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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 chondrogenic differentiation of MSCs. The upregulation of reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) during the late stages of chondrogenic differentiation downregulates the expression of MT1-MMP (MMP-14), MMP-2, and MMP-9, and directly inhibits them through its enzymatic activity. Expression of MMP-2 is upregulated by the increase in P38 activity resulting in stimulation of the chondrogenic differentiation of MSCs. MMP-2 also regulates the association of FAK and β1 integrin through its degradation of fibronectin. This degradation results in the inhibition of MAPK pathway through P38 to stop the production of more MMP-2 at late stages of the process. ECM extracellular matrix, MMP matrix metalloproteinase, FAK focal adhesion kinase
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Fig1: MMPs and chondrogenic differentiation of MSCs. The upregulation of reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) during the late stages of chondrogenic differentiation downregulates the expression of MT1-MMP (MMP-14), MMP-2, and MMP-9, and directly inhibits them through its enzymatic activity. Expression of MMP-2 is upregulated by the increase in P38 activity resulting in stimulation of the chondrogenic differentiation of MSCs. MMP-2 also regulates the association of FAK and β1 integrin through its degradation of fibronectin. This degradation results in the inhibition of MAPK pathway through P38 to stop the production of more MMP-2 at late stages of the process. ECM extracellular matrix, MMP matrix metalloproteinase, FAK focal adhesion kinase

Mentions: Jin and colleagues [23] investigated the role of MMP-2 in chondrogenic differentiation of MSCs. Their data showed that the silencing of MMP-2 by siRNA impaired chondrogenic differentiation, and increased the protein level of fibronectin and β1 integrin. Treatment with a MMP-2 activator resulted in the activation of chondrogenesis. These results also indicated that the downregulation of P38 mitogen-activated protein kinase (MAPK) resulted in the inhibition of MMP-2 expression [23]. Moreover, MMP-2 is involved in the chondrogenic differentiation of MSCs via downregulation of focal adhesion kinase (FAK)–β1 integrin interaction, which leads to phosphorylation of FAK (Fig. 1) [23]. In another study, a group of scientists investigated the role of the degradation of MMPs on the chondrogenesis of MSCs. The study investigated the chondrogenic differentiation in MMP-sensitive hydrolytically hydrogel scaffold in comparison with MMP-insensitive hydrogels [24]. They found that the MSCs in the MMP-sensitive hydrogels had more morphological changes and chondrogenic markers compared with MSCs in the MMP-insensitive hydrogel group which remained round in shape [24]. A similar study was carried out using degradable or nondegradable polyethylene glycol gels. The human MSCs were evaluated for their proliferation, morphology, and chondrogenic differentiation in the two different gels. MSCs in the degradable gel showed more morphological changes and chondrogenic differentiation compared with MSCs in nondegradable gel after 21 days [25]. These studies revealed that the degradation of MMPs enhances the chondrogenic differentiation of MSCs by allowing the morphological changes and increasing the contents of glycosaminoglycans (GAG) and expression of chondrogenic markers. A chondrogenic cell line (ATDC5) was examined for chondrogenic differentiation, and the expression of MMP-2, MMP-9, and MT1-MMP was upregulated during the early stages of chondrogenic differentiation with a downregulation in the expression of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) [26]. However, RECK was shown to be upregulated in the later phase of differentiation. The knockdown of RECK revealed a suppression in the later ECM accumulation in the cartilaginous nodules. The data suggested that RECK and MMPs have an important effect in the chondrogenic differentiation through regulating tissue morphogenesis (Fig. 1) [26]. Previous studies showed that the upregulation of MMP-13 occurs during chondrogenic differentiation, and MMP-13 has been found to be upregulated in patients with osteoarthritis, suggesting a pathological role of MMP-13 in the disease process. Salinas and her group monitored the expression of MMP-13 during chondrogenic differentiation of MSCs, and they found an increased expression of MMP-13 followed by an increase in GAG content by day 9 until day 14 in vitro. The results indicate that the increase in production of MMP-13 drives the MSC differentiation to chondrocytes by degrading the cleavable components of the ECM, and regulating integrin-binding peptides [27].Fig. 1


Effects of matrix metalloproteinases on the fate of mesenchymal stem cells
MMPs and chondrogenic differentiation of MSCs. The upregulation of reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) during the late stages of chondrogenic differentiation downregulates the expression of MT1-MMP (MMP-14), MMP-2, and MMP-9, and directly inhibits them through its enzymatic activity. Expression of MMP-2 is upregulated by the increase in P38 activity resulting in stimulation of the chondrogenic differentiation of MSCs. MMP-2 also regulates the association of FAK and β1 integrin through its degradation of fibronectin. This degradation results in the inhibition of MAPK pathway through P38 to stop the production of more MMP-2 at late stages of the process. ECM extracellular matrix, MMP matrix metalloproteinase, FAK focal adhesion kinase
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: MMPs and chondrogenic differentiation of MSCs. The upregulation of reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) during the late stages of chondrogenic differentiation downregulates the expression of MT1-MMP (MMP-14), MMP-2, and MMP-9, and directly inhibits them through its enzymatic activity. Expression of MMP-2 is upregulated by the increase in P38 activity resulting in stimulation of the chondrogenic differentiation of MSCs. MMP-2 also regulates the association of FAK and β1 integrin through its degradation of fibronectin. This degradation results in the inhibition of MAPK pathway through P38 to stop the production of more MMP-2 at late stages of the process. ECM extracellular matrix, MMP matrix metalloproteinase, FAK focal adhesion kinase
Mentions: Jin and colleagues [23] investigated the role of MMP-2 in chondrogenic differentiation of MSCs. Their data showed that the silencing of MMP-2 by siRNA impaired chondrogenic differentiation, and increased the protein level of fibronectin and β1 integrin. Treatment with a MMP-2 activator resulted in the activation of chondrogenesis. These results also indicated that the downregulation of P38 mitogen-activated protein kinase (MAPK) resulted in the inhibition of MMP-2 expression [23]. Moreover, MMP-2 is involved in the chondrogenic differentiation of MSCs via downregulation of focal adhesion kinase (FAK)–β1 integrin interaction, which leads to phosphorylation of FAK (Fig. 1) [23]. In another study, a group of scientists investigated the role of the degradation of MMPs on the chondrogenesis of MSCs. The study investigated the chondrogenic differentiation in MMP-sensitive hydrolytically hydrogel scaffold in comparison with MMP-insensitive hydrogels [24]. They found that the MSCs in the MMP-sensitive hydrogels had more morphological changes and chondrogenic markers compared with MSCs in the MMP-insensitive hydrogel group which remained round in shape [24]. A similar study was carried out using degradable or nondegradable polyethylene glycol gels. The human MSCs were evaluated for their proliferation, morphology, and chondrogenic differentiation in the two different gels. MSCs in the degradable gel showed more morphological changes and chondrogenic differentiation compared with MSCs in nondegradable gel after 21 days [25]. These studies revealed that the degradation of MMPs enhances the chondrogenic differentiation of MSCs by allowing the morphological changes and increasing the contents of glycosaminoglycans (GAG) and expression of chondrogenic markers. A chondrogenic cell line (ATDC5) was examined for chondrogenic differentiation, and the expression of MMP-2, MMP-9, and MT1-MMP was upregulated during the early stages of chondrogenic differentiation with a downregulation in the expression of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) [26]. However, RECK was shown to be upregulated in the later phase of differentiation. The knockdown of RECK revealed a suppression in the later ECM accumulation in the cartilaginous nodules. The data suggested that RECK and MMPs have an important effect in the chondrogenic differentiation through regulating tissue morphogenesis (Fig. 1) [26]. Previous studies showed that the upregulation of MMP-13 occurs during chondrogenic differentiation, and MMP-13 has been found to be upregulated in patients with osteoarthritis, suggesting a pathological role of MMP-13 in the disease process. Salinas and her group monitored the expression of MMP-13 during chondrogenic differentiation of MSCs, and they found an increased expression of MMP-13 followed by an increase in GAG content by day 9 until day 14 in vitro. The results indicate that the increase in production of MMP-13 drives the MSC differentiation to chondrocytes by degrading the cleavable components of the ECM, and regulating integrin-binding peptides [27].Fig. 1

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