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

Abstract

Recent advances in cell based therapies for lung diseases and critical illnesses offer significant promise. Despite encouraging preclinical results, the translation of efficacy to the clinical settings have not been successful. One of the possible reasons for this is the lack of understanding of the complex interaction between mesenchymal stromal cells (MSCs) and the host environment. Other challenges for MSC cell therapies include cell sources, dosing, disease target, donor variability, and cell product manufacturing. Here we provide an overview on advances and current issues with a focus on MSC-based cell therapies for inflammatory acute respiratory distress syndrome varieties and other inflammatory lung diseases.

Extracellular Vesicles and Alveolar Epithelial-Capillary Barrier Disruption in Acute Respiratory Distress Syndrome: Pathophysiological Role and Therapeutic Potential

“…In this context, one of the major challenges in MSC-based therapies is to develop methods that mimic the injury environment, without compromising cell quality and function. Thus, currently explored in vitro preconditioning strategies include environmental stimuli (such as exposure to hypoxia), treatment with cytokines or pharmacological agents, physical factor preconditioning or genetic engineering (summarized in Table 4 ; Ferreira et al, 2018 ; Han et al, 2019 ; Gorgun et al, 2021 ; Rolandsson Enes et al, 2021 ).…”

“…Mesenchymal stem cells sense the environment through various damage-associated and pathogen-associated cell surface receptors and respond differentially depending on the environmental requirements ( Waterman et al, 2010 ; Mastri et al, 2012 ; Rolandsson Enes et al, 2021 ). For example, stimulation of TLR3 and TLR4 appeared to polarize MSCs into two different immune regulatory phenotypes.…”

The Inflammatory Lung Microenvironment; a Key Mediator in MSC Licensing

“…Clinical trials have investigated MSC therapy (BM and UC) in IPF [ 15 ], COPD [ 16 , 17 , 18 ], ARDS [ 19 , 20 ] and in COVID-19 associated ARDS [ 21 ] showing safety but have not yet shown efficacy. While MSCs (BM or AT) have been approved in some countries for use in treating acute graft versus host disease (aGvHD) [ 22 , 23 , 24 ] and for Crohn’s fistula [ 25 , 26 ], MSC therapy has not yet been approved for lung inflammatory disorders [ 27 ]. However, MSCs have a proven safety profile in clinical trials [ 27 ] for inflammatory lung disorders and there are currently 151 clinical trials investigating MSCs as a lung intervention ( , accessed on 5 October 2021), many of these for COVID-19-associated ARDS.…”

“…While MSCs (BM or AT) have been approved in some countries for use in treating acute graft versus host disease (aGvHD) [ 22 , 23 , 24 ] and for Crohn’s fistula [ 25 , 26 ], MSC therapy has not yet been approved for lung inflammatory disorders [ 27 ]. However, MSCs have a proven safety profile in clinical trials [ 27 ] for inflammatory lung disorders and there are currently 151 clinical trials investigating MSCs as a lung intervention ( , accessed on 5 October 2021), many of these for COVID-19-associated ARDS. While significant progress has been made in understanding the mechanisms by which MSC mediate their anti-inflammatory and pro-reparative effects in vitro, there are gaps in our understanding of how MSCs mediate their therapeutic effects in vivo [ 28 , 29 ].…”

“…A significant body of work has clearly identified the requirement for MSCs to be activated or licensed by signals such as pro-inflammatory cytokines to mediate MSC therapeutic effects [ 28 , 30 ]. It is becoming increasingly apparent that the disease inflammatory environment into which MSCs are administered is of critical importance for MSC capacity to suppress inflammation and promote repair [ 27 , 28 ]. The success of clinical application of MSC administration is limited by unclear understanding of the role of the microenvironment on MSC capacity to suppress inflammation and modulate immune responses.…”