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      Shattering barriers toward clinically meaningful MSC therapies

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          Abstract

          To realize the potential of MSCs, bioengineering is needed to boost potency and control heterogeneity.

          Abstract

          More than 1050 clinical trials are registered at FDA.gov that explore multipotent mesenchymal stromal cells (MSCs) for nearly every clinical application imaginable, including neurodegenerative and cardiac disorders, perianal fistulas, graft-versus-host disease, COVID-19, and cancer. Several companies have or are in the process of commercializing MSC-based therapies. However, most of the clinical-stage MSC therapies have been unable to meet primary efficacy end points. The innate therapeutic functions of MSCs administered to humans are not as robust as demonstrated in preclinical studies, and in general, the translation of cell-based therapy is impaired by a myriad of steps that introduce heterogeneity. In this review, we discuss the major clinical challenges with MSC therapies, the details of these challenges, and the potential bioengineering approaches that leverage the unique biology of MSCs to overcome the challenges and achieve more potent and versatile therapies.

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          Most cited references127

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          Fibroblast precursors in normal and irradiated mouse hematopoietic organs.

          Using the in vitro colony assay, clonogenic fibroblast precursor cells (CFU-F) were detected in the bone marrow, spleen and thymus from adult mice. The survival curve for CFU-F of mouse bone marrow irradiated in vitro has a D0 of 220 r. Regeneration of bone marrow CFU-F after whole-body irradiation with 150 r is characterized by a marked secondary loss and post-irradiation lag and dip, lasting 6 days, followed by return to normal values by about the 25th day. This pattern of post-radiation recovery of CFU-F is similar to that of the CFU-s. In addition, during the first 6 hours following irradiation the number of CFU-F increased approximately twofold.
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            Extracellular matrix as a driver of progressive fibrosis.

            The extracellular matrix (ECM) is dynamically tuned to optimize physiological function. Its major properties, including composition and mechanics, profoundly influence cell biology. Cell-ECM interactions operate through an integrated set of sensor and effector circuits that use several classes of receptors and signal transduction pathways. At the single-cell level, the ECM governs differentiation, metabolism, motility, orientation, proliferation, and survival. At the cell population level, the ECM provides higher-order guidance that is essential for physiological function. When pathological changes in the ECM lead to impairment of organ function, we use the term "fibrosis." In this Review, we differentiate fibrosis initiation from progression and focus primarily on progressive lung fibrosis impairing organ function. We present a working model to explain how the altered ECM is not only a consequence but also a driver of fibrosis. Additionally, we advance the concept that fibrosis progression occurs in a fibrogenic niche that is composed of a fibrogenic ECM that nurtures fibrogenic mesenchymal progenitor cells and their fibrogenic progeny.
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              Transplantation of hypoxia-preconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis.

              This study explored the novel strategy of hypoxic preconditioning of bone marrow mesenchymal stem cells before transplantation into the infarcted heart to promote their survival and therapeutic potential of mesenchymal stem cell transplantation after myocardial ischemia. Mesenchymal stem cells from green fluorescent protein transgenic mice were cultured under normoxic or hypoxic (0.5% oxygen for 24 hours) conditions. Expression of growth factors and anti-apoptotic genes were examined by immunoblot. Normoxic or hypoxic stem cells were intramyocardially injected into the peri-infarct region of rats 30 minutes after permanent myocardial infarction. Death of mesenchymal stem cells was assessed in vitro and in vivo after transplantation. Angiogenesis, infarct size, and heart function were measured 6 weeks after transplantation. Hypoxic preconditioning increased expression of pro-survival and pro-angiogenic factors including hypoxia-inducible factor 1, angiopoietin-1, vascular endothelial growth factor and its receptor, Flk-1, erythropoietin, Bcl-2, and Bcl-xL. Cell death of hypoxic stem cells and caspase-3 activation in these cells were significantly lower compared with that in normoxic stem cells both in vitro and in vivo. Transplantation of hypoxic versus normoxic mesenchymal stem cells after myocardial infarction resulted in an increase in angiogenesis, as well as enhanced morphologic and functional benefits of stem cell therapy. Hypoxic preconditioning enhances the capacity of mesenchymal stem cells to repair infarcted myocardium, attributable to reduced cell death and apoptosis of implanted cells, increased angiogenesis/vascularization, and paracrine effects.
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                Author and article information

                Journal
                Sci Adv
                Sci Adv
                SciAdv
                advances
                Science Advances
                American Association for the Advancement of Science
                2375-2548
                July 2020
                22 July 2020
                : 6
                : 30
                : eaba6884
                Affiliations
                [1 ]Center for Nanomedicine and Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA.
                [2 ]BWH Center of Excellence for Biomedicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
                [3 ]Center for Stem Cell Therapeutics and Imaging, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
                [4 ]Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
                [5 ]Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
                [6 ]National Center of Pharmaceutical Technology, Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia.
                [7 ]KACST Center of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia.
                [8 ]Broad Institute of MIT and Harvard, Cambridge, MA, USA.
                Author notes
                [*]

                These authors equally contributed to this work.

                []Corresponding author. Email: jmkarp@ 123456bwh.harvard.edu (J.M.K); kshah@ 123456bwh.harvard.edu (K.S.)
                Author information
                http://orcid.org/0000-0003-0825-0568
                http://orcid.org/0000-0003-2324-1272
                http://orcid.org/0000-0002-5060-5425
                http://orcid.org/0000-0003-4142-5518
                http://orcid.org/0000-0001-8823-4458
                http://orcid.org/0000-0003-2186-6930
                http://orcid.org/0000-0002-3968-3414
                http://orcid.org/0000-0003-4789-5422
                http://orcid.org/0000-0001-9181-3792
                http://orcid.org/0000-0002-5474-0974
                http://orcid.org/0000-0002-4752-7374
                Article
                aba6884
                10.1126/sciadv.aba6884
                7439491
                32832666
                153e4cad-419f-450b-94f2-906368876dea
                Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                : 23 December 2019
                : 05 June 2020
                Funding
                Funded by: doi http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: HL095722
                Funded by: doi http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: NS107857
                Funded by: doi http://dx.doi.org/10.13039/501100004919, King Abdulaziz City for Science and Technology;
                Categories
                Review
                Reviews
                SciAdv reviews
                Health and Medicine
                Applied Sciences and Engineering
                Health and Medicine
                Custom metadata
                Eunice Diego

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