Mesenchymal stromal cells for acute respiratory distress syndrome (ARDS), sepsis, and COVID-19 infection: optimizing the therapeutic potential

ABSTRACT

Introduction: Mesenchymal stromal (stem) cell (MSC) therapies are emerging as a promising therapeutic intervention in patients with Acute Respiratory Distress Syndrome (ARDS) and sepsis due to their reparative, immunomodulatory, and antimicrobial properties.

Areas covered: This review provides an overview of Mesenchymal stromal cells (MSCs) and their mechanisms of effect in ARDS and sepsis. The preclinical and clinical evidence to support MSC therapy in ARDS and sepsis is discussed. The potential for MSC therapy in COVID-19 ARDS is discussed with insights from respiratory viral models and early clinical reports of MSC therapy in COVID-19. Strategies to optimize the therapeutic potential of MSCs in ARDS and sepsis are considered including preconditioning, altered gene expression, and alternative cell-free MSC-derived products, such as extracellular vesicles and conditioned medium.

Expert opinion: MSC products present considerable therapeutic promise for ARDS and sepsis. Preclinical investigations report significant benefits and early phase clinical studies have not highlighted safety concerns. Optimization of MSC function in preclinical models of ARDS and sepsis has enhanced their beneficial effects. MSC-derived products, as cell-free alternatives, may provide further advantages in this field. These strategies present opportunity for the clinical development of MSCs and MSC-derived products with enhanced therapeutic efficacy.

KEYWORDS:

• Acute Respiratory Distress Syndrome
• ARDS
• advanced Therapeutic Medicinal Product
• ATMP
• COVID-19
• mesenchymal stromal cell
• MSC
• sepsis
• septic Shock

Article highlights

• This article reviews the existing literature and clinical trial databases relating to the use of MSCs in critical illness including sepsis, Acute Respiratory Distress Syndrome (ARDS), and SARS-CoV-2 infection causing COVID-19.

• The immunomodulatory, pro-reparative, and anti-microbial properties of MSCs, as relevant to critical illness, are reviewed in detail.

• Data relating to safety in clinical trials of MSCs in patients, with particular emphasis on critical illness, are reviewed.

• Current clinical trials of MSCs in sepsis, ARDS, and COVID-19 are summarised and tabulated.

Mechanisms of optimizing MSC therapy are reviewed, and the preclinical studies of genetic modification/other optimization are summarised.

Declaration of interest

CO Kane reports grants from MRC, Wellcome Trust and NI HSC R&D Office for investigation of effects of MSCs in the Lung and for treatment of ARDS. CO collaborates with Orbsen for the investigation of MSCs as a treatment for ARDS. CO’s spouse has received consultancy from Novartis, Bayer, GSK and Boehringer for ARDS. D McAuley reports grants from MRC, Wellcome Trust and NI HSC R&D Office for investigation of effects of MSCs in the Lung and for treatment of ARDS. DM collaborates with Orbsen for the investigation of MSCs as a treatment for ARDS. DM has received consultancy from Bayer, GSK, Novartis and Boehringer for ARDS. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Drs Gorman and Millar report no conflicts related to the subject of the manuscript.

Disclosure Statement

No potential conflict of interest was reported by the author(s).

Reviewer disclosures

A reviewer on this manuscript has disclosed that they are part of a team that is in the process of initiating a phase 2 clinical trial using MSC for septic shock (CISS2), and also a part-time employee for a cell therapeutic company that is working on modified MSC for sepsis (Northern Therapeutics Inc).

Additional information

Funding

This paper was not funded.