Current status of mesenchymal stem cell therapy for immune/inflammatory lung disorders: Gleaning insights for possible use in COVID-19

Abstract

The broad immunomodulatory properties of human mesenchymal stem cells (MSCs) have allowed for wide application in regenerative medicine as well as immune/inflammatory diseases, including unmatched allogeneic use. The novel coronavirus disease COVID-19 has unleashed a pandemic in record time accompanied by an alarming mortality rate mainly due to pulmonary injury and acute respiratory distress syndrome. Because there are no effective preventive or curative therapies currently, MSC therapy (MSCT) has emerged as a possible candidate despite the lack of preclinical data of MSCs for COVID-19. Interestingly, MSCT preclinical data specifically on immune/inflammatory disorders of the lungs were among the earliest to be reported in 2003, with the first clinical use of MSCT for graft-vs-host disease reported in 2004. Since these first reports, preclinical data showing beneficial effects of MSC immunomodulation have accumulated substantially, and as a consequence, over a third of MSCT clinical trials now target immune/inflammatory diseases. There is much preclinical evidence for MSCT in noninfectious-including chronic obstructive pulmonary disease, asthma, and idiopathic pulmonary fibrosis-as well as infectious bacterial immune/inflammatory lung disorders, with data generally demonstrating therapeutic effects; however, for infectious viral pulmonary conditions, the preclinical evidence is more scarce with some inconsistent outcomes. In this article, we review the mechanistic evidence for clinical use of MSCs in pulmonary immune/inflammatory disorders, and survey the ongoing clinical trials-including for COVID-19-of MSCT for these diseases, with some perspectives and comment on MSCT for COVID-19.

Keywords: ARDS; COPD; COVID-19; asthma; bacterial pneumonia; clinical trial; cytokine storm; idiopathic pulmonary fibrosis; influenza; mesenchymal stem cells.

FIGURE 1

Current disease distribution of clinical trials using human MSC for immune/inflammatory pulmonary disorders. Numbers of MSC clinical trials for various immune/inflammatory pulmonary disorders as registered on the NIH Clinical Trial Registry website (https://ClinicalTrials.gov/) as accessed on May 2020. ARDS, acute respiratory distress syndrome; COPD, chronic obstructive pulmonary disease; COVID‐19, coronavirus disease 2019; IPF, idiopathic pulmonary fibrosis; MSC, mesenchymal stem cell

FIGURE 2

Mechanisms involved in MSC therapy for immune/inflammatory pulmonary disorders. Mechanisms reported in in vivo preclinical studies of MSC therapy for immune/inflammatory lung diseases of non‐infectious etiology—including asthma, IPF, and COPDs—and infectious etiology—including bacterial and/or LPS and viral infection and related ARDS. Detailed descriptions can be found in the text. Ang‐1, angiopoietin‐1; ARDS, acute respiratory distress syndrome; COPD, chronic obstructive lung disease; EGF, epidermal growth factor; EV, extracellular vesicles; HGF, hepatocyte growth factor; IL‐1RA, interleukin‐1 receptor antagonist; IPF, idiopathic pulmonary fibrosis; KGF, keratinocyte growth factor; LPS, lipopolysaccharide; MΦ, macrophage; miRs, microRNAs; mitoch, mitochondria; MSC, mesenchymal stem cell; OCR, oxygen consumption rate; PMNs, polymorphonuclear leukocytes/neutrophils; Th2, T helper type 2 lymphocytes; TNF‐α, tumor necrosis factor‐α; Treg, regulatory T lymphocytes; TSF‐6, TNF‐stimulated gene 6 protein; VEGF, vascular endothelial growth factor; WBCs, white blood cells

FIGURE 3

Sources of human MSCs used in immune/inflammatory lung disease clinical trials. Number of trials using different sources of human MSCs is shown, and whether sources are autologous (AUTO‐MSC), allogeneic (ALLO‐MSC), unspecified (UNSP‐MSC), and/or noncell exosomes/conditioned medium (MSC‐derived products). Data accessed on May 2020 from the NIH Clinical Trial website (https://ClinicalTrials.gov/). MSC, mesenchymal stem cell

FIGURE 4

Immune/inflammatory lung disease clinical trials. Number of trials using various methods of MSC administration. Data accessed on May 2020 from the NIH Clinical Trial website (https://ClinicalTrials.gov/). MSC, mesenchymal stem cell

FIGURE 5

Sources of MSCs used and mechanical ventilation status of patients in COVID‐19 clinical trials. A, Number of trials using different sources of human MSCs is shown, and whether sources are autologous (AUTO‐MSC), allogeneic (ALLO‐MSC), unspecified (UNSP‐MSC), and/or noncell exosomes/conditioned medium (MSC‐derived products). B, Number of trials with regards to mechanical ventilation status for patient inclusion in COVID‐19 trials. Three trials have mechanical ventilation as an inclusion criteria (ONLY); 22 trials have inclusion criteria which would only capture hospitalized/severely ill patients (LIKELY), that is, including patients in the ICU and those who requiring exogenous oxygen and/or intubation; two trials only have COVID‐19 positivity as inclusion criteria so it is unclear whether very ill, mechanically ventilated patients would be included (UNCLEAR). Two trials exclude intubated patients (EXCLUDE), and two trials include asymptomatic individuals (ASYMP). All data accessed on May 2020 from the NIH Clinical Trial website (https://ClinicalTrials.gov/). ICU, intensive care unit; MSC, mesenchymal stem cell