title: Human mesenchymal stem cells generate a distinct pericellular zone of MMP activities via binding of MMPs and secretion of high levels of TIMPs.
abstract: Mesenchymal stem cells (MSCs) are attractive candidates for inclusion in cell-based therapies by virtue of their abilities to home to wound sites. However, in-depth characterization of the specific effects of MSCs on their microenvironments is needed to realize their full therapeutic potentials. Furthermore, since MSCs of varying properties can be isolated from a diverse spectrum of tissues, a strategic and rational approach in MSC sourcing for a particular application has yet to be achieved. For example, MSCs that activate their proteolytic environments may promote tissue remodeling, while those from different tissue sources may inhibit proteases and promote tissue stabilization. This study attempts to address these issues by analyzing MSCs isolated from three adult tissue sources in terms of their effects on their proteolytic microenvironments. Human bone marrow, adipose, and traumatized muscle derived MSCs were compared in their soluble and cellular-associated MMP components and activity. For all types of MSCs, MMP activity associated with the cell surface, but activity levels and MMP profiles differed with tissue source. All MSC types bound exogenous active MMPs at their surfaces. MSCs were also able to activate exogenous proMMP-2 and proMMP-13. This is in marked contrast to the MSC soluble compartment, which strongly inhibited MMPs via endogenous TIMPs. The exact TIMP used to inhibit the exogenous MMP differed with MSC type. Thus, MSCs saturate their environment with both MMPs and TIMPs. Since they bind and activate MMPs at their surfaces, the net result is a very controlled pericellular localization of MMP activities by MSCs.
authors.affiliation: Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Lozito
authors.affiliation: Orthopaedic Research Group, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, United States.
authors.forename: Wesley M
authors.initials: WM
authors.lastname: Jackson
authors.affiliation: Orthopaedic Research Group, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, United States; Department of Orthopaedics and Rehabilitation, Walter Reed Army Medical Center, Washington, DC, United States; Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, United States.
authors.forename: Leon J
authors.initials: LJ
authors.lastname: Nesti
authors.affiliation: Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States. Electronic address: rst13@pitt.edu.
authors.forename: Rocky S
authors.initials: RS
authors.lastname: Tuan
mesh_terms: D002478:Cells, Cultured; D060833:Cellular Microenvironment / Q000235:genetics; D004792:Enzyme Precursors / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D011485:Protein Binding; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D000097792:Tissue Inhibitor of Metalloproteinase-4
chemical_list: D004792:Enzyme Precursors; D018093:Gelatinases; D053509:Matrix Metalloproteinase 13; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4; C069860:progelatinase
keywords: Matrix metalloprotease (MMP); Mesenchymal stem cells (MSCs); Tissue inhibitors of metalloprotease (TIMP)