Heparan sulfate analogue

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Heparan sulfate analogues are polymers engineered to mimic several properties of heparan sulfates. [1] They can be constituted with a backbone of polysaccharides, such as poly glucose or glucuronates [2] or a polyester such as co polymers of lactic or malic acid [3] to which sulfates, sulfonate or carboxylgroups are added in controlled amounts and location. They have a molecular weight that can range from a few thousands 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.[ citation needed ] 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 [1] [4] [5] [6] giving free access to protease to degrade the ECM and a subsequent loss of GFs and cytokines that disrupts the normal tissue homeostasis. [1] [4] [5] [6] Heparan sulfate analogues obtain many of the characteristics of heparan sulfates including the ability to sequester GFs and bind and protect matrix proteins. [7] However, heparan sulfate analogues are resistant to enzymatic degradation. [1] This way they strengthen the healing potential of the wound bed by repositioning GFs and cytokines back into the ECM. [1] [6] [8]

Contents

Structure formula of a heparan sulfate analogue subunit such as OTR4120 with a glucose subunit based backbone Heparan sulfate analogue.png
Structure formula of a heparan sulfate analogue subunit such as OTR4120 with a glucose subunit based backbone

Heparan sulfate analogues

Several Heparan sulfate analogues (also known as ReGeneraTing Agents, RGTA) have been developed from a poly glucose backbone. One named OTR4120 is a 85KD biopolymer and used for topical or ophthalmological application and marketed under the name CACIPLIQ20 or CACICOL20, respectively. [9] Heparan sulfate analogues will occupy the free heparan sulfate binding sites on ECM macromolecules like collagen, fibronectin and laminin that become available following heparan sulfate degradation. In many characteristics heparan sulfate analogues are similar to the natural heparan sulfate. [10] The most important difference is their resistance to enzymatic degradation. [1] [5] The resistance of RGTA is caused by the coupling of the subunits internal bond of the molecules. The β1-4 oxygen-linked binding of the subunits of heparan sulfate is prone to enzymatic cleavage whereas the α1-6 carbon-carbon binding of the subunits of RGTA are resistant to cleavage by all known mammalian glycanases and heparanases. [1] [4] [5] [6] [8] [10] This way RGTA can recreate a scaffold with the ECM proteins and will reposition GFs back into the matrix where they can re-unfold their natural action in wound repair. This way heparan sulfate analogues may contribute to chronic wound healing as will be discussed later on.

Target and function

Heparan sulfate analogues are thought to display identical properties as heparan sulfate with exception of being stable in a proteolytic and glycolytic environment like a wound. [1] Because heparan sulfate is broken down in chronic wounds by heparanase, the analogues only bind at sites where natural heparan sulfate is absent.[ citation needed ] Also the function of the heparan sulfate analogues is the same as heparan sulfate: structuring the ECM scaffold and protecting a variety of protein ligands such as ECM proteins growth factors and cytokines. By positioning and holding them in place, in a reconstituted organization mimicking that of before the wound, the tissue can then use these different proteins properly and spatially displayed for inducing cell migration, proliferation and differentiation. This results in improved tissue repair and sometimes a real regeneration process. [11]

Wound repair

Normal wound repair consists of three different phases: hemostasis and inflammation, proliferation and tissue remodeling.[ citation needed ] In disturbed wound healing, these stages cannot be completed often resulting in a reduced anatomical and functional outcome. [12]

Multiple factors determine the average healing time of the different phases. These factors can be classified into local factors such as infection and ischemia, and systemic factors such as age, stress, Diabetes Mellitus and smoking. [13] In chronic wounds, factors as mentioned above, make it impossible for the tissue to regenerate properly. [12] After injury, the extracellular matrix, and thereby also the heparan sulfate is broken down by different local enzymes, produced by macrophages such as, heparanases, serine proteases and metalloproteinases (MMPs). [14] Heparan sulfate analogues replace the broken heparan sulfate at the wound site and bind to the free heparan sulfate binding sites of the extracellular matrix. Heparan sulfate is slightly negatively charged and so it can bind the positively charged units of the proteins and secure the ECM scaffold. That ensures a supply of the different protein ligands at the wound site. [1] [5] [6] [8]

Clinical use

Regenerative medicine is the "process of replacing or regenerating human cells, tissues or organs to restore or establish normal function." [15] Heparan sulfate analogues are one of the early examples of regenerative medicine that reached daily clinical use. Multiple articles of animal wound models demonstrated vast effects on improving wound healing heparan sulfate analogues. [1] [6] [8] These findings formed a rationale for its clinical application. The first clinical studies also show a significant improvement in wound healing. [4] Different cases have shown improvement and better wound healing over time and persistent ulcer healing after usage of heparan sulfate analogues. [4] Even though several studies show that heparan sulfate analogues contribute to the wound healing, more research in the form of a Randomized controlled trial is needed to obtain conclusive evidence.

Clinical case of the function of heparan sulfate analogues in a 60 year old diabetic patient Clinical case heparan sulfate analogues.jpg
Clinical case of the function of heparan sulfate analogues in a 60 year old diabetic patient

See also

Related Research Articles

Fibronectin

Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collagen, fibrin, and heparan sulfate proteoglycans.

Extracellular matrix Network of proteins and molecules outside cells that provides structural support for cells

In biology, the extracellular matrix (ECM) is a three-dimensional 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.

Wound healing

Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue.

A chronic wound is a wound that does not heal in an orderly set of stages and in a predictable amount of time the way most wounds do; wounds that do not heal within three months are often considered chronic. Chronic wounds seem to be detained in one or more of the phases of wound healing. For example, chronic wounds often remain in the inflammatory stage for too long. To overcome that stage and jump-start the healing process a number of factors need to be addressed such as bacterial burden, necrotic tissue, and moisture balance of the whole wound. In acute wounds, there is a precise balance between production and degradation of molecules such as collagen; in chronic wounds this balance is lost and degradation plays too large a role.

Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in their function lead to a range of developmental defects. These growth factors typically act as systemic or locally circulating molecules of extracellular origin that activate cell surface receptors. A defining property of FGFs is that they bind to heparin and to heparan sulfate. Thus, some are sequestered in the extracellular matrix of tissues that contains heparan sulfate proteoglycans and are released locally upon injury or tissue remodeling.

Perlecan

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.

Heparan sulfate Linear polysaccharide in all animal tissues

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. A recent study reports that cellular heparan sulfate has a role in SARS-CoV-2 Infection, particularly when the virus attaches with ACE2.

Agrin

Agrin is a large proteoglycan whose best-characterised role is in the development of the neuromuscular junction during embryogenesis. Agrin is named based on its involvement in the aggregation of acetylcholine receptors during synaptogenesis. In humans, this protein is encoded by the AGRN gene.

Hepatocyte growth factor

Hepatocyte growth factor (HGF) or scatter factor (SF) is a paracrine cellular growth, motility and morphogenic factor. It is secreted by mesenchymal cells and targets and acts primarily upon epithelial cells and endothelial cells, but also acts on haemopoietic progenitor cells and T cells. It has been shown to have a major role in embryonic organ development, specifically in myogenesis, in adult organ regeneration, and in wound healing.

Syndecan 1 Protein is a transmembrane (type I) heparan sulfate proteoglycan and is a member of the syndecan proteoglycan family.

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.

Syndecan

Syndecans are single transmembrane domain proteins that are thought to act as coreceptors, especially for G protein-coupled receptors. More specifically, these core proteins carry three to five heparan sulfate and chondroitin sulfate chains, i.e. they are proteoglycans, which allow for interaction with a large variety of ligands including fibroblast growth factors, vascular endothelial growth factor, transforming growth factor-beta, fibronectin and antithrombin-1. Interactions between fibronectin and some syndecans can be modulated by the extracellular matrix protein tenascin C.

MMP7

Matrilysin also known as matrix metalloproteinase-7 (MMP-7), pump-1 protease (PUMP-1), or uterine metalloproteinase is an enzyme in humans that is encoded by the MMP7 gene. The enzyme has also been known as matrin, putative metalloproteinase-1, matrix metalloproteinase pump 1, PUMP-1 proteinase, PUMP, metalloproteinase pump-1, putative metalloproteinase, MMP).

SULF1 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.

Desmoplasia

In medicine, desmoplasia is the growth of fibrous or connective tissue. It is also called desmoplastic reaction to emphasize that it is secondary to an insult. Desmoplasia may occur around a neoplasm, causing dense fibrosis around the tumor, or scar tissue (adhesions) within the abdomen after abdominal surgery.

Metastatic breast cancer

Metastatic breast cancer, also referred to as metastases, advanced breast cancer, secondary tumors, secondaries or stage IV breast cancer, is a stage of breast cancer where the breast cancer cells have spread to distant sites beyond the axillary lymph nodes. There is no cure for metastatic breast cancer; it often can be effectively treated. There is no stage after IV.

A fibrin scaffold is a network of protein that holds together and supports a variety of living tissues. It is produced naturally by the body after injury, but also can be engineered as a tissue substitute to speed healing. The scaffold consists of naturally occurring biomaterials composed of a cross-linked fibrin network and has a broad use in biomedical applications.

Acellular dermis is a type of biomaterial derived from processing human or animal tissues to remove cells and retain portions of the extracellular matrix (ECM). These materials are typically cell-free, distinguishing them from classical allografts and xenografts, can be integrated or incorporated into the body, and have been FDA approved for human use for more than 10 years in a wide range of clinical indications.

Carbohydrate sulfotransferase

Carbohydrate sulfotransferases are sulfotransferase enzymes that transfer sulfate to carbohydrate groups in glycoproteins and glycolipids. Carbohydrates are used by cells for a wide range of functions from structural purposes to extracellular communication. Carbohydrates are suitable for such a wide variety of functions due to the diversity in structure generated from monosaccharide composition, glycosidic linkage positions, chain branching, and covalent modification. Possible covalent modifications include acetylation, methylation, phosphorylation, and sulfation. Sulfation, performed by carbohydrate sulfotransferases, generates carbohydrate sulfate esters. These sulfate esters are only located extracellularly, whether through excretion into the extracellular matrix (ECM) or by presentation on the cell surface. As extracellular compounds, sulfated carbohydrates are mediators of intercellular communication, cellular adhesion, and ECM maintenance.

Diabetic foot ulcer

Diabetic foot ulcer is a major complication of diabetes mellitus, and probably the major component of the diabetic foot.

Artificial cartilage is a synthetic material made of hydrogels or polymers that aims to mimic the functional properties of natural cartilage in the human body. Tissue engineering principles are used in order to create a non-degradable and biocompatible material that can replace cartilage. While creating a useful synthetic cartilage material, certain challenges need to be overcome. First, cartilage is an avascular structure in the body and therefore does not repair itself. This creates issues in regeneration of the tissue. Synthetic cartilage also needs to be stably attached to its underlying surface, bone. Lastly, in the case of creating synthetic cartilage to be used in joint spaces, high mechanical strength under compression needs to be an intrinsic property of the material.

References

  1. 1 2 3 4 5 6 7 8 9 10 Tong et al, Stimulated neovascularization, inflammation resolution and collagen maturation in healing rat cutaneous wounds by a heparan sulfate glycosaminoglycan mimetic, OTR4120. Wound Repair Regen. 2009 Nov-Dec;17(6):840-52.
  2. ↑ Petit et al, Controlled sulfatation of natural anionic bacterial polysaccharides can yield agents with specific regenerating activity in vivo. Biomacromolecules 2004;5:445-52
  3. ↑ Jeanbat-Mimaud et al, Bioactive functionalized polymer of malic acid for bone repair and muscle regeneration. J Biomater Sci Polym Ed. 2000;11(9):979-91.
  4. 1 2 3 4 5 Groah et al, Regenerating matrix-based therapy for chronic wound healing: a prospective within-subject pilot study. Int Wound J. 2011 Feb;8(1):85-95.
  5. 1 2 3 4 5 Barbier-Chassefière et al, Matrix therapy in regenerative medicine, a new approach to chronic wound healing. J Biomed Mater Res A. 2009 Sep 1;90(3):641-7.
  6. 1 2 3 4 5 6 Tong et al, RGTA OTR 4120, a heparan sulfate proteoglycan mimetic, increases wound breaking strength and vasodilatory capability in healing rat full-thickness excisional wounds. Wound Repair Regen. 2008 Mar-Apr;16(2):294-9.
  7. ↑ Morvan et al, An engineered biopolymer prevents mucositis induced by 5-fluorouracil in hamsters. Am J Pathol. 2004;164(2);739-46.
  8. 1 2 3 4 Tong et al, Heparan sulfate glycosaminoglycan mimetic improves pressure ulcer healing in a rat model of cutaneous ischemia-reperfusion injury. Wound Repair Regen. 2011 Jul;19(4):505-14.
  9. ↑ "OTR3" . Retrieved 2011-10-26.CS1 maint: discouraged parameter (link)
  10. 1 2 Barritault et al, Regenerating agents (RGTAs): a new therapeutic approach. Ann Pharm Fr. 2006 Mar;64(2):135-44.
  11. ↑ Blanquaert et al, Heparan like molecules induce the repair of skul defects. Bone 1995;17(6):499-506.
  12. 1 2 Lazarus et al, Definitions and guidelines for assessment of wounds and evaluation of healing. Wound Repair Regen. 1994 Jul;2(3):165-70.
  13. ↑ Guo et al, Factors affecting wound healing. J Dent Res. 2010 Mar;89(3):219-29. Epub 2010 Feb 5. Review.
  14. ↑ Henry et al, Inflammatory mediators in wound healing. Surg Clin North Am. 2003 Jun;83(3):483-507. Review.
  15. ↑ Regenerative Medicine, 2008, 3(1), 1–5 [47]
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