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      Engineering of hybrid spheroids of mesenchymal stem cells and drug depots for immunomodulating effect in islet xenotransplantation

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          Abstract

          Immunomodulation is an essential consideration for cell replacement procedures. Unfortunately, lifelong exposure to nonspecific systemic immunosuppression results in immunodeficiency and has toxic effects on nonimmune cells. Here, we engineered hybrid spheroids of mesenchymal stem cells (MSCs) with rapamycin-releasing poly(lactic- co-glycolic acid) microparticles (RAP-MPs) to prevent immune rejection of islet xenografts in diabetic C57BL/6 mice. Hybrid spheroids were rapidly formed by incubating cell-particle mixture in methylcellulose solution while maintaining high cell viability. RAP-MPs were uniformly distributed in hybrid spheroids and sustainably released RAP for ~3 weeks. Locoregional transplantation of hybrid spheroids containing low doses of RAP-MPs (200- to 4000-ng RAP per recipient) significantly prolonged islet survival times and promoted the generation of regional regulatory T cells. Enhanced programmed death-ligand 1 expression by MSCs was found to be responsible for the immunomodulatory performance of hybrid spheroids. Our results suggest that these hybrid spheroids offer a promising platform for the efficient use of MSCs in the transplantation field.

          Abstract

          Abstract

          Engineered hybrid spheroids of mesenchymal stem cells and rapamycin depots protect xenogeneic islets from immune rejection.

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          The diverse functions of the PD1 inhibitory pathway

          T cell activation is a highly regulated process involving peptide-MHC engagement of the T cell receptor and positive costimulatory signals. Upon activation, coinhibitory 'checkpoints', including programmed cell death protein 1 (PD1), become induced to regulate T cells. PD1 has an essential role in balancing protective immunity and immunopathology, homeostasis and tolerance. However, during responses to chronic pathogens and tumours, PD1 expression can limit protective immunity. Recently developed PD1 pathway inhibitors have revolutionized cancer treatment for some patients, but the majority of patients do not show complete responses, and adverse events have been noted. This Review discusses the diverse roles of the PD1 pathway in regulating immune responses and how this knowledge can improve cancer immunotherapy as well as restore and/or maintain tolerance during autoimmunity and transplantation.
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            Rapamycin: one drug, many effects.

            The mammalian target of rapamycin (mTOR) signaling pathway is a master regulator of cell growth and metabolism. Deregulation of the mTOR pathway has been implicated in a number of human diseases such as cancer, diabetes, obesity, neurological diseases, and genetic disorders. Rapamycin, a specific inhibitor of mTOR, has been shown to be useful in the treatment of certain diseases. Here we discuss its mechanism of action and highlight recent findings regarding the effects and limitations of rapamycin monotherapy and the potential utility of combination therapy with rapamycin. Copyright © 2014 Elsevier Inc. All rights reserved.
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              Mesenchymal Stem Cell Immunomodulation: Mechanisms and Therapeutic Potential

              Mesenchymal stem/stromal cells (MSCs) are multipotent cells that are emerging as the most promising means of allogeneic cell therapy. MSCs have inherent immunomodulatory characteristics, trophic activity, high invitro self-renewal ability, and can be readily engineered to enhance their immunomodulatory functions. MSCs affect the functions of most immune effector cells via direct contact with immune cells and local microenvironmental factors. Previous studies have confirmed that the immunomodulatory effects of MSCs are mainly communicated via MSC-secreted cytokines; however, apoptotic and metabolically inactivated MSCs have more recently been shown to possess immunomodulatory potential, in which regulatory T cells and monocytes play a key role. We review the immunomodulatory aspects of naïve and engineered MSCs, and discuss strategies for increasing the potential of successfully using MSCs in clinical settings.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing - original draft
                Role: Formal analysisRole: Investigation
                Role: Investigation
                Role: InvestigationRole: Resources
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: Investigation
                Role: Writing - review & editing
                Role: Formal analysisRole: Investigation
                Role: Investigation
                Role: ConceptualizationRole: InvestigationRole: Resources
                Role: ConceptualizationRole: Formal analysisRole: ValidationRole: Writing - review & editing
                Role: MethodologyRole: ResourcesRole: Validation
                Role: Formal analysisRole: MethodologyRole: SoftwareRole: Writing - review & editing
                Role: Writing - review & editing
                Role: Methodology
                Role: MethodologyRole: Validation
                Role: Resources
                Role: SupervisionRole: Writing - review & editing
                Role: ResourcesRole: Writing - review & editing
                Role: Writing - review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: ResourcesRole: Validation
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Journal
                Sci Adv
                Sci Adv
                sciadv
                advances
                Science Advances
                American Association for the Advancement of Science
                2375-2548
                August 2022
                24 August 2022
                : 8
                : 34
                : eabn8614
                Affiliations
                [ 1 ]College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea.
                [ 2 ]College of Pharmacy, Keimyung University, Daegu, 42601, Republic of Korea.
                [ 3 ]College of Medicine, Yeungnam University, Daegu, 42415, Republic of Korea.
                [ 4 ]College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 21983, Republic of Korea.
                [ 5 ]Epibiotech Co. Ltd., Incheon, 21983, Republic of Korea.
                [ 6 ]State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
                [ 7 ]Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing, 210009, China.
                [ 8 ]Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, 210009, China.
                [ 9 ]NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing, 210009, China.
                [ 10 ]Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan, 50612, Republic of Korea.
                [ 11 ]Dental and Life Science Institute, Pusan National University, Yangsan, 50612, Republic of Korea.
                [ 12 ]Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
                Author notes
                [* ]Corresponding author. Email: jeeheon@ 123456skku.edu (J.-H.J.); ysimmyung@ 123456kmu.ac.kr (S.Y.)
                Author information
                https://orcid.org/0000-0003-0377-1153
                https://orcid.org/0000-0002-3098-3541
                https://orcid.org/0000-0001-5771-2664
                https://orcid.org/0000-0003-0757-5299
                https://orcid.org/0000-0002-3853-7925
                https://orcid.org/0000-0003-2025-6698
                https://orcid.org/0000-0002-4057-1313
                https://orcid.org/0000-0001-6937-6135
                https://orcid.org/0000-0002-1001-6570
                https://orcid.org/0000-0002-6555-9716
                https://orcid.org/0000-0002-2428-8403
                https://orcid.org/0000-0002-4929-851X
                https://orcid.org/0000-0002-1620-1777
                https://orcid.org/0000-0002-7588-7393
                https://orcid.org/0000-0003-2129-1890
                https://orcid.org/0000-0002-7120-169X
                Article
                abn8614
                10.1126/sciadv.abn8614
                9401619
                36001671
                5938d1eb-dffa-46ff-8a44-9d1785cd3f4e
                Copyright © 2022 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
                : 06 January 2022
                : 11 July 2022
                Funding
                Funded by: Cooperative Research Program for Agriculture Science and Technology Development, Rural Development Administration, Republic of Korea;
                Award ID: PJ015596
                Funded by: National Research Foundation of Korea (NRF), Ministry of Science and ICT., Republic of Korea;
                Award ID: 2020R1C1C1004733
                Funded by: National Research Foundation of Korea (NRF), Ministry of Science and ICT., Republic of Korea;
                Award ID: 2021K1A3A1A20002609
                Categories
                Research Article
                Biomedicine and Life Sciences
                SciAdv r-articles
                Immunology
                Research Methods
                Immunology
                Custom metadata
                Karla Peñamante

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