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      Mesenchymal Stromal Cell Homing: Mechanisms and Strategies for Improvement

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          Abstract

          Mesenchymal stromal cells (MSCs) have been widely investigated for their therapeutic potential in regenerative medicine, owing to their ability to home damaged tissue and serve as a reservoir of growth factors and regenerative molecules. As such, clinical applications of MSCs are reliant on these cells successfully migrating to the desired tissue following their administration. Unfortunately, MSC homing is inefficient, with only a small percentage of cells reaching the target tissue following systemic administration. This attrition represents a major bottleneck in realizing the full therapeutic potential of MSC-based therapies. Accordingly, a variety of strategies have been employed in the hope of improving this process. Here, we review the molecular mechanisms underlying MSC homing, based on a multistep model involving (1) initial tethering by selectins, (2) activation by cytokines, (3) arrest by integrins, (4) diapedesis or transmigration using matrix remodelers, and (5) extravascular migration toward chemokine gradients. We then review the various strategies that have been investigated for improving MSC homing, including genetic modification, cell surface engineering, in vitro priming of MSCs, and in particular, ultrasound techniques, which have recently gained significant interest. Contextualizing these strategies within the multistep homing model emphasizes that our ability to optimize this process hinges on our understanding of its molecular mechanisms. Moving forward, it is only with a combined effort of basic biology and translational work that the potential of MSC-based therapies can be realized.

          Graphical Abstract

          Highlights

          • •

            Mesenchymal stromal cells (MSCs) are a promising platform for regenerative medicine

          • •

            A major bottleneck of MSC therapies is their efficiency in homing damaged tissue

          • •

            MSC homing is a multi-step process involving specific molecular interactions

          • •

            A variety of strategies have been employed to optimize MSC homing

          Abstract

          Biological Sciences; Cell Biology; Stem Cells Research

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          Most cited references127

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          Mesenchymal stem cells in the Wharton's jelly of the human umbilical cord.

          Hwai-Shi Wang, Shih-Chieh Hung, Shu-Tine Peng … (2004)
          The Wharton's jelly of the umbilical cord contains mucoid connective tissue and fibroblast-like cells. Using flow cytometric analysis, we found that mesenchymal cells isolated from the umbilical cord express matrix receptors (CD44, CD105) and integrin markers (CD29, CD51) but not hematopoietic lineage markers (CD34, CD45). Interestingly, these cells also express significant amounts of mesenchymal stem cell markers (SH2, SH3). We therefore investigated the potential of these cells to differentiate into cardiomyocytes by treating them with 5-azacytidine or by culturing them in cardiomyocyte-conditioned medium and found that both sets of conditions resulted in the expression of cardiomyocyte markers, namely N-cadherin and cardiac troponin I. We also showed that these cells have multilineage potential and that, under suitable culture conditions, are able to differentiate into cells of the adipogenic and osteogenic lineages. These findings may have a significant impact on studies of early human cardiac differentiation, functional genomics, pharmacological testing, cell therapy, and tissue engineering by helping to eliminate worrying ethical and technical issues.
          Article 0 comments Cited 356 times – based on 0 reviews     Review now
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            Why are MSCs therapeutic? New data: new insight.

            A Caplan (2009)
            Adult marrow-derived mesenchymal stem cells (MSCs) are able to differentiate into bone, cartilage, muscle, marrow stroma, tendon-ligament, fat and other connective tissues. The questions can be asked, what do MSCs do naturally and where is the MSC niche? New insight and clinical experience suggest that MSCs are naturally found as perivascular cells, summarily referred to as pericytes, which are released at sites of injury, where they secrete large quantities of bioactive factors that are both immunomodulatory and trophic. The trophic activity inhibits ischaemia-caused apoptosis and scarring while stimulating angiogenesis and the mitosis of tissue intrinsic progenitor cells. The immunomodulation inhibits lymphocyte surveillance of the injured tissue, thus preventing autoimmunity, and allows allogeneic MSCs to be used in a variety of clinical situations. Thus, a new, enlightened era of experimentation and clinical trials has been initiated with xenogenic and allogeneic MSCs.
            Article 0 comments Cited 307 times – based on 0 reviews     Review now
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              Mesenchymal stem cells: mechanisms of inflammation.

              Nora Singer, Arnold I. Caplan (2011)
              In adults, human mesenchymal stem cells (hMSCs) are found in vivo at low frequency and are defined by their capacity to differentiate into bone, cartilage, and adipose tissue, depending on the stimuli and culture conditions under which they are expanded. Although MSCs were initially hypothesized to be the panacea for regenerating tissues, MSCs appear to be more important in therapeutics to regulate the immune response invoked in settings such as tissue injury, transplantation, and autoimmunity. MSCs have been used therapeutically in clinical trials and subsequently in practice to treat graft-versus-host disease following bone marrow transplantation. Reports of successful immune modulation suggest efficacy in a wide range of autoimmune conditions, such as demyelinating neurological disease (multiple sclerosis), systemic lupus erythematosus, and Crohn's disease, among others. This review provides background information about hMSCs and also describes their putative mechanisms of action in inflammation. We provide a summary of ongoing clinical trials to allow (a) full comprehension of the range of diseases in which hMSC therapy may be beneficial and (b) identification of gaps in our knowledge about the mechanisms of action of therapeutic MSCs in disease.
              Article 0 comments Cited 280 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Avnesh S. Thakor
                Journal
                Journal ID (nlm-ta): iScience
                Journal ID (iso-abbrev): iScience
                Title: iScience
                Publisher: Elsevier
                ISSN (Electronic): 2589-0042
                Publication date PMC-release: 09 May 2019
                Publication date Collection: 31 May 2019
                Publication date (Electronic): 09 May 2019
                Volume: 15
                Pages: 421-438
                Affiliations
                [1 ]Interventional Regenerative Medicine and Imaging Laboratory, Stanford University School of Medicine, Department of Radiology, Palo Alto, CA 94304, USA
                Author notes
                [∗ ]Corresponding author asthakor@ 123456stanford.edu
                [2]

                These authors contributed equally

                [3]

                Lead Contact

                Article
                Publisher ID: S2589-0042(19)30141-5
                DOI: 10.1016/j.isci.2019.05.004
                PMC ID: 6529790
                PubMed ID: 31121468
                SO-VID: 8b86e41b-5bb9-487a-b621-9ff281a9b26d
                Copyright © © 2019 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Categories
                Subject: Review

                Keywords: biological sciences,cell biology,stem cells research
                Data availability:
                Keywords: biological sciences, cell biology, stem cells research

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