Fractone

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Fractone
Electron micrograph of a Fractone.jpg
Transmission electron micrograph of a fractone displaying typical fractal ultrastructural characteristics
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Anatomical terms of microanatomy

In biology, fractones are structures consisting primarily of laminin and heparan sulfate proteoglycan (HSPG) first discovered in the extracellular matrix niche of the subventricular zone of the lateral ventricle (SVZa) in the mouse brain. [1] [2] Recent research has suggested its importance in adult neurogenesis, gliogenesis, and angiogenesis. [3]

Contents

Fractones are found near or connected to stem cells, and are highly implicated in cell proliferation, differentiation and migration.

New work suggests that fractones are implicated in corticalization during embryogenesis, [4] as well as in cancer and neurodegenerative disease.

History

The term fractone is derived from fractal, a term coined by Benoît Mandelbrot in 1975.

Fractones were discovered in 2002 in the extracellular matrix niche of the subventricular zone of the lateral ventricule (SVZa) in a mouse brain. [1] Originally found in the neurogenic areas of the brain, recent studies indicate that fractones are also present in multiple organisms, including but not limited to plants, fungi, invertebrates, and vertebrate animals. [5] As the discovery of fractones marked a turning point in neurosciences and the understanding of stem cell niches in the mammal brain, other projects have been conducted in different organs and Fractones were found to be highly implicated not only in physiology but also in numerous pathologies. For instance, fractones are extremely reduced in Autism [6] [7] but highly represented in inflammation, cancer and other pathologies.

Properties

Fractones are structures composed of proteoglycans, consisting primarily but not limited to laminin and HSPG. Different patterns of sulfation in HSPG and chain length are responsible for numerous pathways in physiology as well as in pathology, being involved in most growth factor bindings, and in embryo development, viral infection, cancer, and other pathologies.

The HSPG part of fractones is responsible for growth factor binding, retention and release in the extracellular matrix. Moreover, fractones are always linked to cell processes, thus connecting up to 20 different cells to a single fractone, acting as a control panel for all of them.

Physiology

Fractones are extracellular matrix structures first discovered in the neurogenic zone of the brain. Fractones primarily consist of proteoglycans such as laminin and HSPG. These proteoglycans bind growth factor in the extracellular matrix to regulate stem cell proliferation, which has been demonstrated in the adult brain neurogenic zone, where fractones are responsible for the production and differenciation of new neurons. The main role of these structures, linked to a wide array of cells, is to act as a control panel for cell proliferation, differentiation and migration. Fractones also regulate stem cell fate in the brain, controlling how a stem cell should evolve. [2]

Embryonic development

Fractones have been described in the early development of the mouse embryo as punctates of laminin and/or HSPG. They adopt different patterns at each stage of the development, from the 2-cell stage to post-natal stages. Recent studies laso show that fractones play a key role in corticalization and the establishment of the subventricular zone and the ventricular zone of the lateral ventricule

Cancer

Recent work suggests that fractones are omnipresent in cancer. As fractones are believed to be either pre- or post-basement membrane structures, [8] analysis of fractone-markers in patients with glioblastoma, intestine and stomach carcinoma, kidney, liver, lung and ovary tumors revealed numerous fractones while basement membranes were usually absent. This may indicates changes in the tumor microenvironment that may rewire cancerous cells and promote growth and proliferation.

Alzheimer's disease

Fractones might have also already been described in Alzheimer's disease (AD) as they are depicted as laminin and/or HSPG punctates. Amyloid plaque-associated punctates of laminin [9] and heparan sulfate proteoglycan have already been described in several sources, but not yet associated with fractone research.

Related Research Articles

<span class="mw-page-title-main">Extracellular matrix</span> Network of proteins and molecules outside cells that provides structural support for cells

In biology, the extracellular matrix (ECM), also called intercellular matrix, is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and biochemical support to surrounding cells. Because multicellularity evolved independently in different multicellular lineages, the composition of ECM varies between multicellular structures; however, cell adhesion, cell-to-cell communication and differentiation are common functions of the ECM.

<span class="mw-page-title-main">Oligodendrocyte</span> Neural cell type

Oligodendrocytes, also known as oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons within the central nervous system (CNS) of jawed vertebrates. Their function is similar to that of Schwann cells, which perform the same task in the peripheral nervous system (PNS). Oligodendrocytes accomplish this by forming the myelin sheath around axons. Unlike Schwann cells, a single oligodendrocyte can extend its processes to cover around 50 axons, with each axon being wrapped in approximately 1 μm of myelin sheath. Furthermore, an oligodendrocyte can provide myelin segments for multiple adjacent axons.

<span class="mw-page-title-main">Glycosaminoglycan</span> Polysaccharides found in animal tissue

Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units. The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case of the sulfated glycosaminoglycan keratan, where, in place of the uronic sugar there is a galactose unit. GAGs are found in vertebrates, invertebrates and bacteria. Because GAGs are highly polar molecules and attract water; the body uses them as lubricants or shock absorbers.

<span class="mw-page-title-main">Chondrocyte</span> Cell that makes up cartilage

Chondrocytes are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans. Although the word chondroblast is commonly used to describe an immature chondrocyte, the term is imprecise, since the progenitor of chondrocytes can differentiate into various cell types, including osteoblasts.

<span class="mw-page-title-main">Basement membrane</span> Thin fibrous layer between the cells and the adjacent connective tissue in animals

The basement membrane, also known as base membrane is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between epithelial tissues including mesothelium and endothelium, and the underlying connective tissue.

<span class="mw-page-title-main">Laminin</span> Protein in the extracellular matrix

Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major components of the basal lamina, the protein network foundation for most cells and organs. The laminins are an important and biologically active part of the basal lamina, influencing cell differentiation, migration, and adhesion.

Oligodendrocyte progenitor cells (OPCs), also known as oligodendrocyte precursor cells, NG2-glia, O2A cells, or polydendrocytes, are a subtype of glia in the central nervous system named for their essential role as precursors to oligodendrocytes. They are typically identified in the human by co-expression of PDGFRA and CSPG4.

<span class="mw-page-title-main">Rostral migratory stream</span> One path neural stem cells take to reach the olfactory bulb


The rostral migratory stream (RMS) is a specialized migratory route found in the brain of some animals along which neuronal precursors that originated in the subventricular zone (SVZ) of the brain migrate to reach the main olfactory bulb (OB). The importance of the RMS lies in its ability to refine and even change an animal's sensitivity to smells, which explains its importance and larger size in the rodent brain as compared to the human brain, as our olfactory sense is not as developed. This pathway has been studied in the rodent, rabbit, and both the squirrel monkey and rhesus monkey. When the neurons reach the OB they differentiate into GABAergic interneurons as they are integrated into either the granule cell layer or periglomerular layer.

<span class="mw-page-title-main">Perlecan</span>

Perlecan (PLC) also known as basement membrane-specific heparan sulfate proteoglycan core protein (HSPG) or heparan sulfate proteoglycan 2 (HSPG2), is a protein that in humans is encoded by the HSPG2 gene. The HSPG2 gene codes for a 4,391 amino acid protein with a molecular weight of 468,829. It is one of the largest known proteins. The name perlecan comes from its appearance as a "string of pearls" in rotary shadowed images.

<span class="mw-page-title-main">Heparan sulfate</span> Macromolecule

Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins. It is in this form that HS binds to a variety of protein ligands, including Wnt, and regulates a wide range of biological activities, including developmental processes, angiogenesis, blood coagulation, abolishing detachment activity by GrB, and tumour metastasis. HS has also been shown to serve as cellular receptor for a number of viruses, including the respiratory syncytial virus. One study suggests that cellular heparan sulfate has a role in SARS-CoV-2 Infection, particularly when the virus attaches with ACE2.

Neural stem cells (NSCs) are self-renewing, multipotent cells that firstly generate the radial glial progenitor cells that generate the neurons and glia of the nervous system of all animals during embryonic development. Some neural progenitor stem cells persist in highly restricted regions in the adult vertebrate brain and continue to produce neurons throughout life. Differences in the size of the central nervous system are among the most important distinctions between the species and thus mutations in the genes that regulate the size of the neural stem cell compartment are among the most important drivers of vertebrate evolution.

<span class="mw-page-title-main">Subventricular zone</span> Region outside each lateral ventricle of the brain

The subventricular zone (SVZ) is a region situated on the outside wall of each lateral ventricle of the vertebrate brain. It is present in both the embryonic and adult brain. In embryonic life, the SVZ refers to a secondary proliferative zone containing neural progenitor cells, which divide to produce neurons in the process of neurogenesis. The primary neural stem cells of the brain and spinal cord, termed radial glial cells, instead reside in the ventricular zone (VZ).

<span class="mw-page-title-main">CTGF</span> Protein-coding gene in the species Homo sapiens

CTGF, also known as CCN2 or connective tissue growth factor, is a matricellular protein of the CCN family of extracellular matrix-associated heparin-binding proteins. CTGF has important roles in many biological processes, including cell adhesion, migration, proliferation, angiogenesis, skeletal development, and tissue wound repair, and is critically involved in fibrotic disease and several forms of cancers.

<span class="mw-page-title-main">Syndecan 1</span> Protein which in humans is encoded by the SDC1 gene

Syndecan 1 is a protein which in humans is encoded by the SDC1 gene. The protein is a transmembrane heparan sulfate proteoglycan and is a member of the syndecan proteoglycan family. The syndecan-1 protein functions as an integral membrane protein and participates in cell proliferation, cell migration and cell-matrix interactions via its receptor for extracellular matrix proteins. Syndecan-1 is a sponge for growth factors and chemokines, with binding largely via heparan sulfate chains. The syndecans mediate cell binding, cell signaling, and cytoskeletal organization and syndecan receptors are required for internalization of the HIV-1 tat protein.

<span class="mw-page-title-main">Subgranular zone</span>

The subgranular zone (SGZ) is a brain region in the hippocampus where adult neurogenesis occurs. The other major site of adult neurogenesis is the subventricular zone (SVZ) in the brain.

<span class="mw-page-title-main">Glial scar</span> Mass formed in response to injury to the nervous system

A glial scar formation (gliosis) is a reactive cellular process involving astrogliosis that occurs after injury to the central nervous system. As with scarring in other organs and tissues, the glial scar is the body's mechanism to protect and begin the healing process in the nervous system.

<span class="mw-page-title-main">Syndecan-2</span> Protein-coding gene in the species Homo sapiens

Syndecan-2 is a protein that in humans is encoded by the SDC2 gene.

<span class="mw-page-title-main">SULF1</span> Protein-coding gene in the species Homo sapiens

Sulfatase 1, also known as SULF1, is an enzyme which in humans is encoded by the SULF1 gene.

<span class="mw-page-title-main">Heparan sulfate analogue</span>

Heparan sulfate analogues are polymers engineered to mimic several properties of heparan sulfates. They can be constituted with a backbone of polysaccharides, such as poly glucose or glucuronates or a polyester such as co polymers of lactic or malic acid to which sulfates, sulfonate or carboxyl groups are added in controlled amounts and location. They have a molecular weight that can range from a few thousand to several hundred thousand Dalton. Heparan sulfates can sequester growth factors (GFs) and cytokines in the extracellular matrix (ECM) thereby protecting them from degradation. This ensures local presence of these signaling proteins to fulfill their function in the ECM which contributes to the preservation of anatomical form and function. Heparan sulfates bind to matrix proteins on specific sites called "heparan sulfate binding sites" on ECM macromolecules like collagen, fibronectin and laminin, to form a scaffold surrounding the cells and to protect ECM proteins and growth factors from proteolytic degradation by steric hindrance. However, at any site of inflammation, so also in wound areas, heparan sulfates are degraded, mainly by heparanases giving free access to protease to degrade the ECM and a subsequent loss of GFs and cytokines that disrupts the normal tissue homeostasis. Heparan sulfate analogues obtain many of the characteristics of heparan sulfates including the ability to sequester GFs and bind and protect matrix proteins. However, heparan sulfate analogues are resistant to enzymatic degradation. This way they strengthen the healing potential of the wound bed by repositioning GFs and cytokines back into the ECM.

Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs), radial glial cells (RGCs), basal progenitors (BPs), intermediate neuronal precursors (INPs), subventricular zone astrocytes, and subgranular zone radial astrocytes, among others.

References

  1. 1 2 Mercier, Frederic; Kitasako, John T.; Hatton, Glenn I. (2002-09-16). "Anatomy of the brain neurogenic zones revisited: fractones and the fibroblast/macrophage network". The Journal of Comparative Neurology. 451 (2): 170–188. doi:10.1002/cne.10342. ISSN   0021-9967. PMID   12209835. S2CID   19919800.
  2. 1 2 Mercier, Frederic (2016). "Fractones: extracellular matrix niche controlling stem cell fate and growth factor activity in the brain in health and disease". Cellular and Molecular Life Sciences. 73 (24): 4661–4674. doi:10.1007/s00018-016-2314-y. PMID   27475964. S2CID   28119663.
  3. Nascimento, Marcos Assis; Coelho-Sampaio, Tatiana; Sorokin, Lydia (14 December 2016). "Fractone bulbs derive from ependymal cells and their laminin composition affects cell proliferation in the subventricular zone". p. 093351. bioRxiv   10.1101/093351 .
  4. Chyba, Monique; Mercier, Frederic; Rader, John; Douet, Vanessa; Arikawa- Hirasawa, Eri (2010). "Dynamic Mathematical modeling of Cell-Fractone interactions". Journal of Math for Industry. 3: 79–88.
  5. Mercier, Frederic; Wheatherby, Tina; Hartline, Daniel (2013). "Meningeal‐like organization of neural tissues in calanoid copepods (Crustacea)". Journal of Comparative Neurology. 521 (4): 760–790. doi:10.1002/cne.23173. PMID   22740424. S2CID   18869879.
  6. Mercier, Frederic; Cho-Kwon, Youngsu; Kodama, Rich (2011). "Meningeal/vascular alterations and loss of extracellular matrix in the neurogenic zone of adult BTBR T+ tf/J mice, animal model for autism". Neuroscience Letters. 498 (3): 173–8. doi:10.1016/j.neulet.2011.05.014. PMID   21600960. S2CID   24456728.
  7. Mercier, Frederic; Cho Kwon, Youngsu; Douet, Vanessa (2012). "Hippocampus/amygdala alterations, loss of heparan sulfates, fractones and ventricle wall reduction in adult BTBR T+ tf/J mice, animal model for autism". Neuroscience Letters. 506 (2): 208–13. doi:10.1016/j.neulet.2011.11.007. PMID   22100909. S2CID   27386697.
  8. Sato, Yuya; Kiyozumi, Daiji; Futaki, Sugiko; Nakano, Itsuko; Shimono, Chisei; Kaneko, Naoko; Ikawa, Masahito; Okabe, Masaru; Sawamoto, Kazunobu; Sekiguchi, Kiyotoshi (2019). Yamashita, Yukiko (ed.). "Ventricular–subventricular zone fractones are speckled basement membranes that function as a neural stem cell niche". Molecular Biology of the Cell. 30 (1): 56–68. doi:10.1091/mbc.E18-05-0286. ISSN   1059-1524. PMC   6337917 . PMID   30379609.
  9. Palu, Edouard; Liesi, Päivi (2002). "Differential Distribution of Laminins in Alzheimer Disease and Normal Human Brain Tissue". Journal of Neuroscience Research. 69 (2): 243–256. doi:10.1002/jnr.10292. PMID   12111806. S2CID   39134037.