Therapeutic potential of mesenchymal stem/stromal cell-derived secretome and vesicles for lung injury and disease

ABSTRACT

Introduction: The acute respiratory distress syndrome (ARDS) is a devastating clinical condition common in patients with respiratory failure. Based largely on numerous preclinical studies and recent Phase I/II clinical trials, administration of stem cells, specifically mesenchymal stem or stromal cells (MSC), as a therapeutic for acute lung injury (ALI) holds great promise. However, concern for the use of stem cells, specifically the risk of iatrogenic tumor formation, remains unresolved. Accumulating evidence now suggest that stem cell-derived conditioned medium (CM) and/or extracellular vesicles (EV) might constitute compelling alternatives.

Areas covered: The current review focuses on the preclinical studies testing MSC CM and/or EV as treatment for ALI and other inflammatory lung diseases.

Expert opinion: Clinical application of MSC or their secreted CM may be limited by the cost of growing enough cells, the logistic of MSC storage, and the lack of standardization of what constitutes MSC CM. However, the clinical application of MSC EV remains promising, primarily due to the ability of EV to maintain the functional phenotype of the parent cell as a therapeutic. However, utilization of MSC EV will also require large-scale production, the cost of which may be prohibitive unless the potency of the EV can be increased.

KEYWORDS:

• Acute lung injury
• acute respiratory distress syndrome
• exosomes
• extracellular vesicles
• mesenchymal stem or stromal cells
• microvesicles

Article Highlights

• Early Phase I and II clinical trials using human bone marrow-derived MSC as a therapeutic for moderate to severe acute respiratory distress syndrome or sepsis have demonstrated that intravenous instillation of the cells is safe.

• Although MSC derived CM can recapitulate the therapeutic effects of MSC in preclinical ALI models, their potential use as a therapeutic may be limited due to the lack of standardization among studies (i.e. preconditioning, volume and concentration of CM instillate) as well as the optimal therapeutic dose, timing, and route of administration.

• MSC derived EV may represent a more attractive area of research for treating inflammatory lung diseases, including ALI, in part due to the mechanisms underlying their therapeutic effects: the transfer of mRNA, microRNA, proteins, receptors, and possibly organelles from the EV to the injured tissue.

• In preclinical models, MSC EV ameliorated most of the major pathologies associated with ALI: increase in lung protein permeability, pulmonary edema, alveolar inflammation, and overwhelming bacterial infection.

• In anticipation for any clinical application, utilization of MSC EV will require some mechanisms to increase the potency of the EV due to the prohibitive cost of growing enough cells to generate the vesicles.

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Declaration of interest

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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was supported by the National Heart, Lung, and Blood Institute grant number HL 113022 (Dr. JW Lee).