The Inflammatory Lung Microenvironment; a Key Mediator in MSC Licensing

Recent clinical trials of mesenchymal stromal cell (MSC) therapy for various inflammatory conditions have highlighted the significant benefit to patients who respond to MSC administration. Thus, there is strong interest in investigating MSC therapy in acute inflammatory lung conditions, such as acute respiratory distress syndrome (ARDS). Unfortunately, not all patients respond, and evidence now suggests that the differential disease microenvironment present across patients and sub-phenotypes of disease or across disease severities influences MSC licensing, function and therapeutic efficacy. Here, we discuss the importance of licensing MSCs and the need to better understand how the disease microenvironment influences MSC activation and therapeutic actions, in addition to the need for a patient-stratification approach.

• Publication year

  2021

• Venue

  Cells

• Publication date

  2021-11-01

• Fields of study

  Biology, Medicine, Environmental Science

• Identifiers
  DOI 10.3390/cells10112982PMID 34831203PMCID 8616504
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Cyclosporine A and IFNγ licencing enhances human mesenchymal stromal cell potency in a humanised mouse model of acute graft versus host disease

  2021influential reference
• Healthy versus inflamed lung environments differentially affect mesenchymal stromal cells

  2021cited by this paper
• Industry updates from the field of stem cell research and regenerative medicine in November 2020.

  2021cited by this paper
• Umbilical cord mesenchymal stem cells for COVID‐19 acute respiratory distress syndrome: A double‐blind, phase 1/2a, randomized controlled trial

  2021cited by this paper
• Heat shock preconditioning mesenchymal stem cells attenuate acute lung injury via reducing NLRP3 inflammasome activation in macrophages

  2021cited by this paper
• Umbilical cord mesenchymal stromal cells as critical COVID‐19 adjuvant therapy: A randomized controlled trial

  2021cited by this paper
• IFN‐γ and PPARδ influence the efficacy and retention of multipotent adult progenitor cells in graft vs host disease

  2021influential reference
• Mesenchymal stromal cells reduce evidence of lung injury in patients with ARDS

  2021cited by this paper
• Effect of mesenchymal stromal cell infusions on lung function in COPD patients with high CRP levels

  2021influential reference
• Identification of distinct clinical subphenotypes in critically ill patients with COVID-19.

  2021cited by this paper
• Industry updates from the field of stem cell research and regenerative medicine in January 2021.

  2021cited by this paper
• Transcriptional profiling of circulating mononuclear cells from patients with chronic obstructive pulmonary disease receiving mesenchymal stromal cell infusions

  2021cited by this paper
• Acute Respiratory Distress Syndrome Subphenotypes beyond the Syndrome: A Step toward Treatable Traits?

  2021cited by this paper
• Research Progress on Strategies that can Enhance the Therapeutic Benefits of Mesenchymal Stromal Cells in Respiratory Diseases With a Specific Focus on Acute Respiratory Distress Syndrome and Other Inflammatory Lung Diseases

  2021cited by this paper
• Differential effects of heat‐inactivated, secretome‐deficient MSC and metabolically active MSC in sepsis and allogenic heart transplantation

  2020cited by this paper
• Human Umbilical Cord-Derived Mesenchymal Stem Cells for Acute Respiratory Distress Syndrome

  2020cited by this paper
• Mesenchymal Stem and Stromal Cells Harness Macrophage-Derived Amphiregulin to Maintain Tissue Homeostasis.

  2020cited by this paper
• Shattering barriers toward clinically meaningful MSC therapies

  2020cited by this paper
• Darvadstrocel for the treatment of perianal fistulas in Crohn’s disease

  2020cited by this paper
• Amniotic MSCs reduce pulmonary fibrosis by hampering lung B‐cell recruitment, retention, and maturation

  2020cited by this paper
• Differential effects of the cystic fibrosis lung inflammatory environment on mesenchymal stromal cells

  2020cited by this paper
• Time-dependent LPS exposure commands MSC immunoplasticity through TLR4 activation leading to opposite therapeutic outcome in EAE

  2020influential reference
• Mesenchymal stromal cells for GVHD: A Trilogy.

  2020cited by this paper
• TNF‐α and IL‐1β sensitize human MSC for IFN‐γ signaling and enhance neutrophil recruitment

  2020cited by this paper
• Immunopathology in schistosomiasis is regulated by TLR2,4- and IFN-γ-activated MSC through modulating Th1/Th2 responses

  2020cited by this paper
• TGF-β1-Licensed Murine MSCs Show Superior Therapeutic Efficacy in Modulating Corneal Allograft Immune Rejection In Vivo

  2020cited by this paper
• Mesenchymal stromal cell extracellular vesicles rescue mitochondrial dysfunction and improve barrier integrity in clinically relevant models of ARDS

  2020influential reference
• Molecular Crosstalk Between Macrophages and Mesenchymal Stromal Cells

  2020cited by this paper
• Phenotypes and personalized medicine in the acute respiratory distress syndrome

  2020cited by this paper
• Mesenchymal stromal cells reprogram monocytes and macrophages with processing bodies

  2020cited by this paper
• Dose and duration of interferon γ pre-licensing interact with donor characteristics to influence the expression and function of indoleamine-2,3-dioxygenase in mesenchymal stromal cells

  2020influential reference
• The potential of mesenchymal stem cell therapy for chronic lung disease

  2020cited by this paper
• CCL2 and CXCL12 Derived from Mesenchymal Stromal Cells Cooperatively Polarize IL-10+ Tissue Macrophages to Mitigate Gut Injury

  2020cited by this paper
• Extracellular Vesicles from Interferon-&ggr;–primed Human Umbilical Cord Mesenchymal Stromal Cells Reduce Escherichia coli–induced Acute Lung Injury in Rats

  2019influential reference
• Precision medicine for cell therapy in acute respiratory distress syndrome.

  2019cited by this paper
• Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies

  2019cited by this paper
• TNF‐α/IL‐1β—licensed mesenchymal stromal cells promote corneal allograft survival via myeloid cell‐mediated induction of Foxp3+ regulatory T cells in the lung

  2019cited by this paper
• Mesenchymal stem cells immunomodulation: The road to IFN-γ licensing and the path ahead.

  2019cited by this paper
• The Necrobiology of Mesenchymal Stromal Cells Affects Therapeutic Efficacy

  2019cited by this paper
• Mesenchymal Stem Cells Reconditioned in Their Own Serum Exhibit Augmented Therapeutic Properties in the Setting of Acute Respiratory Distress Syndrome

  2019cited by this paper
• Mesenchymal Stem Cell–Derived Extracellular Vesicles Decrease Lung Injury in Mice

  2019cited by this paper
• Mesenchymal Stromal Cells Are More Effective Than Their Extracellular Vesicles at Reducing Lung Injury Regardless of Acute Respiratory Distress Syndrome Etiology

  2019influential reference
• Primary Analysis of a Phase 1/2 Study to Assess MultiStem® Cell Therapy, a Regenerative Advanced Therapy Medicinal Product (ATMP), in Acute Respiratory Distress Syndrome (MUST-ARDS)

  2019cited by this paper
• Lung inflammatory environments differentially alter mesenchymal stromal cell behavior

  2019cited by this paper
• Angiopoietin like 4 as a clinical biomarker for acute respiratory distress syndrome

  2019cited by this paper
• Mesenchymal stem cell perspective: cell biology to clinical progress

  2019cited by this paper
• Biophysically Preconditioning Mesenchymal Stem Cells Improves Treatment of Ventilator-Induced Lung Injury.

  2019cited by this paper
• Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial.

  2019influential reference
• Phenotypes in acute respiratory distress syndrome: moving towards precision medicine

  2019cited by this paper
• Identification and Modulation of Microenvironment Is Crucial for Effective Mesenchymal Stromal Cell Therapy in Acute Lung Injury.

  2019influential reference
• Liver Macrophage Depletion Ameliorates The Effect of Mesenchymal Stem Cell Transplantation in a Murine Model of Injured Liver

  2019cited by this paper
• Priming with Toll-like receptor 3 agonist or interferon-gamma enhances the therapeutic effects of human mesenchymal stem cells in a murine model of atopic dermatitis

  2019cited by this paper
• Is a Part Better than the Whole for Cell-based Therapy for Acute Respiratory Distress Syndrome?

  2019cited by this paper
• Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities.

  2018cited by this paper
• Mesenchymal stromal cell infusion modulates systemic immunological responses in stable COPD patients: a phase I pilot study

  2018cited by this paper
• Exosomes originating from MSCs stimulated with TGF‐β and IFN‐γ promote Treg differentiation

  2018cited by this paper
• The TLR4‐PAR1 Axis Regulates Bone Marrow Mesenchymal Stromal Cell Survival and Therapeutic Capacity in Experimental Bacterial Pneumonia

  2018cited by this paper
• Cell therapy in acute respiratory distress syndrome.

  2018cited by this paper
• Serum from Asthmatic Mice Potentiates the Therapeutic Effects of Mesenchymal Stromal Cells in Experimental Allergic Asthma

  2018influential reference
• Strategies to improve the therapeutic effects of mesenchymal stromal cells in respiratory diseases

  2018cited by this paper
• Immunomodulation By Therapeutic Mesenchymal Stromal Cells (MSC) Is Triggered Through Phagocytosis of MSC By Monocytic Cells

  2018cited by this paper
• Multipotent Adult Progenitor Cells Suppress T Cell Activation in In Vivo Models of Homeostatic Proliferation in a Prostaglandin E2-Dependent Manner

  2018cited by this paper
• Effect of Tumor Necrosis Factor Alpha Dose and Exposure Time on Tumor Necrosis Factor-Induced Gene-6 Activation by Neonatal and Adult Mesenchymal Stromal Cells

  2018cited by this paper
• Critical Role of Tumor Necrosis Factor Signaling in Mesenchymal Stem Cell-Based Therapy for Autoimmune and Inflammatory Diseases

  2018cited by this paper
• Syndecan-2–positive, Bone Marrow–derived Human Mesenchymal Stromal Cells Attenuate Bacterial-induced Acute Lung Injury and Enhance Resolution of Ventilator-induced Lung Injury in Rats

  2018cited by this paper
• Mesenchymal stem cells enhance NOX2-dependent reactive oxygen species production and bacterial killing in macrophages during sepsis

  2018cited by this paper
• Inflammation‐Stimulated Mesenchymal Stromal Cell‐Derived Extracellular Vesicles Attenuate Inflammation

  2018cited by this paper
• Mesenchymal stromal cells from human umbilical cord prevent the development of lung fibrosis in immunocompetent mice

  2018cited by this paper
• Therapeutic effects of human mesenchymal stem cell microvesicles in an ex vivo perfused human lung injured with severe E. coli pneumonia

  2018cited by this paper
• Toll-like receptor 2 ligation of mesenchymal stem cells alleviates asthmatic airway inflammation.

  2018cited by this paper
• Left Ventricular Dysfunction Switches Mesenchymal Stromal Cells Toward an Inflammatory Phenotype and Impairs Their Reparative Properties Via Toll-Like Receptor-4

  2017cited by this paper
• Cryopreserved, Xeno-Free Human Umbilical Cord Mesenchymal Stromal Cells Reduce Lung Injury Severity and Bacterial Burden in Rodent Escherichia coli–Induced Acute Respiratory Distress Syndrome

  2017cited by this paper
• The influence of macrophages on mesenchymal stromal cell therapy: passive or aggressive agents?

  2017cited by this paper
• Human adipose tissue mesenchymal stromal cells and their extracellular vesicles act differentially on lung mechanics and inflammation in experimental allergic asthma

  2017cited by this paper
• Hypoxic Preconditioning Promotes the Bioactivities of Mesenchymal Stem Cells via the HIF-1α-GRP78-Akt Axis

  2017cited by this paper
• Kynurenic acid, an IDO metabolite, controls TSG-6-mediated immunosuppression of human mesenchymal stem cells

  2017influential reference
• Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation

  2017cited by this paper
• Fifty Years of Research in ARDS., Cell‐based Therapy for Acute Respiratory Distress Syndrome. Biology and Potential Therapeutic Value

  2017cited by this paper
• Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer

  2017influential reference
• Hypoxia-preconditioned mesenchymal stem cells ameliorate ischemia/reperfusion-induced lung injury

  2017cited by this paper
• Allogeneic Human Mesenchymal Stem Cells in Patients With Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER): A Phase I Safety Clinical Trial

  2017influential reference
• Mesenchymal Stromal Cells and Toll-Like Receptor Priming: A Critical Review

  2017cited by this paper
• Toward Development of iMesenchymal Stem Cells for Immunomodulatory Therapy

  2016cited by this paper
• Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial.

  2016cited by this paper
• Hepatocyte Growth Factor Is Required for Mesenchymal Stromal Cell Protection Against Bleomycin‐Induced Pulmonary Fibrosis

  2016influential reference
• A phase I study for intravenous autologous mesenchymal stromal cell administration to patients with severe emphysema.

  2016cited by this paper
• Mitochondrial Transfer via Tunneling Nanotubes is an Important Mechanism by Which Mesenchymal Stem Cells Enhance Macrophage Phagocytosis in the In Vitro and In Vivo Models of ARDS

  2016cited by this paper
• TLR3 preconditioning enhances the therapeutic efficacy of umbilical cord mesenchymal stem cells in TNBS-induced colitis via the TLR3-Jagged-1-Notch-1 pathway

  2016cited by this paper
• Low levels of TGF-β1 enhance human umbilical cord-derived mesenchymal stem cell fibronectin production and extend survival time in a rat model of lipopolysaccharide-induced acute lung injury.

  2016cited by this paper
• Differential TLR activation of murine mesenchymal stem cells generates distinct immunomodulatory effects in EAE

  2016cited by this paper
• Combined Bone Marrow‐Derived Mesenchymal Stromal Cell Therapy and One‐Way Endobronchial Valve Placement in Patients with Pulmonary Emphysema: A Phase I Clinical Trial

  2016cited by this paper
• Oncostatin M‐Preconditioned Mesenchymal Stem Cells Alleviate Bleomycin‐Induced Pulmonary Fibrosis Through Paracrine Effects of the Hepatocyte Growth Factor

  2016cited by this paper
• iPSC-MSCs with High Intrinsic MIRO1 and Sensitivity to TNF-α Yield Efficacious Mitochondrial Transfer to Rescue Anthracycline-Induced Cardiomyopathy

  2016cited by this paper
• Human mesenchymal stromal cells exert HGF dependent cytoprotective effects in a human relevant pre-clinical model of COPD

  2016cited by this paper
• Extracellular vesicles derived from mesenchymal stromal cells: a therapeutic option in respiratory diseases?

  2016cited by this paper
• Mesenchymal Stem Cells Induce Suppressive Macrophages Through Phagocytosis in a Mouse Model of Asthma

  2016cited by this paper
• Mesenchymal Stromal Cells Induce Peculiar Alternatively Activated Macrophages Capable of Dampening Both Innate and Adaptive Immune Responses

  2016cited by this paper
• PPARβ/δ directs the therapeutic potential of mesenchymal stem cells in arthritis

  2016cited by this paper
• Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial.

  2015cited by this paper
• Hypoxia-preconditioned mesenchymal stem cells attenuate bleomycin-induced pulmonary fibrosis

  2015cited by this paper

• Exercise-Activated Mesenchymal Stem Cells: A Translational Strategy for Age-Related Sarcopenia Management

  2025cites this paper
• Pulmonary Vascular Endothelial Cells in Lung Diseases: Mechanisms, Therapeutic Strategies, and Future Directions

  2025cites this paper
• The PPARβ/δ-induced mesenchymal stromal cell secretome has cytoprotective effects via ANGPTL4 in a pre-clinical model of acute lung inflammation

  2025cites this paper
• Amniotic fluid-derived mesenchymal stem cells as a therapeutic tool against cytokine storm: a comparison with umbilical cord counterparts

  2025cites this paper
• The impact of the inflammatory pulmonary microenvironment on the behavior and function of mesenchymal stromal cells

  2025cites this paper
• Combined treatment with mesenchymal stem cells and ROCK inhibitor Y-27632 ameliorates PM2.5-induced lung injury.

  2025cites this paper
• Carbon monoxide licensing of MSCs enhances their efficacy through autophagy-mediated miRNA mechanisms.

  2024cites this paper
• Mapping the landscape: A bibliometric perspective on autophagy in spinal cord injury

  2024cites this paper
• The ARDS microenvironment enhances MSC-induced repair via VEGF in experimental acute lung inflammation

  2024cites this paper
• The VEGF‐Mediated Cytoprotective Ability of MIF‐Licensed Mesenchymal Stromal Cells in House Dust Mite‐Induced Epithelial Damage

  2024cites this paper
• The MSC-EV-microRNAome: A Perspective on Therapeutic Mechanisms of Action in Sepsis and ARDS

  2024cites this paper
• Unveiling the functional heterogeneity of cytokine-primed human umbilical cord mesenchymal stem cells through single-cell RNA sequencing

  2024cites this paper
• High throughput screening of mesenchymal stromal cell morphological response to inflammatory signals for bioreactor-based manufacturing of extracellular vesicles that modulate microglia

  2024cites this paper
• Mesenchymal stromal cells dampen trained immunity in house dust mite-primed macrophages expressing human macrophage migration inhibitory factor polymorphism.

  2024cites this paper
• Stem cells, cell therapies, and bioengineering in lung biology and diseases 2023

  2024cites this paper
• Detrimental alteration of mesenchymal stem cells by an articular inflammatory microenvironment results in deterioration of osteoarthritis

  2023cites this paper
• Therapeutic Effects of Mesenchymal Stromal Cells Require Mitochondrial Transfer and Quality Control

  2023cites this paper
• High throughput screening of mesenchymal stromal cell morphological response to inflammatory signals for bioreactor-based manufacturing of extracellular vesicles that modulate microglia

  2023cites this paper
• MSC-Based Cell Therapy for COVID-19-Associated ARDS and Classical ARDS: Comparative Perspectives

  2023cites this paper
• Prophylactic Administration of Mesenchymal Stromal Cells Does Not Prevent Arrested Lung Development in Extremely Premature-Born Non-Human Primates

  2023cites this paper
• Key Role of Mesenchymal Stromal Cell Interaction with Macrophages in Promoting Repair of Lung Injury

  2023cites this paper
• Human macrophage migration inhibitory factor potentiates mesenchymal stromal cell efficacy in a clinically relevant model of allergic asthma

  2023cites this paper
• An ISCT MSC Committee Editorial on overcoming limitations in clinical trials of mesenchymal stromal cell therapy for COVID-19: Time for a global registry

  2022cites this paper
• An International Society for Cell and Gene Therapy Mesenchymal Stromal Cells Committee editorial on overcoming limitations in clinical trials of mesenchymal stromal cell therapy for coronavirus disease-19: time for a global registry

  2022cites this paper
• Therapeutic Benefits of Mesenchymal Stem Cells in Acute Respiratory Distress Syndrome: Potential Mechanisms and Challenges

  2022cites this paper
• How to Make Sense out of 75,000 Mesenchymal Stromal Cell Publications?

  2022cites this paper