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. 2020 Nov 1;129(5):1051-1061.
doi: 10.1152/japplphysiol.00205.2020. Epub 2020 Sep 10.

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

D Merrill Dane  1 , Khoa Cao  1 , Yu-An Zhang  1 , Kemp H Kernstine  2 , Amiq Gazdhar  3   4 , Thomas Geiser  3   4 , Connie C W Hsia  1
Affiliations

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

D Merrill Dane et al. J Appl Physiol (1985). .

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 induced pluripotent stem cell 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 days after the last treatment (8 wk post-PNX); detailed quantitative analysis of lung ultrastructure was performed postmortem. Pre-PNX lung function was similar between groups. Compared with CFM control, treatment with iPSC CM attenuated the post-PNX decline in lung diffusing capacity for carbon monoxide and membrane diffusing capacity, accompanied by a 24% larger postmortem lobar volume and distal air spaces. 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 toward the lowest values, whereas 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.NEW & NOTEWORTHY To examine whether the secreted products of human induced pluripotent stem cells (iPSCs) facilitate innate adaptive responses following loss of lung tissue, adult dogs underwent surgical removal of one lung, then received repeated administration of iPSC secretory products via inhalational delivery compared with control treatment. Inhalation of iPSC secretory products enhanced capillary formation and beneficial structural remodeling in the remaining lung, leading to improved lung function.

Keywords: alveolar remodeling; compensatory lung growth; induced pluripotent stem cells; lung diffusing capacity; secretome.

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Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the authors.

Figures

Fig. 1.
Fig. 1.
Timeline of the studies. CFM, cell-free media; iPSC CM, induced pluripotent stem cell-conditioned media; PNX, pneumonectomy.
Fig. 2.
Fig. 2.
Lung volume-transpulmonary pressure relationships pre- and post-PNX. Lung volume at a given transpulmonary pressure was similarly lower post-PNX compared with pre-PNX in animals treated with cell-free media (CFM) or induced pluripotent stem cell-conditioned media (iPSC CM). Means ± SD. Repeated-measures ANOVA. Number of animals = 5 CFM and 6 iPSC CM. PNX, pneumonectomy.
Fig. 3.
Fig. 3.
Lung function pre- and post-PNX in animals treated with cell-free media (CFM) or induced pluripotent stem cell conditioned media (iPSC CM). A: end-inspiratory lung volume (EILV). B: end-expiratory lung volume (EELV). C: pulmonary blood flow. D: lung diffusing capacity for carbon monoxide (DLCO) measured at an inflation volume of 45 mL/kg and inspired O2 concentration of 21% was expressed under standard conditions (hematocrit = 0.45, alveolar Po2 = 120 mmHg). E: membrane diffusing capacity (DMCO). F: pulmonary capillary blood volume. Box: means ± SD; whiskers extend to maximum and minimum values. Factorial and repeated-measures ANOVA. Number of animals = 5 CFM and 6 iPSC CM. PNX, pneumonectomy.
Fig. 4.
Fig. 4.
Changes (post-/pre-PNX ratio) in plasma biomarkers.8-Hydroxy-2′-deoxyguanosine (8-OHdG) (A), 8-isoprostane (B), and total antioxidant capacity (copper-reducing equivalents) (C) in animals treated with cell-free media (CFM) or induced pluripotent stem cell-conditioned media (iPSC CM). Means ± SD. Symbols for P < 0.05 with respect to time post-PNX: † vs. Pre-PNX, ‡ vs. 1 h post-PNX (0 days), § vs. 5 days, # vs. 10 days, @ vs. 20 days, ¶ vs. 30 days, $ vs. 40 days by factorial ANOVA. Overall comparison between the treatment groups by repeated-measures ANOVA: P = 0.69 (A), P = 0.39 (B), and P = 0.25 (C). Number of animals = 5 CFM and 6 iPSC CM. PNX, pneumonectomy.
Fig. 5.
Fig. 5.
Representative distal lung morphology under light and electron microscopy in post-PNX animals treated with cell-free media (CFM) or induced pluripotent stem cell-conditioned media (iPSC CM), illustrating enlarged air spaces and a thinner septal tissue layer in the iPSC CM group on the “thin side” of the blood-gas barrier where the bulk of alveolar gas exchange takes place. Top: bar = 50 µm. Bottom: bar = 2 µm. PNX, pneumonectomy.
Fig. 6.
Fig. 6.
Morphometric results in the left caudal lobe in post-PNX animals treated with cell-free media (CFM) or induced pluripotent stem cell-conditioned media (iPSC CM). A: total lobe volume (intact or serial sectioned). B: volume of alveolar sacs and ducts. C: alveolar surface area. D: prevalence of alveolar double capillary profiles. Box: Means ± SD; whiskers extend to maximum and minimum values. P values indicate iPSC CM versus CFM by unpaired t test. n = 5 animals per group. PNX, pneumonectomy.
Fig. 7.
Fig. 7.
Frequency distribution of harmonic mean thickness of the tissue-plasma barrier in post-PNX animals treated with cell-free media (CFM) or induced pluripotent stem cell-conditioned media (iPSC CM). Box: Means ± SD; whiskers extend to maximum and minimum values. P values indicate iPSC CM versus CFM in each barrier thickness category by unpaired t test. Overall comparison between the treatment groups by repeated-measures ANOVA (P = 0.16). n = 5 animals per group. PNX, pneumonectomy.
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