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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the Role of the Immune System in Improving Tissue Regeneration: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26551.
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Anna Nicholson, Samantha N. Schumm, and Sarah H. Beachy, Rapporteurs Forum on Regenerative Medicine Board on Health Sciences Policy Health and Medicine Division PREPUBLICATION COPY—Uncorrected Proofs

THE NATIONAL ACADEMIES PRESS   500 Fifth Street, NW   Washington, DC 20001 This activity was supported by contracts between the National Academy of Sciences and Advanced Regenerative Manufacturing Institute; Akron Biotech; Alliance for Regenerative Medicine; American Society of Gene & Cell Therapy; Burroughs Well- come Fund (Grant No. 1021433); California Institute for Regenerative Medicine; Centre for Commercialization of Regenerative Medicine; Department of Veterans Affairs (Contract No. 36C24E21C0011; IFCAP-PO # 127-D12013); Food and Drug Administration: Center for Biologics Evaluation and Research (Grant No. 5R13FD006614-03); International Society for Cellular Therapy; International Soci- ety for Stem Cell Research; Johnson & Johnson; National Institute of Standards and Technology; National Institutes of Health: National Center for Advancing Translational Sciences; National Eye Institute; National Heart, Lung, and Blood Institute; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Neurological Disorders and Stroke (Contract No. HHSN263201800029I; Order No. 75N98019F00847; Mod. P00002); The New York Stem Cell Foundation; and United Therapeutics Corporation (No. 4500035476). Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project. International Standard Book Number-13: 978-0-309-XXXXX-X International Standard Book Number-10: 0-309-XXXXX-X Digital Object Identifier: https://doi.org/10.17226/26551 Additional copies of this report are available for sale from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. Copyright 2022 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2022. Understanding the role of the immune system in improving tissue regenera- tion: Proceedings of a workshop. Washington, DC: The National Academies Press. https://doi.org/10.17226/26551. PREPUBLICATION COPY—Uncorrected Proofs

The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president. The National Academy of Engineering was established in 1964 under the charter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. John L. Anderson is president. The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president. The three Academies work together as the National Academies of Sciences, Engineering, and Medicine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine. Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies.org. PREPUBLICATION COPY—Uncorrected Proofs

Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of experts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task. Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies. For information about other products and activities of the National Academies, please visit www.nationalacademies.org/about/whatwedo. PREPUBLICATION COPY—Uncorrected Proofs

PLANNING COMMITTEE ON UNDERSTANDING THE ROLE OF THE IMMUNE SYSTEM IN IMPROVING TISSUE REGENERATION1 NADYA LUMELSKY (Co-Chair), Chief, Integrative Biology and Infectious Diseases Branch; Director, Tissue Engineering and Regenerative Medicine Program, National Institute of Dental and Craniofacial Research, National Institutes of Health KIMBERLEE POTTER (Co-Chair), Scientific Program Manager, Biomedical Laboratory R&D Service, Office of Research & Development, Department of Veterans Affairs STEVEN BECKER, Associate Director, Office of Regenerative Medicine, National Eye Institute, National Institutes of Health (at the time the committee was formed) JENNIFER ELISSEEFF, Jules Stein Professor, Morton Goldberg Professor; Director, Translational Tissue Engineering Center, Johns Hopkins University SADIK KASSIM, Chief Technology Officer, Vor Biopharma CANDACE KERR, Program Officer, Division of Aging Biology, National Institute on Aging, National Institutes of Health CATO LAURENCIN, University Professor, Albert and Wilda Van Dusen Distinguished Professor; Director, The Raymond and Beverly Sackler Center for Biomedical, Biological, Physical, and Engineering Sciences; Chief Executive Officer, The Connecticut Convergence Institute for Translation in Regenerative Engineering, University of Connecticut RICHARD MCFARLAND, Chief Regulatory Officer, Advanced Regenerative Manufacturing Institute RACHEL SALZMAN, Chair, Government Relations Committee, American Society of Gene and Cell Therapy SOHEL TALIB, Senior Science Officer and Director of Therapeutics, California Institute for Regenerative Medicine DANIEL WEISS, Chief Scientific Officer, International Society for Cell & Gene Therapy; Professor, University of Vermont Forum on Regenerative Medicine Staff SARAH H. BEACHY, Senior Program Officer and Forum Director SIOBHAN ADDIE, Program Officer (until August 2021) MEREDITH HACKMANN, Associate Program Officer 1 The National Academies of Sciences, Engineering, and Medicine’s planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published proceedings of a workshop rests with the workshop rap- porteurs and the institution. v PREPUBLICATION COPY—Uncorrected Proofs

SAMANTHA SCHUMM, Associate Program Officer (from September 2021) LYDIA TEFERRA, Research Assistant Board on Health Sciences Policy Staff ANDREW M. POPE, Senior Board Director BRIDGET BOREL, Program Coordinator PREPUBLICATION COPY—Uncorrected Proofs

FORUM ON REGENERATIVE MEDICINE1 TIM COETZEE (Co-Chair), Chief Advocacy, Services, and Science Officer, National Multiple Sclerosis Society KATHERINE TSOKAS (Co-Chair), Vice President, Regulatory, Quality, Risk Management and Drug Safety, Janssen Inc. Canada SANGEETA BHATIA, John J. and Dorothy Wilson Professor, Institute for Medical Engineering and Science, Electrical Engineering and Computer Science, Massachusetts Institute of Technology PHILIP JOHN BROOKS, Program Director, Office of Rare Disease Research, National Center for Advancing Translational Sciences, National Institutes of Health GEORGE Q. DALEY, Director, Stem Cell Transplantation Program, Boston Children’s Hospital and Dana-Farber Cancer Institute; Dean, Harvard Medical School RENA D’SOUZA (from June 2021), Director, National Institute of Dental and Craniofacial Research, National Institutes of Health LAWRENCE GOLDSTEIN, Distinguished Professor, Department of Cellular and Molecular Medicine, Department of Neurosciences; Director, University of California, San Diego Stem Cell Program; Scientific Director, Sanford Consortium for Regenerative Medicine; Director, Sanford Stem Cell Clinical Center, University of California, San Diego School of Medicine CANDACE KERR, Program Officer, Stem Cell Program, Aging Physiology Branch Division of Aging Biology, National Institute on Aging, National Institutes of Health ROBERT S. LANGER, David H. Koch Institute Professor, Massachusetts Institute of Technology CATO T. LAURENCIN, University Professor, Albert and Wilda Van Dusen Distinguished Professor of Orthopaedic Surgery, Professor of Chemical, Materials Science, and Biomedical Engineering; Director, The Raymond and Beverly Sackler Center for Biomedical, Biological, Physical, and Engineering Sciences; Chief Executive Officer, The Connecticut Convergence Institute for Translation in Regenerative Engineering, University of Connecticut TIMOTHY LAVAUTE, Program Director, Division of Neuroscience, National Institute of Neurological Disease and Stroke, National Institutes of Health 1  The National Academies of Sciences, Engineering, and Medicine’s forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published proceedings of a workshop rests with the workshop rapporteurs and the institution. vii PREPUBLICATION COPY—Uncorrected Proofs

TERRY MAGNUSON, Sarah Graham Kenan Professor, Vice Chancellor for Research, University of North Carolina at Chapel Hill MICHAEL MAY, President and Chief Executive Officer, Centre for Commercialization of Regenerative Medicine RICHARD McFARLAND, Chief Regulatory Officer, Advanced Regenerative Manufacturing Institute JACK T. MOSHER, Senior Manager, Scientific Affairs, International Society for Stem Cell Research AMY PATTERSON, Chief Science Advisor and Director of Scientific Research Programs, National Heart, Lung, and Blood Institute, National Institutes of Health DUANQING PEI, Director General, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences THOMAS PETERSEN, Vice President, Regenerative Medicine, United Therapeutics Corporation ANNE PLANT, NIST Fellow, National Institute of Standards and Technology KIMBERLEE POTTER, Scientific Program Manager, Biomedical Laboratory R&D Service, Office of Research and Development, Department of Veterans Affairs DAVID RAMPULLA, Director, Division of Discovery Science & Technology, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health DEREK ROBERTSON, Co-Founder and President, Maryland Sickle Cell Disease Association KELLY ROSE, Program Officer, Burroughs Wellcome Fund KRISHNENDU ROY, Robert A. Milton Chair and Professor in Biomedical Engineering; Technical Lead, National Cell Manufacturing Consortium; Director, Marcus Center for Therapeutic Cell Characterization and Manufacturing, Georgia Institute of Technology KRISHANU SAHA, Associate Professor and Retina Research Foundation Kathryn and Latimer Murfee Chair, Department of Biomedical Engineering, University of Wisconsin–Madison RACHEL SALZMAN, Chair, Government Relations Committee, American Society of Gene and Cell Therapy IVONNE SCHULMAN, Program Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health JAY P. SIEGEL, (retired) Chief Biotechnology Officer and Head, Scientific Strategy and Policy, Johnson & Johnson LANA SKIRBOLL, Vice President, Science Policy, Sanofi SUSAN L. SOLOMAN, Founder and Chief Executive Officer, New York Stem Cell Foundation viii PREPUBLICATION COPY—Uncorrected Proofs

MARTHA SOMERMAN (until June 2021), Director, National Institute of Dental and Craniofacial Research, National Institutes of Health MICHAEL STEINMETZ, Director, Division of Extramural Science Programs, National Eye Institute, National Institutes of Health SOHEL TALIB, Senior Science Officer and Director of Therapeutics, California Institute for Regenerative Medicine DANIEL WEISS, Chief Scientific Officer, International Society for Cell & Gene Therapy MICHAEL WERNER, Co-Founder and Senior Policy Counsel, Alliance for Regenerative Medicine CELIA WITTEN, Deputy Director, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration CLAUDIA ZYLBERBERG, Founder and Chief Executive Officer, Akron Biotech Forum on Regenerative Medicine Staff SARAH H. BEACHY, Senior Program Officer and Forum Director SIOBHAN ADDIE, Program Officer (until August 2021) MEREDITH HACKMANN, Associate Program Officer SAMANTHA SCHUMM, Associate Program Officer (from September 2021) LYDIA TEFERRA, Research Assistant Board on Health Sciences Policy Staff ANDREW M. POPE, Senior Board Director BRIDGET BOREL, Program Coordinator ix PREPUBLICATION COPY—Uncorrected Proofs

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Reviewers This Proceedings of a Workshop was reviewed in draft form by indi- viduals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical com- ments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published proceedings as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the charge. The review comments and draft manuscript remain confidential to protect the integrity of the process. We thank the following individuals for their review of this proceedings: STEVEN BECKER, National Cancer Institute ERIKA MOORE, University of Florida Although the reviewers listed above provided many constructive com- ments and suggestions, they were not asked to endorse the content of the proceedings nor did they see the final draft before its release. The review of this proceedings was overseen by LESLIE Z. BENET, University of California, San Francisco. He was responsible for making certain that an independent examination of this proceedings was carried out in accordance with standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the rapporteurs and the National Academies. We also thank staff member Julie Schuck for reading and providing helpful comments on this manuscript. xi PREPUBLICATION COPY—Uncorrected Proofs

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Acknowledgments The support of the sponsors of the Forum on Regenerative Medicine was crucial to the planning and conduct of the workshop, Understanding the Role of the Immune System in Improving Tissue Regeneration, and for the development of this Proceedings of a Workshop. Federal sponsors were the Department of Veterans Affairs; U.S. Food and Drug Administration: Center for Biologics Evaluation and Research; National Institute of Stan- dards and Technology; National Institutes of Health: National Center for Advancing Translational Sciences; National Eye Institute; National Heart, Lung, and Blood Institute; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; and National Institute of Neurological Disorders and Stroke. Nonfederal sponsorship was provided by Advanced Regenerative Manufacturing Institute; Akron Biotech; Alliance for Regenerative Medi- cine; American Society of Gene & Cell Therapy; Burroughs Wellcome Fund; California Institute for Regenerative Medicine; Centre for Commercializa- tion of Regenerative Medicine; International Society for Cellular Therapy; International Society for Stem Cell Research; Johnson & Johnson; The New York Stem Cell Foundation; and United Therapeutics Corporation. The Forum on Regenerative Medicine wishes to express gratitude to the expert speakers who examined how modulation of the patient immune sys- tem and regenerative medicine products can improve the clinical outcomes xiii PREPUBLICATION COPY—Uncorrected Proofs

xiv ACKNOWLEDGMENTS of tissue repair and regeneration in patients. The Forum also wishes to thank the members of the planning committee for their work in developing an excellent workshop agenda. The project director would like to thank the project staff who worked diligently to develop both the workshop and the resulting Proceedings of a Workshop. PREPUBLICATION COPY—Uncorrected Proofs

Contents BOXES, FIGURES, AND TABLE xix ACRONYMS AND ABBREVIATIONS xxi 1 INTRODUCTION 1 Opening Remarks, 3 Organization of the Proceedings, 5 2 TISSUE HOMEOSTASIS, INFLAMMATION, AND REPAIR 7 Tissue Homeostasis, 8 Common Features of Tissue Organization, 8 Tissue Organization and Composition, 9 Cellular Division of Labor, 10 Minimal Tissue Units and Growth Factor Production, 10 Tissue or Organ Size Control, 13 Tissue Repair and Regeneration, 14 3 LESSONS LEARNED FROM IMMUNE TOLERANCE AND GRAFT ACCEPTANCE 15 The Microbiome and Immune Tolerance: Lessons from Allogeneic Hematopoietic Cell Transplantation, 16 Immune Tolerance and Graft Acceptance: Lessons from Transplant Immunology, 21 Discussion, 26 xv PREPUBLICATION COPY—Uncorrected Proofs

xvi CONTENTS 4 ENGINEERING OF ALLOGENEIC DONOR CELLS FOR ACCEPTANCE BY THE HOST’S IMMUNE SYSTEM 33 Mesenchymal Stromal Cells in Immunomodulatory Therapies, 34 Protecting Transplanted Cells from Immune Rejection, 37 Off-the-Shelf Engineered iPSC-Derived Natural Killer and T Cells for the Treatment of Cancer, 43 Discussion, 47 5 ENDOGENOUS REGENERATION AND THE ROLE OF THE LOCAL ENVIRONMENT IN REPAIR 53 Reversing Aging: Pro-Inflammatory Metabolite Prostaglandin E2 Augments Muscle Regeneration, 54 Biomaterials for Modeling Immune Mediation in Wound Healing, 59 Endogenous Pro-Resolution and Pro-Regenerative Mechanisms in Periodontal Tissue, 63 Discussion, 66 6 MODULATING THE HOST IMMUNE SYSTEM TO CREATE A PRO-REGENERATIVE ENVIRONMENT 73 Cellular Senescence, Senolytics, and Organ Regeneration and Transplantation, 74 Mapping the Immune and Tissue Environment in Healing and Non-healing Wounds, 79 Resolution of Acute Inflammation Stimulates Tissue Regeneration, 85 Discussion, 89 7 TOOLS AND PRECLINICAL MODELS FOR MONITORING AND OPTIMIZING THE HOST’S PRO-REGENERATIVE ENVIRONMENT 95 Tools for Immune Profiling and Monitoring, 96 Engineered Immunity as a Model for Regenerative Medicine, 100 Basic Immunology to Guide Regenerative Therapeutic Design, 104 Discussion, 108 8 HARNESSING THE IMMUNE SYSTEM TO IMPROVE PATIENT OUTCOMES 113 Final Panel Discussion, 114 Reflections on the Workshop, 120 PREPUBLICATION COPY—Uncorrected Proofs

CONTENTS xvii REFERENCES 127 APPENDIXES A WORKSHOP AGENDA 141 B SPEAKER BIOGRAPHICAL SKETCHES 151 C STATEMENT OF TASK 163 PREPUBLICATION COPY—Uncorrected Proofs

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Boxes, Figures, and Table BOXES 1-1 Workshop Statement of Task, 3 4-1 Advantages of Hypoimmune Cell Products, 40 5-1 Key Research Findings on the Role of Prostaglandin Signaling in Muscle Function, 59 6-1 Fundamental Aging Mechanisms and Phenotypes, 75 7-1 Impacts of CD19 CAR Therapy, 105 8-1 Ideas about the Future of Regenerative Medicine with Regard to the Immune System as Shared by Individual Presenters, 122 FIGURES 2-1 Three types of cellular division of labor, 11 2-2 Macrophage-fibroblast two-cell circuit, 13 3-1 Microbiome and antibiotic states and clinical risk of graft-versus-host disease, 20 xix PREPUBLICATION COPY—Uncorrected Proofs

xx THE ROLE OF THE IMMUNE SYSTEM IN TISSUE REGENERATION 4-1 Overview of regenerative stem cell therapy, 38 4-2 Adaptive and innate immune responses to allogeneic cells, 41 4-3 Platform for mass production of induced pluripotent stem cell products, 45 5-1 Immune response to pro-healing versus pro-fibrotic biomaterials implanted in breast tissue, 62 6-1 Foundations of regenerative immunology, 81 6-2 Endogenous control mechanisms in resolution of inflammation, 86 TABLE 2-1 Tissue Homeostasis, 9 PREPUBLICATION COPY—Uncorrected Proofs

Acronyms and Abbreviations 15-PGDH 15-hydroxyprostaglandin dehydrogenase ADCC antibody-dependent cell-mediated cytotoxicity ATAC-Seq Assay for Transposase-Accessible Chromatin with sequencing AUC area under the curve Breg regulatory B cell cAMP cyclic adenosine monophosphate CAR chimeric antigen receptor CD cluster of differentiation CN cellular neighborhood CODEX CO-Detection by indEXing Co1 cytochrome C oxidase I COX cyclooxygenase enzymes CSF-1 colony stimulating factor-1 DAMP damage-associated molecular pattern DEL-1 developmental endothelial locus-1 DHEA dehydroepiandrosterone ECM extracellular matrix EGF epidermal growth factor xxi PREPUBLICATION COPY—Uncorrected Proofs

xxii ACRONYMS AND ABBREVIATIONS EP4 E-type prostanoid receptor 4 ERK1/2 extracellular signal-regulated protein kinase ESC embryonic stem cell FAK focal adhesion kinase FDA U.S. Food and Drug Administration Gal Galalpha1-3Galbeta1-4GlcNAc GVHD graft versus host disease HCT hematopoietic cell transplantation HLA human leukocyte antigen HSCT hematopoietic stem cell transplantation HUVEC human umbilical vein endothelial cell ICAM-1 intercellular adhesion molecule 1 IgM immunoglobulin M IL interleukin iPSC induced pluripotent stem cells LFA-1 lymphocyte function–associated antigen 1 mAb monoclonal antibody MFGE8 milk fat globule-EGF factor 8 protein MGH Massachusetts General Hospital MHC major histocompatibility complex micro-CT micro-computed tomography miHA minor histocompatibility antigens MMP matrix metalloproteinase mRNA messenger RNA MS multiple sclerosis MSC mesenchymal stem/stromal cell mtDNA mitochondrial DNA mTOR mammalian target of rapamycin MuSC muscle stem cell MyoD myoblast determination protein 1 NF-kB nuclear factor kappa B NHP nonhuman primate NK natural killer NSAID non-steroidal anti-inflammatory drug PREPUBLICATION COPY—Uncorrected Proofs

ACRONYMS AND ABBREVATIONS xxiii P passage PAMP pathogen-associated molecular pattern PAX7 paired box 7 PCL polycaprolactone PDGF platelet-derived growth factor PD-L1 programmed death-ligand 1 PGD2 prostaglandin D2 PGE2 prostaglandin E2 PMN polymorphonuclear neutrophil PS phosphatidylserine RGD arginine-glycine-aspartic acid ROC receiver operating characteristic ROCK2 rho-associated coiled-coil-containing protein kinase RUNX2 runt-related transcription factor 2 SASP senescent-associated secretory phenotype SCAP senescent cell anti-apoptotic pathway SPM specialized pro-resolving mediator TGF-beta transforming growth factor beta Th T helper cell TLI total lymphoid irradiation TMJ temporomandibular joint TRAF3 tumor necrosis factor receptor associated factor 3 Treg regulatory T cell uPAR urokinase plasminogen activator receptor VDJ variable, diversity, joining VEGF vascular endothelial growth factor PREPUBLICATION COPY—Uncorrected Proofs

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The Forum on Regenerative Medicine of the National Academies of Sciences, Engineering, and Medicine convened a two-day virtual public workshop to address knowledge gaps in the understanding of promising approaches to manipulate the immune system and/or the regenerative medicine product to improve outcomes of tissue repair and regeneration in patients. The workshop, titled "Understanding the Role of the Immune System in Improving Tissue Regeneration," explored the role of the immune system in the success or failure of regenerative medicine therapies. Participants considered potential strategies to effectively "prepare" patients' immune systems to accept regenerative therapies and increase the likelihood of successful clinical outcomes and also discussed risks associated with modulating the immune system. This Proceedings of a Workshop highlights the presentations and discussions that occurred during the workshop.

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