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Hyaluronan Synthesis, Catabolism, and Signaling in Neurodegenerative Diseases.

Sherman LS, Matsumoto S, Su W, Srivastava T, Back SA - Int J Cell Biol (2015)

Bottom Line: HA is found throughout the CNS as a constituent of proteoglycans, especially within perineuronal nets that have been implicated in regulating neuronal activity.HA is also found in the white matter where it is diffusely distributed around astrocytes and oligodendrocytes.Hyaluronidases that digest high molecular weight HA into smaller fragments are also elevated following CNS insults and can generate HA digestion products that have unique biological activities.

View Article: PubMed Central - PubMed

Affiliation: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA ; Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.

ABSTRACT
The glycosaminoglycan hyaluronan (HA), a component of the extracellular matrix, has been implicated in regulating neural differentiation, survival, proliferation, migration, and cell signaling in the mammalian central nervous system (CNS). HA is found throughout the CNS as a constituent of proteoglycans, especially within perineuronal nets that have been implicated in regulating neuronal activity. HA is also found in the white matter where it is diffusely distributed around astrocytes and oligodendrocytes. Insults to the CNS lead to long-term elevation of HA within damaged tissues, which is linked at least in part to increased transcription of HA synthases. HA accumulation is often accompanied by elevated expression of at least some transmembrane HA receptors including CD44. Hyaluronidases that digest high molecular weight HA into smaller fragments are also elevated following CNS insults and can generate HA digestion products that have unique biological activities. A number of studies, for example, suggest that both the removal of high molecular weight HA and the accumulation of hyaluronidase-generated HA digestion products can impact CNS injuries through mechanisms that include the regulation of progenitor cell differentiation and proliferation. These studies, reviewed here, suggest that targeting HA synthesis, catabolism, and signaling are all potential strategies to promote CNS repair.

No MeSH data available.


Related in: MedlinePlus

A single OL (blue cell) can form myelin (yellow) for multiple internodes of the same axon (gray) or for many axons. In uninjured white matter, HA (red) is diffuse while in perineuronal nets HA is at much higher density (not shown). Following injury, myelin and oligodendrocytes are destroyed and HA is initially disrupted. HA later accumulates at higher than normal levels coincident with the appearance of reactive astrocytes (orange cells). CD44 and possibly other HA receptors (purple) are elevated on astrocytes and OPCs recruited to lesions. Both astrocytes and recruited OPCs (green cell) then express hyaluronidases (including PH20; black arrows in lower panel) that digest the excess HA within lesions. The resulting HA digestion products that accumulate in the injury microenvironment feed back on OPCs (blue arrow in lower panel) and prevent their differentiation and subsequent remyelination.
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fig3: A single OL (blue cell) can form myelin (yellow) for multiple internodes of the same axon (gray) or for many axons. In uninjured white matter, HA (red) is diffuse while in perineuronal nets HA is at much higher density (not shown). Following injury, myelin and oligodendrocytes are destroyed and HA is initially disrupted. HA later accumulates at higher than normal levels coincident with the appearance of reactive astrocytes (orange cells). CD44 and possibly other HA receptors (purple) are elevated on astrocytes and OPCs recruited to lesions. Both astrocytes and recruited OPCs (green cell) then express hyaluronidases (including PH20; black arrows in lower panel) that digest the excess HA within lesions. The resulting HA digestion products that accumulate in the injury microenvironment feed back on OPCs (blue arrow in lower panel) and prevent their differentiation and subsequent remyelination.

Mentions: HA synthesis and catabolism are both induced following insults to various tissues, including the CNS. Following most if not all forms of CNS injury, the HA-based ECM is initially disrupted, leading to the loss of HA within new lesions. However, soon after the initial CNS insult, HA accumulates predominantly through transcriptional upregulation of HAS genes by astrocytes and other reactive glia. HA accumulation is accompanied by transcriptional upregulation of CD44 and possibly other transmembrane HA receptors leading to both enhanced HA signaling and anchoring of cell surface HA, contributing to further HA accumulation in the injury microenvironment. Such anchoring of HA to the cell surface by CD44 has been described in activated brain endothelial cells [82]. In conjunction with the transcriptional activation of HAS genes and HA receptors, the expression of one or more hyaluronidases is also induced, leading to the digestion and clearance of the accumulated HA in the lesions. The balance between HA accumulation and HA degradation by hyaluronidases can influence a number of cell behaviors, such as proliferation and differentiation in NSPC niches (Figure 2). Interestingly, HAS, HA receptor, and hyaluronidase expression may each be influenced by the same milieu of proinflammatory mediators that are induced following tissue damage. Disruption in the balance between HA synthesis and catabolism can lead to either excess high molecular weight HA accumulation or the accumulation of HA digestion products that can negatively impact CNS repair. The best example of this latter outcome has been demonstrated in the case of remyelination failure, where the accumulation of HA digestion products inhibits OPC maturation in demyelinating lesions (Figure 3).


Hyaluronan Synthesis, Catabolism, and Signaling in Neurodegenerative Diseases.

Sherman LS, Matsumoto S, Su W, Srivastava T, Back SA - Int J Cell Biol (2015)

A single OL (blue cell) can form myelin (yellow) for multiple internodes of the same axon (gray) or for many axons. In uninjured white matter, HA (red) is diffuse while in perineuronal nets HA is at much higher density (not shown). Following injury, myelin and oligodendrocytes are destroyed and HA is initially disrupted. HA later accumulates at higher than normal levels coincident with the appearance of reactive astrocytes (orange cells). CD44 and possibly other HA receptors (purple) are elevated on astrocytes and OPCs recruited to lesions. Both astrocytes and recruited OPCs (green cell) then express hyaluronidases (including PH20; black arrows in lower panel) that digest the excess HA within lesions. The resulting HA digestion products that accumulate in the injury microenvironment feed back on OPCs (blue arrow in lower panel) and prevent their differentiation and subsequent remyelination.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4581574&req=5

fig3: A single OL (blue cell) can form myelin (yellow) for multiple internodes of the same axon (gray) or for many axons. In uninjured white matter, HA (red) is diffuse while in perineuronal nets HA is at much higher density (not shown). Following injury, myelin and oligodendrocytes are destroyed and HA is initially disrupted. HA later accumulates at higher than normal levels coincident with the appearance of reactive astrocytes (orange cells). CD44 and possibly other HA receptors (purple) are elevated on astrocytes and OPCs recruited to lesions. Both astrocytes and recruited OPCs (green cell) then express hyaluronidases (including PH20; black arrows in lower panel) that digest the excess HA within lesions. The resulting HA digestion products that accumulate in the injury microenvironment feed back on OPCs (blue arrow in lower panel) and prevent their differentiation and subsequent remyelination.
Mentions: HA synthesis and catabolism are both induced following insults to various tissues, including the CNS. Following most if not all forms of CNS injury, the HA-based ECM is initially disrupted, leading to the loss of HA within new lesions. However, soon after the initial CNS insult, HA accumulates predominantly through transcriptional upregulation of HAS genes by astrocytes and other reactive glia. HA accumulation is accompanied by transcriptional upregulation of CD44 and possibly other transmembrane HA receptors leading to both enhanced HA signaling and anchoring of cell surface HA, contributing to further HA accumulation in the injury microenvironment. Such anchoring of HA to the cell surface by CD44 has been described in activated brain endothelial cells [82]. In conjunction with the transcriptional activation of HAS genes and HA receptors, the expression of one or more hyaluronidases is also induced, leading to the digestion and clearance of the accumulated HA in the lesions. The balance between HA accumulation and HA degradation by hyaluronidases can influence a number of cell behaviors, such as proliferation and differentiation in NSPC niches (Figure 2). Interestingly, HAS, HA receptor, and hyaluronidase expression may each be influenced by the same milieu of proinflammatory mediators that are induced following tissue damage. Disruption in the balance between HA synthesis and catabolism can lead to either excess high molecular weight HA accumulation or the accumulation of HA digestion products that can negatively impact CNS repair. The best example of this latter outcome has been demonstrated in the case of remyelination failure, where the accumulation of HA digestion products inhibits OPC maturation in demyelinating lesions (Figure 3).

Bottom Line: HA is found throughout the CNS as a constituent of proteoglycans, especially within perineuronal nets that have been implicated in regulating neuronal activity.HA is also found in the white matter where it is diffusely distributed around astrocytes and oligodendrocytes.Hyaluronidases that digest high molecular weight HA into smaller fragments are also elevated following CNS insults and can generate HA digestion products that have unique biological activities.

View Article: PubMed Central - PubMed

Affiliation: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA ; Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.

ABSTRACT
The glycosaminoglycan hyaluronan (HA), a component of the extracellular matrix, has been implicated in regulating neural differentiation, survival, proliferation, migration, and cell signaling in the mammalian central nervous system (CNS). HA is found throughout the CNS as a constituent of proteoglycans, especially within perineuronal nets that have been implicated in regulating neuronal activity. HA is also found in the white matter where it is diffusely distributed around astrocytes and oligodendrocytes. Insults to the CNS lead to long-term elevation of HA within damaged tissues, which is linked at least in part to increased transcription of HA synthases. HA accumulation is often accompanied by elevated expression of at least some transmembrane HA receptors including CD44. Hyaluronidases that digest high molecular weight HA into smaller fragments are also elevated following CNS insults and can generate HA digestion products that have unique biological activities. A number of studies, for example, suggest that both the removal of high molecular weight HA and the accumulation of hyaluronidase-generated HA digestion products can impact CNS injuries through mechanisms that include the regulation of progenitor cell differentiation and proliferation. These studies, reviewed here, suggest that targeting HA synthesis, catabolism, and signaling are all potential strategies to promote CNS repair.

No MeSH data available.


Related in: MedlinePlus