Understanding the Role of the
Immune System in Improving
Tissue Regeneration
PROCEEDINGS OF A WORKSHOP
Anna Nicholson, Samantha N. Schumm, and Sarah H. Beachy,
Rapporteurs
Forum on Regenerative Medicine
Board on Health Sciences Policy
Health and Medicine Division
THE NATIONAL ACADEMIES PRESS
Washington, DC
www.nap.edu
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 Wellcome 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 Society 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: 978-0-309-68817-8
International Standard Book Number-10: 0-309-68817-5
Digital Object Identifier: https://doi.org/10.17226/26551
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Suggested citation: 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. https://doi.org/10.17226/26551.
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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, 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 rapporteurs and the institution.
SAMANTHA SCHUMM, Associate Program Officer (from September 2021)
LYDIA TEFERRA, Research Assistant
Board on Health Sciences Policy Staff
BRIDGET BOREL, Program Coordinator
ANDREW M. POPE, Senior Board Director
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, 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.
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
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
BRIDGET BOREL, Program Coordinator
ANDREW M. POPE, Senior Board Director
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Reviewers
This Proceedings of a Workshop was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments 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:
Although the reviewers listed above provided many constructive comments 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.
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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 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; and National Institute of Neurological Disorders and Stroke. Nonfederal sponsorship was provided by Advanced Regenerative Manufacturing Institute; Akron Biotech; Alliance for Regenerative Medicine; American Society of Gene & Cell Therapy; Burroughs Wellcome Fund; California Institute for Regenerative Medicine; Centre for Commercialization 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 system and regenerative medicine products can improve the clinical outcomes
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.
Contents
Organization of the Proceedings
2 TISSUE HOMEOSTASIS, INFLAMMATION, AND REPAIR
Common Features of Tissue Organization
Tissue Organization and Composition
Minimal Tissue Units and Growth Factor Production
Tissue Repair and Regeneration
3 LESSONS LEARNED FROM IMMUNE TOLERANCE AND GRAFT ACCEPTANCE
The Microbiome and Immune Tolerance: Lessons from Allogeneic Hematopoietic Cell Transplantation
Immune Tolerance and Graft Acceptance: Lessons from Transplant Immunology
4 ENGINEERING OF ALLOGENEIC DONOR CELLS FOR ACCEPTANCE BY THE HOST’S IMMUNE SYSTEM
Mesenchymal Stromal Cells in Immunomodulatory Therapies
Protecting Transplanted Cells from Immune Rejection
Off-the-Shelf Engineered iPSC-Derived Natural Killer and T Cells for the Treatment of Cancer
5 ENDOGENOUS REGENERATION AND THE ROLE OF THE LOCAL ENVIRONMENT IN REPAIR
Reversing Aging: Pro-Inflammatory Metabolite Prostaglandin E2 Augments Muscle Regeneration
Biomaterials for Modeling Immune Mediation in Wound Healing
Endogenous Pro-Resolution and Pro-Regenerative Mechanisms in Periodontal Tissue
6 MODULATING THE HOST IMMUNE SYSTEM TO CREATE A PRO-REGENERATIVE ENVIRONMENT
Cellular Senescence, Senolytics, and Organ Regeneration and Transplantation
Mapping the Immune and Tissue Environment in Healing and Non-healing Wounds
Resolution of Acute Inflammation Stimulates Tissue Regeneration
7 TOOLS AND PRECLINICAL MODELS FOR MONITORING AND OPTIMIZING THE HOST’S PRO-REGENERATIVE ENVIRONMENT
Tools for Immune Profiling and Monitoring
Engineered Immunity as a Model for Regenerative Medicine
Basic Immunology to Guide Regenerative Therapeutic Design
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Boxes, Figures, and Table
BOXES
1-1 Workshop Statement of Task
4-1 Advantages of Hypoimmune Cell Products
5-1 Key Research Findings on the Role of Prostaglandin Signaling in Muscle Function
6-1 Fundamental Aging Mechanisms and Phenotypes
7-1 Impacts of CD19 CAR Therapy
FIGURES
2-1 Three types of cellular division of labor
2-2 Macrophage-fibroblast two-cell circuit
3-1 Microbiome and antibiotic states and clinical risk of graft-versus-host disease
4-1 Overview of regenerative stem cell therapy
4-2 Adaptive and innate immune responses to allogeneic cells
4-3 Platform for mass production of induced pluripotent stem cell products
5-1 Immune response to pro-healing versus pro-fibrotic biomaterials implanted in breast tissue
6-1 Foundations of regenerative immunology
6-2 Endogenous control mechanisms in resolution of inflammation
TABLE
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 |
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 |
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 |
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