CD44 Is Critically Involved in Infarct Healing by Regulating the Inflammatory and Fibrotic Response

Huebener, Peter; Abou-Khamis, Tareq; Zymek, Paweł; Bujak, Marcin; Xia, Ying; Chatila, Khaled; Haudek, Sandra B.; Thakker, Geeta D.; Frangogiannis, Nikolaos G.

doi:10.4049/jimmunol.180.4.2625

Cited by 160 publications

(156 citation statements)

References 35 publications

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“…CD44 also exerts fibrogenic actions mediating fibroblast migration and invasion in the wound provisional matrix [285]. Recent experiments from our laboratory tested the hypothesis that CD44 may play an essential role in infarct healing by regulating the inflammatory and fibrotic response [286]. We found that CD44 null mice exhibit enhanced and prolonged inflammation in the infarcted heart followed by reduced myofibroblast infiltration.…”

Section: Clearance Of Apoptotic Neutrophils and Removal Of Matrix Debrismentioning

confidence: 85%

The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

567

499

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Myocardial infarction is the most common cause of cardiac injury and results in acute loss of a large number of myocardial cells. Because the heart has negligible regenerative capacity, cardiomyocyte death triggers a reparative response that ultimately results in formation of a scar and is associated with dilative remodeling of the ventricle. Cardiac injury activates innate immune mechanisms initiating an inflammatory reaction. Toll Like Receptor-mediated pathways, the complement cascade and reactive oxygen generation induce Nuclear Factor (NF)-κB activation and upregulate chemokine and cytokine synthesis in the infarcted heart. Chemokines stimulate the chemotactic recruitment of inflammatory leukocytes into the infarct, while cytokines promote adhesive interactions between leukocytes and endothelial cells, resulting in transmigration of inflammatory cells into the site of injury. Monocyte subsets play distinct roles in phagocytosis of dead cardiomyocytes and in granulation tissue formation through the release of growth factors. Clearance of dead cells and matrix debris may be essential for resolution of inflammation and transition into the reparative phase. Transforming Growth Factor (TGF)-β plays a crucial role in cardiac repair by suppressing inflammation while promoting myofibroblast phenotypic modulation and extracellular matrix deposition. Myofibroblast proliferation and angiogenesis result in formation of highly vascularized granulation tissue. As the healing infarct matures, fibroblasts become apoptotic and a collagen-based matrix is formed, while many infarct neovessels acquire a muscular coat and uncoated vessels regress. Timely resolution of the inflammatory infiltrate and spatial containment of the inflammatory and reparative response into the infarcted area are essential for optimal infarct healing. Targeting inflammatory pathways following infarction may reduce cardiomyocyte injury and attenuate adverse remodeling. In addition, understanding the role of the immune system in cardiac repair is necessary in order to design optimal strategies for cardiac regeneration.

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Section: Clearance Of Apoptotic Neutrophils and Removal Of Matrix Debrismentioning

confidence: 85%

The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

567

499

View full text Add to dashboard Cite

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“…This would occur if such cells were dependent on CD44-mediated "homing" to the site, as has been reported for inflammatory cells and fibroblast progenitors (45,46). Such a deficiency of progenitors in the absence of CD44 would also reduce the total number of cells capable of responding to TGF␤1 to restore the dermal collagen matrix.…”

Section: Discussionmentioning

confidence: 96%

Adamts5 Deletion Blocks Murine Dermal Repair through CD44-mediated Aggrecan Accumulation and Modulation of Transforming Growth Factor β1 (TGFβ1) Signaling

Velasco

DiPietro

et al. 2011

Journal of Biological Chemistry

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ADAMTS5 has been implicated in the degradation of cartilage aggrecan in human osteoarthritis. Here, we describe a novel role for the enzyme in the regulation of TGF␤1 signaling in dermal fibroblasts both in vivo and in vitro. Dermal wound healing involves a series of cellular responses that depend on the coordinated temporal and spatial expression of inflammatory cytokines, proteases, growth factors, and extracellular matrix molecules. The early phases of hemostasis, inflammation, and re-epithelialization are followed by granulation tissue formation and finally dermal remodeling (1, 2). The granulation tissue is a loosely organized collagenous matrix that serves as a template for cellular regeneration (3) of the collagen (4) and proteoglycan (5-7) structures of the dermis proper.There has been a long held consensus that proteinases, such as plasmin and matrix metalloproteinases, are major players in dermal repair; however, many questions remain regarding substrate and product identification and to what extent cleavage of particular proteins is destructive or reparative (reviewed in Ref. 8). Although much interest has focused on matrix metalloproteinases (9), the ADAMTSs have now also been found to play a major role in a range of repair and regeneration processes. For example, evidence of a role for ADAMTS activity in dermal repair comes from the finding that human skin contains abundant aggrecanase-generated catabolic fragments of versican V0 and V1 (5) and that both aggrecan and versican are associated with the dermal region of the hair follicle (7). Moreover, to place dermal matrix turnover in a broader context, cleavage of the hyalectans aggrecan, versican, and brevican by one or more aggrecanases (ADAMTS1, -4, -5, -8, -9, and -15) occurs in the remodeling of cartilage (10), aorta (11, 12), spinal cord (13), meniscus (14, 15) intervertebral disc (16), adipose tissue (17), and brain (18). HA 2 in the skin is most abundant in the epidermal layer (6), and it undergoes partial fragmentation in both the dermis and epidermis of human skin explants (19). Its role in skin biology has largely focused on its binding to the cell-surface receptor CD44, an interaction that prevents PDGF-BB receptor activation and human fibroblast migration (20). It also appears to be required for MMP9-mediated activation of TGF␤1 (21). HA has been shown to ligate RHAMM to promote the association of CD44 and p-ERK, an interaction that directly activates cell migration and thereby is required for efficient dermal repair (22,23). HA also regulates the proliferative response of dermal fibroblasts to TGF␤1 (24), and HA12 oligosaccharides stimulate Col3 and TGF␤1 expression (25), a finding that is very relevant to the data described here.TGF␤1 is a key regulator of multiple processes in dermal wound healing (26). In the context of this study, TGF␤1 stimulates col1 and col3 production by fibroblasts and is required for terminal differentiation of myofibroblasts during wound * This work was supported, in whole or in part, by National Institutes o...

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“…In experimental models, release of type I collagen fragments in the serum has been documented within 30 minutes after coronary occlusion (37). Fragmentation of components of the basement membrane, such as collagen IV, and of noncollagenous matrix constituents has also been demonstrated in the infarcted myocardium (38)(39)(40)(41). Low-molecular weight hyaluronan fragments exert potent proinflammatory actions in the infarcted region; impaired clearance of these fragments has been shown to prolong and accentuate proinflammatory signaling in leukocytes and vascular cells (42,43).…”

Section: Ecm During the Proliferative Phase Of Infarct Healingmentioning

confidence: 99%

“…In vitro, pericellular hyaluronan was required to maintain a myofibroblast phenotype in TGF-β-stimulated cells (67). In vivo, loss of CD44, the main receptor for haluronan, impaired collagen synthesis in infarct fibroblasts (40). Versican loss in dermal fibroblasts attenuated myofibroblast conversion (68).…”

Section: Ecm During the Proliferative Phase Of Infarct Healingmentioning

confidence: 99%