can be tested and biomedically exploited. Here, we highlight two recent areas of progress which may facilitate much-needed progress on the cancer problem. First, we review the roles that endogenous bioelectrical networks, operating across many tissues in vivo, play as a medium of information processing in tumor suppression, progression, and reprogramming. Second, we provide a primer to the development of computational theory and tools for quantifying the information and causal control structures in cancer and other complex biological systems. Rigorous mathematical formalisms now exist to...

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Section: Spatio-temporal Gradients Of V Mem Are Instructive Cues Mainmentioning

confidence: 99%

Cancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem

Moore

Walker

Levin

2017

Converg. Sci. Phys. Oncol.

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“…It has long been known that nerve supply is a key factor in regeneration (Bodemer, 1964;Singer, 1952;Thornton, 1956;Yntema, 1959). The observation that neurites are galvanotactic (Hinkle et al, 1981;McCaig, 1986;McCaig et al, 2002;Pullar et al, 2001;Trollinger et al, 2000) and that applied fields induce hyper-innervation of treated limbs led several investigators to hypothesize that regeneration bud currents induce regeneration by attracting migratory neuronal cells (Hanson and McGinnis, 1994;.…”

Section: Research Articlementioning

confidence: 99%

H+ pump-dependent changes in membrane voltage are an early mechanism necessary and sufficient to induceXenopustail regeneration

Adams¹,

Masi²,

Levin³

2007

Development

252

311

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In many systems, ion flows and long-term endogenous voltage gradients regulate patterning events, but molecular details remain mysterious. To establish a mechanistic link between biophysical events and regeneration, we investigated the role of ion transport during Xenopus tail regeneration. We show that activity of the V-ATPase H+ pump is required for regeneration but not wound healing or tail development. The V-ATPase is specifically upregulated in existing wound cells by 6 hours post-amputation. Pharmacological or molecular genetic loss of V-ATPase function and the consequent strong depolarization abrogates regeneration without inducing apoptosis. Uncut tails are normally mostly polarized, with discrete populations of depolarized cells throughout. After amputation, the normal regeneration bud is depolarized, but by 24 hours post-amputation becomes rapidly repolarized by the activity of the V-ATPase, and an island of depolarized cells appears just anterior to the regeneration bud. Tail buds in a non-regenerative `refractory' state instead remain highly depolarized relative to uncut or regenerating tails. Depolarization caused by V-ATPase loss-of-function results in a drastic reduction of cell proliferation in the bud, a profound mispatterning of neural components, and a failure to regenerate. Crucially, induction of H+ flux is sufficient to rescue axonal patterning and tail outgrowth in otherwise non-regenerative conditions. These data provide the first detailed mechanistic synthesis of bioelectrical,molecular and cell-biological events underlying the regeneration of a complex vertebrate structure that includes spinal cord, and suggest a model of the biophysical and molecular steps underlying tail regeneration. Control of H+ flows represents a very important new modality that, together with traditional biochemical approaches, may eventually allow augmentation of regeneration for therapeutic applications.

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“…By regulation of apoptotic remodeling and downstream activity of genes such as Wnt11 [115], the physiological gradient determines the anatomy of the organs built after injury. In vertebrates, where electric fields were long ago implicated in limb regeneration [116–123], recent experiments showed that driving proton and sodium fluxes can initiate complete tail [124,125] or limb [126] regeneration in a range of non-regenerative conditions. The mechanisms involve guidance of innervation into the stump, activation of blastema genes such as MSX1, Notch, Delta, BMP2, and BMP4, and induction of cell proliferation in the wound mesenchyme.…”

Section: Introductionmentioning

confidence: 99%

Endogenous Voltage Potentials and the Microenvironment: Bioelectric Signals that Reveal, Induce and Normalize Cancer

Chernet¹,

Levin²

2014

J Clin Exp Oncol

137

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Cancer may be a disease of geometry: a misregulation of the field of information that orchestrates individual cells’ activities towards normal anatomy. Recent work identified molecular mechanisms underlying a novel system of developmental control: bioelectric gradients. Endogenous spatio-temporal differences in resting potential of non-neural cells provide instructive cues for cell regulation and complex patterning during embryogenesis and regeneration. It is now appreciated that these cues are an important layer of the dysregulation of cell: cell interactions that leads to cancer. Abnormal depolarization of resting potential (Vmem) is a convenient marker for neoplasia and activates a metastatic phenotype in genetically-normal cells in vivo. Moreover, oncogene expression depolarizes cells that form tumor-like structures, but is unable to form tumors if this depolarization is artificially prevented by misexpression of hyperpolarizing ion channels. Vmem triggers metastatic behaviors at considerable distance, mediated by transcriptional and epigenetic effects of electrically-modulated flows of serotonin and butyrate. While in vivo data on voltages in carcinogenesis comes mainly from the amphibian model, unbiased genetic screens and network profiling in rodents and human tissues reveal several ion channel proteins as bona fide oncogene and promising targets for cancer drug development. However, we propose that a focus on specific channel genes is just the tip of the iceberg. Bioelectric state is determined by post-translational gating of ion channels, not only from genetically-specified complements of ion translocators. A better model is a statistical dynamics view of spatial Vmem gradients. Cancer may not originate at the single cell level, since gap junctional coupling results in multi-cellular physiological networks with multiple stable attractors in bioelectrical state space. New medical applications await a detailed understanding of the mechanisms by which organ target morphology stored in real-time patterns of ion flows is perceived or mis-perceived by cells. Mastery of somatic voltage gradients will lead to cancer normalization or rebooting strategies, such as those that occur in regenerating and embryonic organs, resulting in transformative advances in basic biology and oncology.

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Evocation of regrowth phenomena in anuran limbs by electrical stimulation of the nerve supply

Cited by 22 publications

References 25 publications

Cancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem

Cancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem

H+ pump-dependent changes in membrane voltage are an early mechanism necessary and sufficient to induceXenopustail regeneration

Endogenous Voltage Potentials and the Microenvironment: Bioelectric Signals that Reveal, Induce and Normalize Cancer

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