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Stem cells and fluid flow drive cyst formation in an invertebrate excretory organ.

ABSTRACT: Cystic kidney diseases (CKDs) affect millions of people worldwide. The defining pathological features are fluid-filled cysts developing from nephric tubules due to defective flow sensing, cell proliferation and differentiation. The underlying molecular mechanisms, however, remain poorly understood, and the derived excretory systems of established invertebrate models (Caenorhabditis elegans and Drosophila melanogaster) are unsuitable to model CKDs. Systematic structure/function comparisons revealed that the combination of ultrafiltration and flow-associated filtrate modification that is central to CKD etiology is remarkably conserved between the planarian excretory system and the vertebrate nephron. Consistently, both RNA-mediated genetic interference (RNAi) of planarian orthologues of human CKD genes and inhibition of tubule flow led to tubular cystogenesis that share many features with vertebrate CKDs, suggesting deep mechanistic conservation. Our results demonstrate a common evolutionary origin of animal excretory systems and establish planarians as a novel and experimentally accessible invertebrate model for the study of human kidney pathologies.

SUBMITTER: Thi-Kim Vu H

PROVIDER: S-EPMC4500094 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Stem cells and fluid flow drive cyst formation in an invertebrate excretory organ.

Thi-Kim Vu Hanh H Rink Jochen C JC McKinney Sean A SA McClain Melainia M Lakshmanaperumal Naharajan N Alexander Richard R Sánchez Alvarado Alejandro A

eLife 20150609

Cystic kidney diseases (CKDs) affect millions of people worldwide. The defining pathological features are fluid-filled cysts developing from nephric tubules due to defective flow sensing, cell proliferation and differentiation. The underlying molecular mechanisms, however, remain poorly understood, and the derived excretory systems of established invertebrate models (Caenorhabditis elegans and Drosophila melanogaster) are unsuitable to model CKDs. Systematic structure/function comparisons reveal ...[more]

PMID: 26057828

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Project description:BACKGROUND: There is little knowledge concerning the content and the mechanisms of filling of arachnoid cysts. The aim of this study was to compare the protein content of arachnoid cysts and cerebrospinal fluid by quantitative proteomics to increase the understanding of arachnoid cysts. METHODS: Arachnoid cyst fluid and cerebrospinal fluid from five patients were analyzed by quantitative proteomics in two separate experiments.In a label-free experiment arachnoid cyst fluid and cerebrospinal fluid samples from individual patients were trypsin digested and analyzed by Orbitrap mass spectrometry in a label-free manner followed by data analysis using the Progenesis software.In the second proteomics experiment, a patient sample pooling strategy was followed by MARS-14 immunodepletion of high abundant proteins, trypsin digestion, iTRAQ labelling, and peptide separation by mix-phase chromatography followed by Orbitrap mass spectrometry analysis. The results from these analyzes were compared to previously published mRNA microarray data obtained from arachnoid membranes. RESULTS: We quantified 348 proteins by the label-free individual patient approach and 1425 proteins in the iTRAQ experiment using a pool from five patients of arachnoid cyst fluid and cerebrospinal fluid. This is by far the largest number of arachnoid cyst fluid proteins ever identified, and the first large-scale quantitative comparison between the protein content of arachnoid cyst fluid and cerebrospinal fluid from the same patients at the same time. Consistently in both experiment, we found 22 proteins with significantly increased abundance in arachnoid cysts compared to cerebrospinal fluid and 24 proteins with significantly decreased abundance. We did not observe any molecular weight gradient over the arachnoid cyst membrane. Of the 46 proteins we identified as differentially abundant in our study, 45 were also detected from the mRNA expression level study. None of them were previously reported as differentially expressed. We did not quantify any of the proteins corresponding to gene products from the ten genes previously reported as differentially abundant between arachnoid cysts and control arachnoid membranes. CONCLUSIONS: From our experiments, the protein content of arachnoid cyst fluid and cerebrospinal fluid appears to be similar. There were, however, proteins that were significantly differentially abundant between arachnoid cyst fluid and cerebrospinal fluid. This could reflect the possibility that these proteins are affected by the filling mechanism of arachnoid cysts or are shed from the membranes into arachnoid cyst fluid. Our results do not support the proposed filling mechanisms of oncotic pressure or valves.

Project description:Background: * Researchers are trying to learn what causes certain types of cancer to spread to other organs in the body (metastasis). Cancer tumors may produce a very small number of specific cells (cancer stem cells) that cause the tumors to grow in other organs throughout the body. * By examining cancer tumor tissue, normal tissue, blood, bone marrow, and other body fluids, researchers may determine whether these samples contain cancer stem cells. Cancer stem cells may provide information on whether the cancer will come back or spread before other routine x-ray studies or lab tests indicate its presence. Objectives: * To acquire a collection of solid organ cancer stem cells for future study. * To analyze solid organ cancer stem cells from various types of cancer on a genetic level. * To determine if solid organ cancer stem cells are present in the blood or bone marrow. Eligibility: * Patients 16 years of age and older who have solid organ cancer (cancer in the liver, colon, rectum, anus, pancreas, stomach, breast, skin, muscles, fat, connective tissue, uterus, ovary, cervix, vagina, vulva, or inner lining of the abdomen) or a precancerous growth, and who are scheduled to have a biopsy or surgery to remove the cancer as part of their treatment. Design: * This is a prospective trial designed to procure solid organ cancer stem cells before either surgery or biopsy. * All patients registered to this trial will undergo surgery to extirpate their cancer in the NCI * Prior to surgery or biopsy, 8 tablespoons of blood will be drawn. * During the surgery or biopsy, a sample of normal tissue will be removed along with the cancerous or precancerous tissue. If separate consent is given, samples of bone marrow will also be taken. * After discharge, patients will return to the clinic for routine visits every month for the first 3 months following surgery, and then about every 3 months for 2 years, and then every 6 months for 3 years. During the visits, patients will have routine blood and imaging studies done, and researchers will take additional blood samples (about 8 tablespoons at each visit) and optional bone marrow samples (4 teaspoons every 6 months) to be used for research.

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Stem cells and fluid flow drive cyst formation in an invertebrate excretory organ.

Publications

Stem cells and fluid flow drive cyst formation in an invertebrate excretory organ.

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