Current status of cell-based therapies for respiratory virus infections: applicability to COVID-19

Abstract

The severe respiratory consequences of the coronavirus disease 2019 (COVID-19) pandemic have prompted urgent need for novel therapies. Cell-based approaches, primarily using mesenchymal stem (stromal) cells (MSCs), have demonstrated safety and possible efficacy in patients with acute respiratory distress syndrome (ARDS), although they are not yet well studied in respiratory virus-induced ARDS. Limited pre-clinical data suggest that systemic MSC administration can significantly reduce respiratory virus (influenza strains H5N1 and H9N2)-induced lung injury; however, there are no available data in models of coronavirus respiratory infection.There is a rapidly increasing number of clinical investigations of cell-based therapy approaches for COVID-19. These utilise a range of different cell sources, doses, dosing strategies and targeted patient populations. To provide a rational strategy to maximise potential therapeutic use, it is critically important to understand the relevant pre-clinical studies and postulated mechanisms of MSC actions in respiratory virus-induced lung injuries. This review presents these, along with consideration of current clinical investigations.

FIGURE 1

Potential therapeutic effects of mesenchymal stem (stromal) cells (MSCs) in respiratory lung injury are mediated by different mechanisms, including but not limited to secreted paracrine factors, extracellular vesicles (EVs) and possibly mitochondrial transfer, promoting tissue protection, immunomodulation and possibly viral resistance. a) Schematic of a healthy alveolus (top) and inflamed/oedematous alveolus (bottom) and mechanisms involved in acute respiratory distress syndrome (ARDS) pathogenesis. b) Schematic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infecting a lung epithelial cell, with subsequent lysis and cytokine storm (left), and of potential MSC infection by SARS-CoV-2, with unknown downstream consequences (right). c) Some of the known mechanisms by which MSCs ameliorate non-viral acute lung injury. Adapted from Laffey and Matthay [9]. d) Limited information on mechanisms by which MSCs might ameliorate SARS-CoV-2 lung damage, based on limited pre-clinical data in influenza infection models. e) Current state-of-the-art of cell-based therapy in coronavirus disease 2019 (COVID-19), based on pre-clinical and clinical studies. MIF: macrophage migration inhibitory factor; TNF: tumour necrosis factor; IL: interleukin; ROS: reactive oxygen species; ACE2: angiotensin-converting enzyme 2; Ang-1: angiopoietin-1; PGE2: prostaglandin E2; KGF: keratinocyte growth factor; IL1-Ra: IL-1 receptor antagonist; TSG-6: TNF-stimulated gene 6; IGF-1: insulin-like growth factor 1; miRNAs: microRNAs; MΦ: macrophage; M2 MΦ: macrophage type 2; HGF: hepatocyte growth factor; NK cells: natural killer cells; ISGs: interferon-stimulated genes; hACE2: human ACE2.

FIGURE 2

Representative volcano plot analysis of gene expression of the interferon-stimulated genes (ISGs) in human bone marrow-derived mesenchymal stem (stromal) cells (BM-MSCs) activated with pro-inflammatory cytokines (interleukin-1β, tumour necrosis factor-α and interferon (IFN)-γ), versus control, in GEO dataset GSE68610. Gene expression analysis of a) constitutive and b) non-constitutive ISGs. ISG15: ubiquitin-like protein; CCL2: C-C motif chemokine 2; IFI6: IFN-α-inducible protein 6; PMAIP1: phorbol-12-myristate-13-acetate-induced protein 1; IFITM: IFN-induced transmembrane protein; CYP1B1: cytochrome p450 1b1; NPAS2: neuronal PAS domain-containing protein 2; TIMP-1: metalloproteinase inhibitor 1; MT1G/MT1X: metallothionein 1G/X; SERPING1: serpin family G member 1 (plasma protease C1 inhibitor); SAT1: sulfate anion transporter 1; GCA: grancalcin; IFNAR2: IFN-α/β receptor 2; SLC16A1: monocarboxylate transporter 1; ODC1: ornithine decarboxylase 1; FZD-5: Frizzled-5.