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THE STEM CELL NICHE |
Institute of Histology and Laboratory Analysis, Faculty of Sciences, University "Carlo Bo," Urbino, Italy
Key Words. Bone marrow stromal cells • Homing • Tissue inhibitors of metalloproteinases • Mesenchymal stem cells Differentiation • Cell surface markers • Matrix metalloproteinases • Umbilical cord blood mesenchymal stem cells
Correspondence: Ferdinando Mannello, Ph.D., Istituto di Istologia ed Analisi di laboratorio, Via O. Ubaldini, 7, Università "Carlo Bo", 61029 Urbino, Italy. Telephone: +39-0722-35149; Fax: +39-0722-322370; e-mail: f.mannello{at}uniurb.it
Received December 5, 2005;
accepted for publication April 28, 2006.
First published online in STEM CELLS EXPRESS May 4, 2006.
The evidence that stem cells are spread throughout the organism in every tissue is increasingly keen [1], demonstrating that the basic trait is plasticity, whereas self-renewal and hierarchical structuring may be optional and only needed for rapid expansion upon call [2]. Although pluripotential properties do not define the stem cell per se, stemness has been suggested as a state in the life cycle in which the cell may proliferate, migrate, and enter into a differentiation stage [3]. Although convincing data supporting the stemness of the unfractionated plastic-adherent cells was lacking [4, 5], it is commonly believed that stem cells are basically equal and share common properties characteristic of the stem state, defined as self-renewal, hierarchical organization, pluripotency, transdifferentiation capability, and plasticity [2].
Where are we today in understanding the cellular and biomolecular mechanisms of cell plasticity to enable the control of cell fate and navigation? Embryonic stem cells, pluripotent cells derived from blastocysts that can be indefinitely propagated undifferentiated in vitro, may differentiate into all cell lineages in vivo and can be induced to differentiate into most cell types [6]. On the other hand, the ability to purify, culture, and manipulate multipotent stem cells of nonembryonic origin provides investigators with an invaluable cell source for the study of cell and organ development. In fact, stem cells have been identified in most fetal and adult organ tissues, such as hematopoietic, neural, gastrointestinal, epidermal, hepatic, adipose, bone, and cartilage tissues; umbilical cord blood; fetal and adult peripheral blood; dental pulp; chorionic villi; and placental membranes. These cells, under in vitro culture condition, exhibit pluripotent capacity comparable to that of embryonic stem cells [2, 7]. The plastic-adherent cells, showing multipotent differentiation capacity in vitro, were diffusely termed as stromal and/or mesenchymal stem cells [8], but recently, the term multipotent mesenchymal stromal cells (maintaining the widely used acronym MSCs) has been proposed for the plastic-adherent population derived from multipotential adult progenitor cells, without implying unproven biologic or therapeutic potential [9]. Although the signaling pathways involved in the maintenance and development of the stem cell are critical and are yet to be discovered, stem cell function is controlled by intrinsic genetic programs and by extracellular cues from the (specialized and/or ubiquitous) stem cell niche [10]. In fact, the MSC pool comprises not only putative mesenchymal stem cells but also subpopulations at different states of differentiation potential [11]. Unlike epithelial stem cells [12], MSCs may not have their own protective niche and seem not to be restricted to their tissue of origin, spreading throughout the organism in every tissue with differentiating capability upon call differentiating into mesodermal, ectodermal, and endodermal derivatives due to their heterogeneity [2, 11].
The stem cell migration property, termed homing, is thought to be a coordinated multistep process involving intracellular-surface antigens and cell adhesion molecules (e.g., chemokines and their receptors [CXC and CXCR, respectively], leukocyte function-associated antigen 1 or CD11a/CD18 [LFA-1], very late antigen-4/5 or CD49d/CD49e [VLA-4/5], focal adhesion kinase, protein kinase C-
, CD44, CD54, cytokines, hyaluronic acid, and cytoskeletal proteins), growth factors (e.g., stromal-derived factor 1 [SDF-1], hepatocyte growth factor [HGF], and stem cell factor [SCF]), and proteolytic enzymes (e.g., elastases, cathepsins, membrane type-1, type-2, -3, -9, and -13 matrix metalloproteinases [MT1-MMP, MMP-2, -3, -9, and -13, respectively] and tissue inhibitor of metalloproteinases [TIMP]) [13, 14]. MSCs may both migrate and differentiate extensively; in fact, they are probably quiescent most of the time and are triggered to mend local microdamages occurring in tissues [15].
The biomolecular bases of the stem state of MSCs are yet to be fully defined, but they seem to entail a promiscuous gene expression pattern [16–18]. In fact, the profile of gene expression in MSCs identifies the crucial contribution of extracellular protein products, adhesion molecules, and degrading enzymes as part of their transcriptome, suggesting their involvement in cytoskeletal organization, cell-cell and cell-matrix interactions, and matrix remodeling pathways [17]. The exciting reports of high gene expression of several matrix metalloproteinases (MMPs) and TIMPs in MSCs (i.e., MMP-1, -2, and -19 and TIMP-1, -2, and -3) [16–18] has suggested the hypothesis of their crucial function in the MSC differentiation, playing key roles in the responses of stem cells to their microenvironment and guiding cell fate during MSC commitment [19].
Although it is intuitive how MMPs and TIMPs participate in cell physiology [20], such as cell communication and migration in tissues, and apoptosis [21, 22], it is not fully understood how their activity may influence MSC differentiation. MSCs are supposed to decide their fate and to give rise to a number of mature cells, not through a long cascade of steps but rather by shifting direction under the guidance of the microenvironment (via paracrine/autocrine mechanisms, through the secretion in the extracellular matrix of biocompounds that can regulate stem cell differentiation through intra- and extracellular signaling) [23, 24]. Several extracellular matrix components may coordinately activate or suppress the expression (at RNA and protein levels) of different MMPs that are capable of matrix remodeling (favoring cell migration to a specific tissue or modulating the engraftment of specific cells) [25–27]. Extracellular matrix (ECM) structural proteins, cytokines, and growth factors, which have the potentiality of interacting with cryptic sites of MMPs [28] may, through a cascade of steps, shift differentiation directions under the guidance of the microenvironment [29]. On the other hand, inactive or bound stromal and growth factors and chemokines may be activated by the proteolytic action of MMPs favoring differentiation, homing, and engraftment [15, 25, 30].
In a recent issue of STEM CELLS, Son et al. [31] unequivocally identified the presence in undifferentiated bone marrow and umbilical cord blood MSCs of MMP-2 and membrane-anchored type 1 (MT1)-MMP transcripts and proteins, suggesting their role in facilitating MSC migration through the degradation of the basement membrane in the presence of peculiar stromal and growth factors. Starting from the evidence that chemokines (e.g., CXCL12, known as stromal-derived factor 1 [SDF-1]) and growth factors (e.g., HGF) become upregulated at sites of tissue damage [15, 30], Son et al. demonstrated the presence in MSCs of CXCR4 and the MET proto-oncogene c-met (unique receptors of SDF-1 and HGF, respectively). Their results prove that both SDF-1/CXCR4 and HGF/c-met axes may regulate, by the activation of MMPs, the tethering, proliferation, and homing of stem cells, crucial clues for MSC guidance to target damaged tissues in vivo.
These observations support the hypothesis that MMPs may play a key role in both proliferation and migration of MSCs [19]. In fact, during tissue/organ damage, several ECM compounds are upregulated and bind to MSC, "stored" in the stem cell niche, by their cognate receptors. The gradient-dependent stimulation by stromal factors activates MT1-MMP, which is able to both degrade ECM proteins and specifically activate MMP-2, a key metalloproteinase playing role in developmental processes (e.g., adipogenic, chondrogenic, and neurogenic differentiation) [19, 32, 33].
According to the transcriptome machinery [16–18] and intracellular localization [31] of MMPs in MSCs, and the current understanding of MMP/TIMP balance [21, 22, 28], it can be hypothesized that on the MSC surface there is a building machinery that, through MT1-MMP/TIMP-2/proMMP-2 complex formation, may activate or inhibit MMP-2, a key proteolytic enzyme regulating collagen degradation, cell-cell interaction, and cell-matrix interaction.
MT1-MMP is a transmembrane collagenase that participates in pericellular proteolysis of not only extracellular matrix molecules, influencing the cellular microenvironment, affecting cell signaling pathways, and altering cellular behavior [34]. Cellular regulation of MT1-MMP includes activation, trafficking to the cell surface, homophilic complex formation, autodegradation, inhibition by inhibitors, internalization by clathrin-dependent pathways, and an efficient recycling mechanism back to the cell surface (Fig. 1A). MT1-MMP may be an intriguing cell-function modifier that, by the formation of a homo-oligomer complex, regulates MMP-2 activation. By forming such a complex, two MT1-MMP molecules, one acting as a receptor and the other as an activator, can keep the appropriate arrangement for MMP regulation. Active MT1-MMP anchored to the membrane binds the N-terminal domain of TIMP-2, inhibiting its activity. MMP-2 proenzyme subsequently binds tightly to the C-terminal domain of TIMP-2 through its hemopexin domain. The second active MT1-MMP, free of TIMP-2, may then link the bait region of proMMP-2 (Fig. 1B). Clustering of MT1-MMP/TIMP-2/proMMP-2/MT1-MMP complex can embrace several ways (Fig. 1C). a) Release of active MT1-MMP: it can break several substrates (e.g., several collagen types, the standard form of CD44, syndecan-1 by activating extracellular signal-regulated kinase, E-selectin, 
v chain of integrin, t-transglutaminase, and 
2 chain of laminin-5), generating signals that promote cell migration and proliferation. b) Inhibition/inactivation of MT1-MMP: MT1-MMP displayed on the cell surface is a target of inactivation by TIMP-2 and can also be internalized to substitute for old or partly degraded MT1-MMP molecules. The clathrin-dependent internalization may allow recycling back to the cell surface of new MT1-MMP molecules [34] or fully degrade old/damaged MT1-MMP by CD63-positive lysosomes. c) Release of activated MMP-2: active MMP-2 dissociates from the membrane-anchored complex and, after complete activation by intermolecular processing [20], may either bind to TIMP-2 (inhibiting MMP-2 function) or freely degrade various substrates, such as ECM proteins (e.g., pro-tumor necrosis factor, aggrecan, elastin, and interlukin-1ß), MMP proforms (e.g., proMMP-9 and proMMP-13), and nuclear matrix proteins (e.g., poly-ADP-ribose-polymerase and lamins) [20, 22, 28]. d) Release of free TIMP molecules: unbound TIMPs may, other than inhibiting MMP isoforms, directly affect cell differentiation, proliferation, and apoptotic processes [21, 28].
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Although we do not know how the MMP may regulate the recruitment and differentiation of MSCs, the results of Son et al. [31] represent the first piece of MSC puzzle, suggesting that MMP/TIMP balance may actively trigger intracellular (e.g., proteolyzing zymogens, modulating cytoplasmic trafficking, modifying nuclear/nucleolar signaling, and regulating nuclear transcriptions) [22] and extracellular (e.g., releasing bound factors, activating biologically important proteins, and modulating cell-matrix interactions) microenvironments [20]. On the other hand, MMPs and TIMPs may be themselves the targets of CXC chemokine/receptor axes [31] and injured-related signals [30]. Even though the growing knowledge of biological characteristics of MSCs apparently opens more questions than answers, the presence in uncommitted MSCs of proMMP-2/TIMP-2/MT1-MMP machinery represents the first inlay of the complex mosaic depicting the role of MMP/TIMP balance during the differentiation of multipotent mesenchymal stromal cells resident in a "ubiquitous" niche [19].
The involvement of both MMPs and TIMPs in controlling MSC mobilization, homing properties, and differentiation program to various tissue types and specific signaling required for lineage specifications may be the possible result of the opening of Pandora’s stem cell box. If the hypotheses are fulfilled, it will be possible to control the stem cell fate and to direct MSCs to the desired pathway, creating new tools for tissue and organ replacement in human diseases, a therapeutic promise of this fascinating stem cell population.
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DISCLOSURES |
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