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作者：Ferdinando Mannelloa, Gaetana A.M. Tontia, Gian Paolo Bagnarac,d, Stefano Papab作者单位：a Institute of Histology and Laboratory Analysis andb Institute of Morphological Sciences, Center of Cytometry, University Carlo Bo of Urbino, Urbino, Italy;c Department of Histology, Embryology, and Applied Biology andd Stem Cell Research Center, University of Bologna, Bologna, Italy + }1 V2 ~" C2 b9 m
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. Y) o0 k ]) ~ S, c" R 【摘要】$ h5 J% P1 M6 z# I9 c0 z
Matrix metalloproteinases (MMPs), known as matrixins, are Ca- and Zn-dependent endoproteinases involved in a wide variety of developmental and disease-associated processes, proving to be crucial protagonists in many physiological and pathological mechanisms. The ability of MMPs to alter, by limited proteolysis and through the fine control of tissue inhibitors of metalloproteinases, the activity or function of numerous proteins, enzymes, and receptors suggests that they are also involved in various important cellular functions during development. In this review, we focus on the differentiation of mesenchymal stem cells (including those of the myoblastic, osteoblastic, chondroblastic, neural, and apidoblastic lineages) and the possible, if unexpected, biological significance of MMPs in its regulation. The MMP system has been implicated in several differentiation events that suggests that it mediates the proliferative and prodifferentiating effect of the matrixin proteolytic cascade. We summarize these regulatory effects of MMPs on the differentiation of mesenchymal stem cells and hypothesize on the function of MMPs in the stem cell differentiation processes. X# ?9 D6 @ x+ Y/ }) q- F
【关键词】 Mesenchymal stem cell Matrix metalloproteinase Tissue inhibitor of metalloproteinases Gene and protein expression Differentiation Osteogenesis Chondrogenesis Adipogenesis Neurogenesis Myogenesis# a0 B3 J' \- p/ O; A
INTRODUCTION
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* ^5 A* K' R: n7 p7 n( q: h; H$ qAdult Mesenchymal Stem Cells% G6 E+ w8 l9 |8 k
3 u: v0 g) V' FMesenchymal stem cells (MSCs) have generated a great deal of excitement and expectation as a potential source of cells for cell-based therapeutic strategies, primarily because of their intrinsic ability to self-renew and differentiate into functional cell types that constitute the tissue in which they exist .' ]% G1 b% n$ o. O Y! G" S
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Recently, biomolecular studies highlighted, in MSCs, the gene expression involved in the connection between cell-matrix and cell-cell external signals, as well as in the intracellular signalling pathways. In fact, MMP genes have been identified in MSCs derived from different biological sources, indicating both their common ontogeny and the activation of similar sets of genes because of their close functional roles. Their gene-expression profiles, as part of the transcriptome of MSCs, may provide possible explanations for MSC functioning and behavior.
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MMPs and TIMPs( _- N1 |3 y- k7 I
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MMPs are a family of Ca- and Zn-dependent endopeptidases with the capacity to cleave most of the ECM components, expressed ubiquitously or in a tissue-specific way as intracellular and intranuclear enzymes .0 ?1 y; n9 s! M T$ ^
: n. A- u0 N+ BMMPs were originally referred to as intracellular or transmembrane enzymes that regulate the activity of many biological molecules by cleaving or releasing them .8 u. {7 _' I) a9 b- j/ G
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These enzymes and their specific inhibitors represent multipotent effectors with a huge activity spectrum in cellular development and physiology. In addition to the well-known roles and functions of MMPs and TIMPs in many disease processes involving both ECM and nuclear matrix degradation and remodeling (e.g. inflammatory and degenerative diseases, and cancer) .
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ROLE AND FUNCTION OF MMPS AND TIMPS DURING DIFFERENTIATION0 c, n0 H% J+ N7 v( \
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Myogenesis
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) e5 @% `+ S2 l! ?. DModifications of the ECM environment and the breakdown of connective tissue barriers are necessary and fundamental events in the differentiation, development, and regeneration of myoblasts and the stem cell replenishment of muscle that require cell migration and fusion .. _% d Z. n/ H! c0 p$ N, E
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The involvement of MMPs in the fusion of muscle cells was demonstrated by the high fusion index of a myoblast cell line expressing MMP-7. In particular, matrilysin MMP-7 expression may be useful in increasing myoblast transplantation success, improving the myogenic potential of myoblasts in vitro and the fusion of myoblasts with host fibers in vivo . Although there is not a direct connection between growth factor stimulation/ECM protein secretion and MMP activity, it is clear that MMPs and their inhibitors, TIMPs, are essential in ruling myogenesis, myoblast differentiation, and the migration process.+ ]7 I% L _# l% |& c2 F
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Neurogenesis
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# u+ V1 X/ T7 F) F! q5 C: }The first reports suggesting that MMPs may play important and unexpected roles during neuronal development took into consideration the embryonic development of the mouse brain. In particular, high MMP-9 expression levels were found in progenitor cells associated with the development of specific structures, such as the hypophysis, choroid plexus, ganglion cell layer of the retina, and uveal tract, and in aggregates that would later form the highly vascular grey matter of the brain .
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The expression of MMP-2, but not MMP-9, and all TIMPs has been found in neuroepithelial stem cells isolated from the human CNS. In particular, low expression levels of both MMP-2 and TIMP-4 were found in mature CNS cells, with higher concentrations in stem cells. Moreover, while the expression levels of TIMP-1, TIMP-2, and TIMP-3 were unchanged following stem cell differentiation into neurons and glia, the high expression level of TIMP-4 in neuroectodermal precursor cells was associated with stem cells, in which its molecular level remained unchanged upon differentiation . In conclusion, MMPs and TIMPs may play important regulatory roles during differentiation of neural/neuronal precursor cells, suggesting unexpected roles in stem cell development.+ f7 p: z4 [! V$ O6 I
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Chondrogenesis. v8 Z( L( z1 r- }2 o
1 U! ]; S4 D% y7 qProteolytic remodeling of the ECM is an important event during skeletal formation, strictly regulated at both the temporal and spatial levels, requiring chondrocytic cells that undergo continuous differentiation processes. During endochondral ossification in mice, chondrocytes of the lower zone of hypertrophic cartilage expressed MMP-13 together with type X collagen at specific embryonic stages, suggesting differentiation-dependent expression of this collagenase .
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! D( s- L m0 m7 G z6 X' GIn cartilage rudiment cultures and in primary chondrocyte cultures undergoing endochondral ossification, the expression of MMP-13 was increased by treatment with retinoic acid (RA, an effector of several events during bone differentiation) .
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! P6 l. e' B8 {" W3 YReports analyzing the in vitro differentiation pathway of chondrocyte-like cells and in vivo cartilage repair processes have highlighted the role of MT1-MMP in regulating pericellular proteolysis, either directly or through the involvement of other MMPs (such as MMP-2, MMP-9, and MMP-13) , ultimately leading to an essential role in chondrocytic differentiation pathways.
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Because of their degradative properties, MMPs may also be involved in the induction of chondrocytic chondrolysis in inflammatory and degenerative joint diseases, suggesting a physiological role in the degradation of the cartilage matrix and in differentiation pathways of chondrocytic stem cells .! B. Z: B, ~( A
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Osteogenesis
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The differentiation and proliferation of osteoblast progenitors is a complex process that requires continuous ECM remodeling and the interaction of numerous hormones, autocrine and paracrine processes, and systemic growth factors. Matrix elaboration and modification are fundamental in osteoclast-dependent bone resorption, and MMPs are necessary for the migration of precursor and immature osteoclasts to the bone surface .: ^2 w5 ~) {& ?7 Q
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As osteocytes are the result of the final differentiation step of osteogenic mesenchymal progenitors (immobilized in the bone matrix, interacting with other cells through extension of cell processes), it is feasible that osteocytes actively interact with their ECM environment and in particular with type I collagen, which is the most abundant protein in the osteocyte environment. Both collagenolytic activity and osteocyte process extension have been demonstrated to be dependent on MT1-MMP expression, which is necessary for both osteocytogenesis and the maintenance of the osteocyte phenotype .
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* Y1 T' i8 O" {, S8 Q+ }The importance of MMPs in osteoclastic resorption has been supported by studies showing that MMP inhibitors (such as tetracyclines and their modified derivatives) .
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Activation of parathyroid hormone receptors in osteoblasts has been shown to increase the expression levels of several MMPs (MMP-9, MMP-13) through increased stimulation of the phospholipase C pathway, leading to upregulated expression of the AP-1 factors c-jun and c-fos .
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Adipogenesis
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The development of the fat mass consists of adipocyte hypertrophy and hyperplasia resulting from the recruitment and differentiation of preadipocytes into adipocytes. Moreover, for correct growth of the fat depot, angiogenesis and ECM proteo-lytic remodeling are also of great importance . All the MMP and TIMP modulations reveal the crucial role that they may play during fat cell differentiation and conversion.+ u0 q3 t4 H, S* u% f) t
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FUTURE PERSPECTIVES FOR THE BIOLOGICAL CHARACTERIZATION OF MSCS9 m+ e. T5 ]+ D0 |0 L4 n$ G
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MMPs and TIMPs play essential positive and negative roles in the differentiation of chondroblasts, osteoblasts, and adipo-blasts, which are derived from adult common MSCs, even though these proteins seem to also be involved in the commitment of myoblasts and neuronal/glial cells. MMPs may be involved in the early stage of the differentiation of all cell lineages and may relocate to plasma membranes or nuclear fractions. A vast amount of work remains to be done in the field of MSC differentiation. In particular, several pieces of evidence demonstrate that uncommitted MSCs contain the biomolecular machinery of MMP and TIMP expression; as well, differentiated cells show a characteristic distribution of MMPs and TIMPs. Figure 1 depicts what happens to MMPs and TIMPs during MSC differentiation. Although out, understanding of the promoter and enhancer regions of MMP genes during MSC differentiation is still in its infancy , a great number of factors can stimulate or repress matrixin proteolytic expression and upregulate or downregulate TIMP function, leading to the following questions. How are the effects of MMPs and TIMPs produced on the genes in the stem and/or committed cell compartment? Why and how is ECM so intimately linked with this expression? Are MMPs to be expected in the activated form or, if not, what mechanisms exist for the activation of MMP enzymes? During MSC differentiation, do MMP protein domains remain unmodified or undergo structural alterations (e.g., the addition or loss of domains originally found in the ancestral MMPs)? Does protein modification influence the functional activity and substrate specificity of MMPs during the different differentiation states? Do increased MMP and TIMP activities play a role in the dedifferentiation of fully committed cells? Does the MMP/TIMP balance modulate the predetermined cell fate of MSCs?
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7 z& W5 q- a: o: e$ [" x" p8 q$ x1 `0 oFigure 1. Involvement of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in the differentiation hierarchy of human adult mesenchymal stem cells (MSCs). The scheme depicts the three compartments of adult MSC differentiation: the uncommitted multipotent MSC has the potential for self-renewal and to give rise to a less potent precursor cell population via asymmetric cell division; the committed mesenchymal progenitors cells show a lower level of stemness and a more restricted differentiation potential, via symmetric cell division. The uni-and tripotent precursor cells generate, via symmetric division, cells with predetermined cell fates, progenitors named colony-forming unit (CFUs). These cells give rise to fully committed/differentiated/mature mesenchymal phenotypes that may, under particular conditions, dedifferentiate into more potent cells with a higher level of stemness. During adult MSC differentiation, transcriptional and phenotypic modifications increase, whereas proliferative potential progressively decreases, concomitantly with limited multilineage potential. It is known that several MMPs and TIMPs play crucial roles and functions during the terminal stages of MSC progenitor differentiation into mature phenotypes. Because molecular studies have provided evidence that both MMP and TIMP genes are present in multipotent MSCs, the MMP/TIMP balance may play a key role in self-renewal as well as in the precursor and progenitor differentiation of human adult MSCs. Abbreviations: O, osteocyte; C, chondrocyte; A, adipocyte; sk, skeletal, sm, smooth muscle cell; c, cardiac muscle cell; As, astrocyte; Ol, oligodendrocyte; N, neuron.
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5 I- r% d- t1 L: g: w8 lAlthough this unexplored field of research produces more questions than answers, the MMP/TIMP balance may represent a sophisticated vision of specific proteolytic events during MSC differentiation, targeting both matrix and nonmatrix substrates driving cellular proliferation, apoptosis, and development. However, there is a paucity of information about the effects of MMPs and TIMPs on the transcriptional factors that function in the differentiation of MSC-derived blasts, even though consistent evidence underlines the significant relationship between MMPs and the ECM during differentiation. This opens up new frontiers on the modulation of ECM components through the production of MMPs and their fine control by TIMPs as important key regulators during MSC differentiation. The MMP/TIMP system thus plays important roles in cell proliferation . In fact, this balance regulates the amounts of several biologically active cellular components that participate in MSC differentiation, even though it is not exactly clear how the MMP/ TIMP system works in the different stages of differentiation. In this respect, the identification and characterization of the bio-molecular expression of both MMPs and TIMPs in MSCs isolated from different biological sources (umbilical cord vein, placental and fetal membranes, and dental pulp) are currently in progress (F. Mannello et al., in preparation). Understanding how the various biologically active molecules are upregulated or downregulated by the MMP/TIMP balance in the course of MSC differentiation remains an important area for future research and may lead to the development of novel therapeutic approaches against diseases that involve stem cell differentiation.
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7 r4 H) q- o' f- G* {1 A# wDISCLOSURES0 d* E) W% U. j3 u
; f( t9 P; O2 P/ ^" g6 a. N, aThe authors indicate no potential conflicts of interest.
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