Optimized administration of human embryonic stem cell-derived immunity-and-matrix regulatory cells for mouse lung injury and fibrosis

Abstract

Background Lung injury and pulmonary fibrosis (PF), frequently arising as sequelae of severe and acute lung disease, currently face a dearth of effective therapeutic potions. Mesenchymal stem cells (MSCs) with immunomodulatory and tissue repair functions have immense potential to treat lung injury and PF. However, the optimal route of administration, timing, and frequency of dosing remain elusive. Human embryonic stem cell-derived immunity-and-matrix-regulatory cells (IMRCs) have shown therapeutic potential for lung injury and PF. Methods To ascertain the optimal therapeutic regimen for IMRCs in PF, we conducted an experimental study. Utilizing a mouse model of PF induced by bleomycin (BLM), IMRCs were administered via either a single or double intravenous (IV) or intratracheal (IT) injection on the first and seventh days post-BLM induction. Results Our findings revealed that IV infusion of IMRCs surpassed IT infusion in enhancing survival rates, facilitating body weight recovery, and optimizing Ashcroft and Szapiel scores among the model mice. Notably, IV administration exhibited a more profound ability to mitigate lung inflammation and fibrosis. Moreover, earlier and more frequent administrations of IMRCs were found to be advantageous in enhancing their therapeutic effects. Specifically, early administration with two IV infusions significantly improved body weight, lung organ coefficient, pulmonary ventilation and diffusion functions, and PF. This was accompanied by an increase in alveolar type I and II epithelial cells and a suppression of macrophage infiltration via CD24. Conclusion Collectively, these results suggested that IMRCs infusion ameliorated lung injury by promoting lung regeneration and inhibiting macrophage infiltration in a route, time, and frequency-dependent manner.

1. Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease with an elusive etiology. IPF predominantly affects middle-aged and elderly individuals, and is characterized by a gradual exacerbation of dyspnea and irreversible deterioration of pulmonary function [1]. Although the discovery and application of antifibrotic drugs pirfenidone and nintedanib have brought hope to IPF patients in the past decade, the disease progression of most patients is still irreversible and disease mortality remains high. The median survival duration for patients who do not undergo lung transplantation is approximately 3 to 5 years following diagnosis [2, 3].

Stem cell therapy represents a promising and burgeoning therapeutic approach for managing a spectrum of degenerative disorders, including IPF. Among these, immunity-and-matrix-regulatory cells (IMRCs), mesenchymal-like stem cells derived from human embryonic stem cells (hESCs), possess several notable advantages such as abundant availability, an absence of teratoma formation, exceptional homogeneity, and the circumvention of tumorigenicity and immune rejection risks [4]. Moreover, IMRCs showed a good therapeutic effect in a mouse model of bleomycin (BLM)-induced lung injury [4], and have been used to treat COVID-19 critical illness (NCT04331613) [5] and PF (ChiCTR2000031139) [6] in patients caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, owing to the limited number of cases, more data are needed to optimize treatment of lung injury and PF with IMRCs. Crucially, the limited preclinical evidence supporting the application of IMRCs in IPF underscores the necessity for prudence in future research endeavors, particularly pertaining to the optimal route of administration, timing, and dosing intervals. Nonetheless, the establishment of standardized protocols could motivate scientists to delve deeper.