A group of researchers discussed the still controversial role of mesenchymal stromal/stem cells (MSCs) in the pathogenesis and clinical management of idiopathic pulmonary fibrosis (IPF) in a comprehensive review recently published in Frontiers in Pharmacology.

The authors presented a dualistic scenario, in which “although endogenous MSCs may play a critical role in lung repair, they are also involved in cellular senescence and tissue aging  processes with loss of lung regenerative potential.” 

Upheld by solid scientific research, Samarelli et al discussed in detail the cellular and molecular mechanisms underlying IPF, as well as the role of lung resident MSCs (LR-MSCs) in lung physiology and pathology, which are far from being completely understood. They also revisited preclinical and clinical studies that supported the potential use of MSC-based therapies in lung fibrosis. 


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MSCs have anti-inflammatory and immunomodulatory properties. Results from preclinical studies demonstrated that exogenous MSCs administration can alleviate acute lung inflammation and prevent lung fibrosis in multiple lung disease models. However, in most studies, MSCs were not able to revert established fibrotic changes as those typically observed in IPF patients at the time of diagnosis. In fact, according to the authors, there was only one study that did report the reversion of established fibrosis following administration of bone marrow MSCs (BM-MSCs) in albino rats.

Hepatocyte growth factor (HGF)-based gene therapy has been used to boost the effects of MSCs on lung injury. Different studies have demonstrated that MSCs overexpressing HGF — an anti-inflammatory, antiapoptotic, and pro-reparative growth factor — had increased viability and improved anti-inflammatory properties when compared to wild-type MSCs.

Increasing attention has also been given to MSC-derived secretome and extracellular vesicles as a novel therapeutic approach for lung fibrosis. For instance:

  • Human lung spheroid cell-derived secretome and exosomes attenuated bleomycin‑induced fibrosis and restored normal alveolar structure in a bleomycin mouse model
  • Exosomes from human BM‑MSCs prevented and reverted pulmonary fibrosis, as well as modulated monocyte phenotypes in a bleomycin mouse model
  • Bronchoalveolar lavage fluid from experimental lung fibrosis and IPF patients was enriched in MSC-derived extracellular vesicles, particularly exosomes, that contain important signaling mediators for disease pathogenesis.

Samarelli et al described the findings of two phase 1 trials that studied the safety of 2 MSC‑based therapies in IPF patients: one used endobronchial infusion of autologous adipose-derived stromal cells‑stromal vascular fraction (n=14) and the other used intravenous infusion of human BM‑MSCs (n=9). Both trials reported acceptable safety profiles, but they were not designed to evaluate efficacy. 

The review authors underscored that “when MSCs are systemically infused, the high level of procoagulant tissue factor expressed might trigger the instant blood-mediated inflammatory reaction with potentially lethal consequences for patients. Thus, it has become crucial to find strategies aiming at modulating MSCs hemocompatibility in order to increase safety and efficacy of intravascular MSCs therapies.”

Reference

Samarelli AV, Tonelli R, Heijink I, et al. Dissecting the role of mesenchymal stem cells in idiopathic pulmonary fibrosis: cause or solution. Front Pharmacol. 2021;12:1656. doi:10.3389/fphar.2021.692551