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      Modern Concepts in Regenerative Therapy for Ischemic Stroke: From Stem Cells for Promoting Angiogenesis to 3D-Bioprinted Scaffolds Customized via Carotid Shear Stress Analysis

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          Abstract

          Ischemic stroke is associated with a tremendous economic and societal burden, and only a few therapies are currently available for the treatment of this devastating disease. The main therapeutic approaches used nowadays for the treatment of ischemic brain injury aim to achieve reperfusion, neuroprotection and neurorecovery. Therapeutic angiogenesis also seems to represent a promising tool to improve the prognosis of cerebral ischemia. This review aims to present the modern concepts and the current status of regenerative therapy for ischemic stroke and discuss the main results of major clinical trials addressing the effectiveness of stem cell therapy for achieving neuroregeneration in ischemic stroke. At the same time, as a glimpse into the future, this article describes modern concepts for stroke prevention, such as the implantation of bioprinted scaffolds seeded with stem cells, whose 3D geometry is customized according to carotid shear stress.

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          Aggregation of human mesenchymal stromal cells (MSCs) into 3D spheroids enhances their antiinflammatory properties.

          Thomas Bartosh, Joni Ylöstalo, Arezoo Mohammadipoor … (2010)
          Previous reports suggested that culture as 3D aggregates or as spheroids can increase the therapeutic potential of the adult stem/progenitor cells referred to as mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs). Here we used a hanging drop protocol to prepare human MSCs (hMSCs) as spheroids that maximally expressed TNFalpha stimulated gene/protein 6 (TSG-6), the antiinflammatory protein that was expressed at high levels by hMSCs trapped in the lung after i.v. infusion and that largely explained the beneficial effects of hMSCs in mice with myocardial infarcts. The properties of spheroid hMSCs were found to depend critically on the culture conditions. Under optimal conditions for expression of TSG-6, the hMSCs also expressed high levels of stanniocalcin-1, a protein with both antiinflammatory and antiapoptotic properties. In addition, they expressed high levels of three anticancer proteins: IL-24, TNFalpha-related apoptosis inducing ligand, and CD82. The spheroid hMSCs were more effective than hMSCs from adherent monolayer cultures in suppressing inflammatory responses in a coculture system with LPS-activated macrophages and in a mouse model for peritonitis. In addition, the spheroid hMSCs were about one-fourth the volume of hMSCs from adherent cultures. Apparently as a result, larger numbers of the cells trafficked through the lung after i.v. infusion and were recovered in spleen, liver, kidney, and heart. The data suggest that spheroid hMSCs may be more effective than hMSCs from adherent cultures in therapies for diseases characterized by sterile tissue injury and unresolved inflammation and for some cancers that are sensitive to antiinflammatory agents.
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            3D bioprinting for biomedical devices and tissue engineering: A review of recent trends and advances

            Soroosh Derakhshanfar, Rene Mbeleck, Kaige Xu … (2018)
            3D printing, an additive manufacturing based technology for precise 3D construction, is currently widely employed to enhance applicability and function of cell laden scaffolds. Research on novel compatible biomaterials for bioprinting exhibiting fast crosslinking properties is an essential prerequisite toward advancing 3D printing applications in tissue engineering. Printability to improve fabrication process and cell encapsulation are two of the main factors to be considered in development of 3D bioprinting. Other important factors include but are not limited to printing fidelity, stability, crosslinking time, biocompatibility, cell encapsulation and proliferation, shear-thinning properties, and mechanical properties such as mechanical strength and elasticity. In this review, we recite recent promising advances in bioink development as well as bioprinting methods. Also, an effort has been made to include studies with diverse types of crosslinking methods such as photo, chemical and ultraviolet (UV). We also propose the challenges and future outlook of 3D bioprinting application in medical sciences and discuss the high performance bioinks.
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              Directed differentiation of embryonic stem cells into motor neurons.

              Hynek Wichterle, Ivo Lieberam, Jeffery Porter … (2002)
              Inductive signals and transcription factors involved in motor neuron generation have been identified, raising the question of whether these developmental insights can be used to direct stem cells to a motor neuron fate. We show that developmentally relevant signaling factors can induce mouse embryonic stem (ES) cells to differentiate into spinal progenitor cells, and subsequently into motor neurons, through a pathway recapitulating that used in vivo. ES cell-derived motor neurons can populate the embryonic spinal cord, extend axons, and form synapses with target muscles. Thus, inductive signals involved in normal pathways of neurogenesis can direct ES cells to form specific classes of CNS neurons.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 25 May 2019
                Publication date Collection: May 2019
                Volume: 20
                Issue: 10
                Electronic Location Identifier: 2574
                Affiliations
                Clinic of Cardiology, Cardiac Critical Care Unit, University of Medicine and Pharmacy, Gheorghe Marinescu 38, 540139 Târgu Mureș, Romania; annabell.benedek@ 123456yahoo.com (A.B.); andras.mester@ 123456yahoo.com (A.M.); diana.opincardiu@ 123456yahoo.ro (D.O.); roxana.hodas@ 123456yahoo.ro (R.H.); ioana_patricia@ 123456yahoo.com (I.R.); johannakeri@ 123456gmail.com (J.K.); theodora.benedek@ 123456gmail.com (T.B.)
                Author notes
                [* ]Correspondence: daniel.cernica@ 123456gmail.com ; Tel.: +40-758364410
                Article
                Publisher ID: ijms-20-02574
                DOI: 10.3390/ijms20102574
                PMC ID: 6566983
                PubMed ID: 31130624
                SO-VID: eb606ad4-e629-4da1-aaab-d95fa2f16c38
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 01 May 2019
                Date accepted : 22 May 2019
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: ischemic stroke,endothelial shear stress,neuroprotection,neuroregeneration,3d-bioprinted scaffolds,stem cells,regenerative therapy
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: ischemic stroke, endothelial shear stress, neuroprotection, neuroregeneration, 3d-bioprinted scaffolds, stem cells, regenerative therapy

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