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Effects of matrix metalloproteinases on the fate of mesenchymal stem cells

View Article: PubMed Central - PubMed

ABSTRACT

Mesenchymal stem cells (MSCs) have great potential as a source of cells for cell-based therapy because of their ability for self-renewal and differentiation into functional cells. Moreover, matrix metalloproteinases (MMPs) have a critical role in the differentiation of MSCs into different lineages. MSCs also interact with exogenous MMPs at their surface, and regulate the pericellular localization of MMP activities. The fate of MSCs is regulated by specific MMPs associated with a key cell lineage. Recent reports suggest the integration of MMPs in the differentiation, angiogenesis, proliferation, and migration of MSCs. These interactions are not fully understood and warrant further investigation, especially for their application as therapeutic tools to treat different diseases. Therefore, overexpression of a single MMP or tissue-specific inhibitor of metalloproteinase in MSCs may promote transdifferentiation into a specific cell lineage, which can be used for the treatment of some diseases. In this review, we critically discuss the identification of various MMPs and the signaling pathways that affect the differentiation, migration, angiogenesis, and proliferation of MSCs.

No MeSH data available.


Related in: MedlinePlus

MMPs and osteogenic differentiation of MSCs. β1 integrins engage with fibronectin and collagen type I in the ECM, resulting in the formation of MT1-MMP and β1 integrin complex. This complex initiates the expression of proMMP-2 and ALP, which is required for the formation of nodules and their mineralization, and allows the activation of proMMP-2 through MT1-MMP during the osteogenic differentiation. ECM extracellular matrix, MMP matrix metalloproteinase, MT-MMP membrane type-matrix metalloproteinase
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Fig2: MMPs and osteogenic differentiation of MSCs. β1 integrins engage with fibronectin and collagen type I in the ECM, resulting in the formation of MT1-MMP and β1 integrin complex. This complex initiates the expression of proMMP-2 and ALP, which is required for the formation of nodules and their mineralization, and allows the activation of proMMP-2 through MT1-MMP during the osteogenic differentiation. ECM extracellular matrix, MMP matrix metalloproteinase, MT-MMP membrane type-matrix metalloproteinase

Mentions: Osteogenic differentiation and bone regeneration are characterized by ECM remodeling and hormonal and growth factor interactions. MSCs are very important cells for bone regeneration because of their capability to migrate into sites of injury and differentiate into osteocytes. Bone undergoes different physiological processes, including bone modeling and remodeling. Bone modeling leads to a change in bone shape in response to biomechanical forces. However, bone remodeling maintains bone strength through the resorption of old bones and the formation of new bones by dependent actions of osteoclasts and osteoblasts [33]. The differentiation of osteoblasts and bone formation are controlled by bone morphogenetic protein (BMP) and wingless (Wnt) signaling pathways, leading to the synthesis of collagen type I, whereas osteoclast differentiation is controlled by the receptor activator of nuclear factor kB (RANK) signaling pathway through macrophage colony-stimulating factor (MCSF) [34]. The role of MMPs on osteogenic differentiation has been studied, and their effect in osteoclastic resorption has been supported by studies indicating that MMP inhibition may block the osteoclastogenesis. Specific inhibition of several MMPs showed an important role for MMP-13 in MSC differentiation to osteocytes. The inhibition of MMPs by a broad-spectrum inhibitor revealed a huge alteration in osteogenic differentiation of MSCs [35]. These findings suggest that MSC differentiation is correlated with MMP and TIMP activity and the balance between the two molecules [35]. In another study, a broad-spectrum inhibitor for MMPs was used to determine the need for ECM remodeling during osteogenic differentiation of preosteoblasts, and the data revealed that MMP activity is necessary for the transition to osteoblasts [36]. The absence of MMP-13 affects the remodeling process during osteogenesis and after bone marrow transplantation, suggesting its key role in the osteogenic differentiation. This indicates that MMP-13 is involved in skeletal repair, and acts in the early stages of ECM degradation prior to invasion of osteoclasts and blood vessels [28]. Manduca and colleagues [37] have investigated the role of MMPs in osteogenic differentiation. In this study, the plating of preosteoblasts on MMP-inducing substrata resulted in the formation of β1 integrin complexed with MT1-MMP. The MT1-MMP senses the surrounding microenvironment through the binding of β1 integrin and the ECM. Moreover, overexpressing MT1-MMP during osteogenic differentiation was found to upregulate alkaline phosphatase (ALP) which is involved in crystal deposition on the scaffold of collagen type I fibers in the ECM of osteoblasts. The data suggest that MT1-MMP expression is crucial in the formation of nodules and mineral deposition during osteogenic differentiation. The expression of MT1-MMP during osteogenesis allows ECM remodeling, and initiates the expression of ALP and proMMP-2 (Fig. 2) [37].Fig. 2


Effects of matrix metalloproteinases on the fate of mesenchymal stem cells
MMPs and osteogenic differentiation of MSCs. β1 integrins engage with fibronectin and collagen type I in the ECM, resulting in the formation of MT1-MMP and β1 integrin complex. This complex initiates the expression of proMMP-2 and ALP, which is required for the formation of nodules and their mineralization, and allows the activation of proMMP-2 through MT1-MMP during the osteogenic differentiation. ECM extracellular matrix, MMP matrix metalloproteinase, MT-MMP membrane type-matrix metalloproteinase
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5016871&req=5

Fig2: MMPs and osteogenic differentiation of MSCs. β1 integrins engage with fibronectin and collagen type I in the ECM, resulting in the formation of MT1-MMP and β1 integrin complex. This complex initiates the expression of proMMP-2 and ALP, which is required for the formation of nodules and their mineralization, and allows the activation of proMMP-2 through MT1-MMP during the osteogenic differentiation. ECM extracellular matrix, MMP matrix metalloproteinase, MT-MMP membrane type-matrix metalloproteinase
Mentions: Osteogenic differentiation and bone regeneration are characterized by ECM remodeling and hormonal and growth factor interactions. MSCs are very important cells for bone regeneration because of their capability to migrate into sites of injury and differentiate into osteocytes. Bone undergoes different physiological processes, including bone modeling and remodeling. Bone modeling leads to a change in bone shape in response to biomechanical forces. However, bone remodeling maintains bone strength through the resorption of old bones and the formation of new bones by dependent actions of osteoclasts and osteoblasts [33]. The differentiation of osteoblasts and bone formation are controlled by bone morphogenetic protein (BMP) and wingless (Wnt) signaling pathways, leading to the synthesis of collagen type I, whereas osteoclast differentiation is controlled by the receptor activator of nuclear factor kB (RANK) signaling pathway through macrophage colony-stimulating factor (MCSF) [34]. The role of MMPs on osteogenic differentiation has been studied, and their effect in osteoclastic resorption has been supported by studies indicating that MMP inhibition may block the osteoclastogenesis. Specific inhibition of several MMPs showed an important role for MMP-13 in MSC differentiation to osteocytes. The inhibition of MMPs by a broad-spectrum inhibitor revealed a huge alteration in osteogenic differentiation of MSCs [35]. These findings suggest that MSC differentiation is correlated with MMP and TIMP activity and the balance between the two molecules [35]. In another study, a broad-spectrum inhibitor for MMPs was used to determine the need for ECM remodeling during osteogenic differentiation of preosteoblasts, and the data revealed that MMP activity is necessary for the transition to osteoblasts [36]. The absence of MMP-13 affects the remodeling process during osteogenesis and after bone marrow transplantation, suggesting its key role in the osteogenic differentiation. This indicates that MMP-13 is involved in skeletal repair, and acts in the early stages of ECM degradation prior to invasion of osteoclasts and blood vessels [28]. Manduca and colleagues [37] have investigated the role of MMPs in osteogenic differentiation. In this study, the plating of preosteoblasts on MMP-inducing substrata resulted in the formation of β1 integrin complexed with MT1-MMP. The MT1-MMP senses the surrounding microenvironment through the binding of β1 integrin and the ECM. Moreover, overexpressing MT1-MMP during osteogenic differentiation was found to upregulate alkaline phosphatase (ALP) which is involved in crystal deposition on the scaffold of collagen type I fibers in the ECM of osteoblasts. The data suggest that MT1-MMP expression is crucial in the formation of nodules and mineral deposition during osteogenic differentiation. The expression of MT1-MMP during osteogenesis allows ECM remodeling, and initiates the expression of ALP and proMMP-2 (Fig. 2) [37].Fig. 2

View Article: PubMed Central - PubMed

ABSTRACT

Mesenchymal stem cells (MSCs) have great potential as a source of cells for cell-based therapy because of their ability for self-renewal and differentiation into functional cells. Moreover, matrix metalloproteinases (MMPs) have a critical role in the differentiation of MSCs into different lineages. MSCs also interact with exogenous MMPs at their surface, and regulate the pericellular localization of MMP activities. The fate of MSCs is regulated by specific MMPs associated with a key cell lineage. Recent reports suggest the integration of MMPs in the differentiation, angiogenesis, proliferation, and migration of MSCs. These interactions are not fully understood and warrant further investigation, especially for their application as therapeutic tools to treat different diseases. Therefore, overexpression of a single MMP or tissue-specific inhibitor of metalloproteinase in MSCs may promote transdifferentiation into a specific cell lineage, which can be used for the treatment of some diseases. In this review, we critically discuss the identification of various MMPs and the signaling pathways that affect the differentiation, migration, angiogenesis, and proliferation of MSCs.

No MeSH data available.


Related in: MedlinePlus