How Does a Single Cell Know When the Liver Has Reached Its Correct Size?
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{"title"=>"How does a single cell know when the liver has reached its correct size?", "type"=>"journal", "authors"=>[{"first_name"=>"Nadine", "last_name"=>"Hohmann", "scopus_author_id"=>"55539417000"}, {"first_name"=>"Wei", "last_name"=>"Weiwei", "scopus_author_id"=>"56115278500"}, {"first_name"=>"Uta", "last_name"=>"Dahmen", "scopus_author_id"=>"55789262800"}, {"first_name"=>"Olaf", "last_name"=>"Dirsch", "scopus_author_id"=>"7004018031"}, {"first_name"=>"Andreas", "last_name"=>"Deutsch", "scopus_author_id"=>"56027087600"}, {"first_name"=>"Anja", "last_name"=>"Voss-Böhme", "scopus_author_id"=>"37049505100"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"24690888", "doi"=>"10.1371/journal.pone.0093207", "sgr"=>"84898652914", "scopus"=>"2-s2.0-84898652914", "issn"=>"19326203", "pui"=>"372838902"}, "id"=>"d62b2abc-2e9f-30f5-a172-e380bd0516a7", "abstract"=>"The liver is a multi-functional organ that regulates major physiological processes and that possesses a remarkable regeneration capacity. After loss of functional liver mass the liver grows back to its original, individual size through hepatocyte proliferation and apoptosis. How does a single hepatocyte 'know' when the organ has grown to its final size? This work considers the initial growth phase of liver regeneration after partial hepatectomy in which the mass is restored. There are strong and valid arguments that the trigger of proliferation after partial hepatectomy is mediated through the portal blood flow. It remains unclear, if either or both the concentration of metabolites in the blood or the shear stress are crucial to hepatocyte proliferation and liver size control. A cell-based mathematical model is developed that helps discriminate the effects of these two potential triggers. Analysis of the mathematical model shows that a metabolic load and a hemodynamical hypothesis imply different feedback mechanisms at the cellular scale. The predictions of the developed mathematical model are compared to experimental data in rats. The assumption that hepatocytes are able to buffer the metabolic load leads to a robustness against short-term fluctuations of the trigger which can not be achieved with a purely hemodynamical trigger.", "link"=>"http://www.mendeley.com/research/single-cell-know-liver-reached-correct-size", "reader_count"=>17, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Researcher"=>4, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>2, "Student > Master"=>1, "Other"=>2, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Researcher"=>4, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>2, "Student > Master"=>1, "Other"=>2, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>2, "Agricultural and Biological Sciences"=>4, "Medicine and Dentistry"=>6, "Physics and Astronomy"=>1, "Psychology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>4}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>3}}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1442356"], "description"=>"<p><b>A</b> Total liver mass grows back to its original individual size after partial hepatectomy. Depicted is the time course of liver mass regeneration after partial hepatectomy as the relative fraction of remnant liver mass (fraction starting liver mass) at different postoperative days (POD). <b>B</b> Kinetic of proliferation demonstrates a peak on first postoperative day (POD). Depicted is the proliferating index (PI) for the remaining liver lobules after 70% partial hepatectomy. <b>C</b> Liver lobules enlarge after partial hepatectomy <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093207#pone.0093207-Papp1\" target=\"_blank\">[30]</a>. Depicted is the retrograde filling of the hepatic sinusoids through the central veins with green fluorescent resin. The lobular borders are shown in red. (left) Liver lobular structure in control rat. (right) Liver lobular structure at four days after partial hepatectomy in rats (identical scale left and right).</p>", "links"=>[], "tags"=>["regeneration", "hepatectomy"], "article_id"=>980196, "categories"=>["Biological Sciences"], "users"=>["Nadine Hohmann", "Wei Weiwei", "Uta Dahmen", "Olaf Dirsch", "Andreas Deutsch", "Anja Voss-Böhme"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0093207.g001", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Experimental_data_for_liver_regeneration_after_partial_hepatectomy_in_rats_/980196", "title"=>"Experimental data for liver regeneration after partial hepatectomy in rats.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-01 03:25:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1442357"], "description"=>"<p>Portal vein ligation results in hyperperfusion of right lobes (RL)and caudate lobes (CL) and hypoperfusion of median and left lateral lobes (ML+LLL). The observed growth in the respective lobes correlates with the corresponding perfusion changes. (A) Rat liver anatomy and illustration of the surgical procedure for the portal vein ligation (PVL). Depicted is the positioning of the PVL (red cross). Ligated lobes are marked in gray. In case of a 70% pHx the lobes marked in gray are resected. (B) Liver lobe size adjustment at different postoperative days (POD) after of 70% PVL. Ligation of left lateral and median portal vein (70% of liver mass) results in lack of portal perfusion in the ligated 70% of the liver and hyperperfusion of right and caudate liver lobe, similar to the hyperperfusion observed after 70% pHx. Liver lobes adjust their weight according to the portal supply: Ligated lobes shrink to one third of their original weight whereas non-ligated lobes experience a 3-fold increase of their original weight, as seen after 70% pHx. Depicted is the time course of liver mass adaption after portal vein ligation as the relative liver lobe mass in proportion to the initial lobe weight (fold) at different postoperative days (POD).</p>", "links"=>[], "tags"=>["lobe", "regulated", "portal"], "article_id"=>980197, "categories"=>["Biological Sciences"], "users"=>["Nadine Hohmann", "Wei Weiwei", "Uta Dahmen", "Olaf Dirsch", "Andreas Deutsch", "Anja Voss-Böhme"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0093207.g002", "stats"=>{"downloads"=>2, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Liver_lobe_growth_is_regulated_by_portal_blood_supply_/980197", "title"=>"Liver lobe growth is regulated by portal blood supply.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-01 03:25:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1442358"], "description"=>"<p>(A) Sketch of hypothesized mechanisms of liver size regulation after partial hepatectomy. Liver size regulation is modulated by hepatocyte (HC) proliferation and apoptosis. A partial hepatectomy (pHx) alters liver size and therefore the relation between the organ and the organism. As a consequence, changes in the portal blood flow are observed. HCs respond to portal blood flow changes. The two hypothesized triggers for proliferation or apoptosis that relate to the portal blood flow are the altered metabolic load (ML) per HC and the altered hemodynamics (HD). (B) Feedback mechanism for the HD hypothesis. The main assumption is marked in green. The partial hepatectomy results in a change of the shear stress level which triggers proliferation and therefore affects the hepatocyte (HC) number . (C) Feedback mechanism for the ML hypothesis. The main assumption is marked in green. The partial hepatectomy alters the metabolic load per hepatocyte (HC) and hence the intracellular buffer level . The functional relation between the buffer rate and is illustrated in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093207#pone.0093207.s003\" target=\"_blank\">Figure S3B</a>. The intracellular buffer affects the HC number . The according growth rate per hepatocyte is given by , see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093207#pone.0093207.s003\" target=\"_blank\">Figure S3D</a>. At the same time, HCs degrade metabolites from the intracellular buffer at the rate which depends on , see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093207#pone.0093207.s003\" target=\"_blank\">Figure S3C</a>.</p>", "links"=>[], "tags"=>["mechanisms"], "article_id"=>980198, "categories"=>["Biological Sciences"], "users"=>["Nadine Hohmann", "Wei Weiwei", "Uta Dahmen", "Olaf Dirsch", "Andreas Deutsch", "Anja Voss-Böhme"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0093207.g003", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Feedback_mechanisms_of_liver_size_regulation_after_partial_hepatectomy_/980198", "title"=>"Feedback mechanisms of liver size regulation after partial hepatectomy.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-01 03:25:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1442359"], "description"=>"<p>(A) The one-dimensional hepatocyte (HC) layer represents a row of hepatocytes along a sinusoid between <i>portal vein (PV)</i> and <i>central vein (CV)</i>. The space of the hepatocyte layer is discretized by the constant hepatocyte diameter . Each hepatocyte possesses an internal state . The signal layer is considered to be a one-dimensional continuous domain, which is discretized for simulation purposes. The signal strength at a given position is expressed by a real number. The internal state and the signal strength are illustrated here by a color code. (B) Each cell can either proliferate, survive or undergo apoptosis. The model is computationally analyzed with the help of simulations. Each simulation step, a cell is chosen randomly and proliferation, survival and apoptosis are assigned a probability which depends on the signal strength and the internal state. A proliferation event (upper right) is performed with probability . A new cell is inserted right to the mother cell. The mother and daughter cells are marked in green. An apoptosis event (lower right) is performed with probability . Gaps resulting from apoptosis events are closed by rearrangement. The previous position of the cell is marked in green. The state of the signal layer is updated. Here, the update is illustrated using the HD model as an example. In this model the overall signal strength is inversely proportional to the cell number , see (3).</p>", "links"=>[], "tags"=>["hepatocyte", "temporal", "mathematical"], "article_id"=>980199, "categories"=>["Biological Sciences"], "users"=>["Nadine Hohmann", "Wei Weiwei", "Uta Dahmen", "Olaf Dirsch", "Andreas Deutsch", "Anja Voss-Böhme"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0093207.g004", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_State_of_the_hepatocyte_and_the_signal_layer_and_temporal_dynamics_in_the_mathematical_model_/980199", "title"=>"State of the hepatocyte and the signal layer and temporal dynamics in the mathematical model.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-01 03:25:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1442360"], "description"=>"<p><b>A</b> Temporary progression of the lobule size in dependence of , which is the sensitivity of the proliferation response to deviations from the normal shear stress value . <b>B</b> Temporary progression of the lobule size in the simulation with (red curve in <b>A</b>) in the scenarios (pHx), (STP) and (PVL) as given in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093207#pone-0093207-t001\" target=\"_blank\">Table 1</a>. The shear stress strength is illustrated by a color-code for the different scenarios. The time point at which compensatory growth is 90% completed is marked with . <b>C</b> Spatial distribution of proliferation events for the scenario (pHx). For each time point, the hepatocyte layer is equally divided into three sections displayed on the horizontal axis. The proliferation events are recorded for each section over the entire simulation time and are depicted as number of proliferation events for different relative spatial positions. <b>D</b> The frequency of proliferation events for scenario (pHx) is depicted as number of proliferation events per time point.</p>", "links"=>[], "tags"=>["hd"], "article_id"=>980200, "categories"=>["Biological Sciences"], "users"=>["Nadine Hohmann", "Wei Weiwei", "Uta Dahmen", "Olaf Dirsch", "Andreas Deutsch", "Anja Voss-Böhme"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0093207.g005", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Simulation_results_of_the_HD_model_/980200", "title"=>"Simulation results of the HD model.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-01 03:25:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1442361"], "description"=>"<p><b>A</b> Temporary progression of the lobule size in dependence of the potential additional degradation and the tolerance range for changes form the normal buffer level . <b>B</b> Temporary progression of the lobule size in dependence of , the sensitivity to deviations from the normal value . <b>C</b> Temporary progression of the lobule size in the simulation with parameters (blue dashed line in <b>A</b>) in the scenarios (pHx), (STP) and (PVL) as given in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0093207#pone-0093207-t001\" target=\"_blank\">Table 1</a>. The metabolic load in the signal layer is illustrated by a color-code for the different scenarios. The time point at which compensatory growth is 90% completed is marked with . <b>D</b> The frequency distribution of proliferation (blue) and apoptosis (red) events for scenario (pHx) is depicted as number of events per time point. <b>E</b>-<b>H</b> Spatial distribution of proliferation and apoptosis events in the ML model simulation. For each time point, the space of the hepatocyte layer is equally divided into three sections displayed on the horizontal axis. The events are recorded for each section over the entire simulation time and are depicted as number of proliferation events for different relative spatial positions. <b>E</b> and <b>F</b> display the spatial distribution of proliferation (<b>E</b>) and apoptosis (<b>F</b>) events in the ML model with a uniform signal layer. <b>G</b> and <b>H</b> display the spatial distribution of proliferation (<b>G</b>) and apoptosis (<b>H</b>) events in the ML model with a non-uniform signal layer.</p>", "links"=>[], "tags"=>["ml"], "article_id"=>980201, "categories"=>["Biological Sciences"], "users"=>["Nadine Hohmann", "Wei Weiwei", "Uta Dahmen", "Olaf Dirsch", "Andreas Deutsch", "Anja Voss-Böhme"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0093207.g006", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Simulation_results_of_the_ML_model_/980201", "title"=>"Simulation results of the ML model.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-01 03:25:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1442362"], "description"=>"<p>The simulation results are evaluated on the basis of the criteria (O1)–(O5), which are based on experimental observations, see the Analysis.</p>", "links"=>[], "tags"=>[], "article_id"=>980202, "categories"=>["Biological Sciences"], "users"=>["Nadine Hohmann", "Wei Weiwei", "Uta Dahmen", "Olaf Dirsch", "Andreas Deutsch", "Anja Voss-Böhme"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0093207.t002", "stats"=>{"downloads"=>5, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Model_evaluation_on_the_basis_of_experimental_data_/980202", "title"=>"Model evaluation on the basis of experimental data.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-04-01 03:25:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1442363"], "description"=>"<p>For a selected parameter set, the simulation results in the scenarios increased portal blood flow (pHx), reduced portal blood flow (PVL) and short-term perturbations by fluctuations in the portal blood flow (STP) are studied. For each scenario the state of the cell and the signal layer at initialization is given.</p>", "links"=>[], "tags"=>["simulations", "hd", "ml"], "article_id"=>980203, "categories"=>["Biological Sciences"], "users"=>["Nadine Hohmann", "Wei Weiwei", "Uta Dahmen", "Olaf Dirsch", "Andreas Deutsch", "Anja Voss-Böhme"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0093207.t001", "stats"=>{"downloads"=>5, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Model_parameters_for_the_simulations_of_the_HD_and_the_ML_model_/980203", "title"=>"Model parameters for the simulations of the HD and the ML model.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-04-01 03:25:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1442364", "https://ndownloader.figshare.com/files/1442365", "https://ndownloader.figshare.com/files/1442366", "https://ndownloader.figshare.com/files/1442367", "https://ndownloader.figshare.com/files/1442368"], "description"=>"<div><p>The liver is a multi-functional organ that regulates major physiological processes and that possesses a remarkable regeneration capacity. After loss of functional liver mass the liver grows back to its original, individual size through hepatocyte proliferation and apoptosis. How does a single hepatocyte ‘know’ when the organ has grown to its final size? This work considers the initial growth phase of liver regeneration after partial hepatectomy in which the mass is restored. There are strong and valid arguments that the trigger of proliferation after partial hepatectomy is mediated through the portal blood flow. It remains unclear, if either or both the concentration of metabolites in the blood or the shear stress are crucial to hepatocyte proliferation and liver size control. A cell-based mathematical model is developed that helps discriminate the effects of these two potential triggers. Analysis of the mathematical model shows that a metabolic load and a hemodynamical hypothesis imply different feedback mechanisms at the cellular scale. The predictions of the developed mathematical model are compared to experimental data in rats. The assumption that hepatocytes are able to buffer the metabolic load leads to a robustness against short-term fluctuations of the trigger which can not be achieved with a purely hemodynamical trigger.</p></div>", "links"=>[], "tags"=>["reached"], "article_id"=>980204, "categories"=>["Biological Sciences"], "users"=>["Nadine Hohmann", "Wei Weiwei", "Uta Dahmen", "Olaf Dirsch", "Andreas Deutsch", "Anja Voss-Böhme"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0093207.s001", "https://dx.doi.org/10.1371/journal.pone.0093207.s002", "https://dx.doi.org/10.1371/journal.pone.0093207.s003", "https://dx.doi.org/10.1371/journal.pone.0093207.s004", "https://dx.doi.org/10.1371/journal.pone.0093207.s005"], "stats"=>{"downloads"=>7, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_How_Does_a_Single_Cell_Know_When_the_Liver_Has_Reached_Its_Correct_Size_/980204", "title"=>"How Does a Single Cell Know When the Liver Has Reached Its Correct Size?", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-04-01 03:25:30"}

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