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Review
. 2016 Sep 9;7(1):129.
doi: 10.1186/s13287-016-0393-1.

Effects of matrix metalloproteinases on the fate of mesenchymal stem cells

Sami G Almalki  1 , Devendra K Agrawal  2
Affiliations
Review

Effects of matrix metalloproteinases on the fate of mesenchymal stem cells

Sami G Almalki et al. Stem Cell Res Ther. .

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.

Keywords: Adipogenic differentiation; Angiogenesis; Chondrogenic differentiation; Extracellular matrix; Matrix metalloproteinases; Mesenchymal stem cells; Migration; Osteogenic differentiation; Proliferation.

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Figures

Fig. 1
Fig. 1
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
Fig. 2
Fig. 2
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
Fig. 3
Fig. 3
MMP participation in the fate of MSCs. The proliferation, migration, angiogenesis, and differentiation of MSCs are promoted by an increase or decrease in the expression of specific MMPs and/or TIMPs. MMP matrix metalloproteinase, MSC mesenchymal stem cell, TIMP tissue-specific inhibitor of metalloproteinase
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