Inhalational delivery of induced pluripotent stem cell secretome improves postpneumonectomy lung structure and function

Abstract

Cell-free secretory products (secretome) of human induced pluripotent stem cells (iPSCs) have been shown to attenuate tissue injury and facilitate repair and recovery. To examine whether iPSC secretome facilitates mechanically-induced compensatory responses following unilateral pneumonectomy (PNX), litter-matched young adult female hounds underwent right PNX (removing 55-58% of lung units) followed by inhalational delivery of either the nebulized conditioned media containing iPSCs secretome (iPSC CM) or control cell-free media (CFM); inhalation was repeated every 5 days for 10 treatments. Lung function was measured under anesthesia pre-PNX and 10 d after the last treatment (8 weeks post-PNX); detailed quantitative analysis of lung ultrastructure was performed postmortem. Pre-PNX lung function was similar between groups. Compared to CFM control, treatment with iPSC CM attenuated the post-PNX decline in DLCO and DMCO, accompanied by a 24% larger postmortem lobar volume and distal air space enlargement. Alveolar double-capillary profiles were 39% more prevalent consistent with enhanced intussusceptive angiogenesis. Frequency distribution of the harmonic mean thickness of alveolar blood-gas barrier shifted towards the lowest values while alveolar septal tissue volume and arithmetic septal thickness were similar, indicating septal remodeling and reduced diffusive resistance of the blood-gas barrier. Thus, repetitive inhalational delivery of iPSC secretome enhanced post-PNX alveolar angiogenesis and septal remodeling that are associated with improved gas exchange compensation. Results highlight the plasticity of the remaining lung units following major loss of lung mass that are responsive to broad-based modulation provided by the iPSC secretome.

Translational Animal Models Provide Insight Into Mesenchymal Stromal Cell (MSC) Secretome Therapy

“…For example, treatments with CM from human induced pluripotent stem cells (iPSCs) were delivered by inhalation every 5 days following unilateral pneumonectomy (PNX) in a dog model of destructive lung disease. This study revealed that repetitive inhalation of the iPSC secretome increased alveolar angiogenesis and enhanced septal remodeling associated with improved gas exchange compensation in the lungs (Dane et al, 2020). Moreover, intranasal delivery of the MSC secretome may also have neuroprotective effects, as shown in a study evaluating the efficacy of the secretome of the human amnion-derived multipotent progenitor cells, named ST266 (Grinblat et al, 2018).…”

“…Direct administration includes the injection or application of CM from cultured MSCs at the site of injury, e.g., cutaneous wounds, as well as the injection of exosomes (EXOs) systemically into the blood stream (Daneshmandi et al, 2020). The MSC secretome may also be delivered directly by inhalation for certain diseases (Khan et al, 2017;Grinblat et al, 2018;Dane et al, 2020). For example, treatments with CM from human induced pluripotent stem cells (iPSCs) were delivered by inhalation every 5 days following unilateral pneumonectomy (PNX) in a dog model of destructive lung disease.…”

Induced pluripotent stem cells in companion animals: how can we move the field forward?

“…To date, only one study has been conducted in dogs, serving as canine model for using human iPSC-derived cell-free secretome to enhance post-pneumonectomy compensatory response. Human iPSC-derived secretome showed improved angiogenesis and alveolar remodeling leading to enhanced gas exchange after the pneumonectomy ( 191 ). This highlights the therapeutic potential of iPSC-derived secretome and EVs in human and veterinary patients, particularly due to their ease of administration.…”

Extracellular vesicle-mediated cellular crosstalk in lung repair, remodelling and regeneration

“…HiPSCs are derived from adult somatic cells and are reprogrammed into a pluripotent state by induced expression of certain transcription factors, such as Oct4, Sox2, Myc and Klf4 [118,119]. Induced pluripotent stem cell (iPSC) secretome, including EVs has been reported to improve hyperoxia-induced acute lung injury, bleomycin-induced fibrosis, and postpneumonectomy lung structure and function [59,[120][121][122]. However, clear evidence for the efficacy of iPSC-derived EVs in improving lung diseases remain elusive, although one study may have shown some beneficial effects [59].…”