Hailey Hunt

Background: Idiopathic pulmonary fibrosis (IPF) is an irreversible, progressive interstitial lung disease with minimal available treatments and poor prognosis yielding an average life expectancy of 3-5 years after diagnosis. ^1,2 IPF is characterized by the persistence of profibrotic growth factors resulting in excessive deposition of collagen in the extracellular matrix, disrupting normal alveolar structure crucial for gas exchange. ^1,2 Mechanisms including TGF-β signaling and Wnt expression increase mesenchymal gene expression that promotes myofibroblast differentiation and recruit inflammatory mediators.¹ Environmental factors such as exposure to air pollutants, smoking, viruses, and pesticides contribute to chronic alveolar injury that upregulates wound healing mechanisms. ¹ The MUC5B r35705950 allele, prevalent in 38% of IPF patients, causes increased production of mucin and reduced mucous clearance via respiratory cilia. The second most common genetic mutation arises in the desmoplakin gene necessary for cell-to-cell adhesion and maintenance of normal alveolar structure. The most significant risk factor for IPF is aging since prevalence increases exponentially after the age of 50. ¹ The antifibrotic drugs Pirfenidone and Nintedanib remain the only pharmaceutical treatments available for IPF, acting to delay pulmonary function decline and provide protection against acute exacerbations. Side effects of these drugs include nausea and diarrhea, respectively, with the additional possibility of phototoxicity and liver toxicity in nearly 7% of patients.² Patients with severe IPF may undergo lung transplant if they present with no comorbidities. The lack of clinically effective drugs and the irreversible nature of the fibrotic process of IPF has led to studies exploring the use of mesenchymal stem-cell derived extracellular vesicles to alleviate fibrosis progression, but its mechanism is still largely unexplored.³

Objective: Summarize the available literature on the use of human umbilical cord mesenchymal stem cells (hucMSC) and bone marrow mesenchymal stem cells (BM-MSC) to reverse pulmonary fibrosis (PF) in animal models and IPF patients.

Search Methods: An online search in the PubMed database was conducted from February to April of 2024 the following keywords: “idiopathic pulmonary fibrosis”, “mesenchymal stem cells”. Articles were restricted to those released between 2018 and 2024.

Results: Tang et al. transfected hucMSCs into mice with bleomycin-induced PF with results showing significantly lower collagen levels, decreased mortality rates, a greater presence of cell proliferation markers Ki67 and EdU, a greater amount of alveolar type II (AT2) cell marker SPC, and a lower rate of lung fibroblast proliferation contributing to PF. Mitochondria expressed significant levels of inflammatory genes Nos2, Cxcl9, and Cxcl10 and significantly reduced levels of tissue repair genes Mrc1, Arg1, Chil3, and Tgm2.⁴ Chu et al. established that a high dose of hucMSCs administered to rats with bleomycin-induced PF significantly reversed alveolar structure damage and improved lung function at least 42 days after bleomycin injection. ⁵ Chen et al. identified an immunosuppressive role of BM-MSCs as they reduced the inflammatory response by decreasing the expression of the pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-10. Additionally, BM-MSCs protected epithelial cells from paraquat poisoning-induced apoptosis by decreasing the expression of fibrotic markers α-SMA and vimentin, while increasing the expression of the adhesion protein E-cadherin. ⁶ Two clinical trials using BM-MSCs in patients with IPF were reviewed. One trial utilized endobronchial infusion of BM-MSCs which caused serous adverse events after 12 months with functional decline present in six patients, and lung transplant in one, and death related to the trial. It was concluded that endobronchial infusion of BM-MSCs might not be a favorable treatment for IPF patients especially those with severe forms.⁷ The other clinical trial showed that intravenous BM-MSC transplantation in patients with moderate to severe IPF is safe and well tolerated at high doses.⁸

Conclusion: Both hucMSCs and BM-MSCs show promising results in the reversal of PF and improved lung function. However, their mechanisms remain largely unexplored, especially the hucMSCs which have only been used in animal models that do not fully demonstrate the intricacies of IPF progression in humans. The BM-MSC clinical trials were conducted with small sample sizes from isolated areas, yielding results that lack generalizability. Nevertheless, treatment of IPF with mesenchymal stem cells may alleviate the burden of disease and replace current treatments that merely aim to extend lifespan for a few years by slowing disease progression.

Works Cited

1. Moss BJ, Ryter SW, Rosas IO. Pathogenic Mechanisms Underlying Idiopathic Pulmonary Fibrosis. Annu Rev Pathol. 2022;17:515-546. doi:10.1146/annurev-pathol-042320-030240
2. Wijsenbeek M, Suzuki A, Maher TM. Interstitial lung diseases. Lancet. 2022;400(10354):769-786. doi:10.1016/S0140-6736(22)01052-2
3. Huang Y, Yang L. Mesenchymal stem cell-derived extracellular vesicles in therapy against fibrotic diseases. Stem Cell Res Ther. 2021;12(1):435. Published 2021 Aug 4. doi:10.1186/s13287-021-02524-1
4. Tang Z, Gao J, Wu J, et al. Human umbilical cord mesenchymal stromal cells attenuate pulmonary fibrosis via regulatory T cell through interaction with macrophage. Stem Cell Res Ther. 2021;12(1):397. Published 2021 Jul 13. doi:10.1186/s13287-021-02469-5
5. Chu KA, Wang SY, Yeh CC, et al. Reversal of bleomycin-induced rat pulmonary fibrosis by a xenograft of human umbilical mesenchymal stem cells from Wharton’s jelly. Theranostics. 2019;9(22):6646-6664. Published 2019 Sep 17. doi:10.7150/thno.33741
6. Chen J, Si L, Zhou L and Deng Y. Role of bone marrow mesenchymal stem cells in the development of PQ‑induced pulmonary fibrosis. Mol Med Rep. 2019;19:3283-3290. doi:10.3892/mmr.2019.9976
7. Campo A, González-Ruiz JM, Andreu E, et al. Endobronchial autologous bone marrow-mesenchymal stromal cells in idiopathic pulmonary fibrosis: a phase I trial. ERJ Open Res. 2021;7(2):00773-2020. Published 2021 Jun 28. doi:10.1183/23120541.00773-2020
8. Campo A, González-Ruiz JM, Andreu E, et al. Endobronchial autologous bone marrow-mesenchymal stromal cells in idiopathic pulmonary fibrosis: a phase I trial. ERJ Open Res. 2021;7(2):00773-2020. Published 2021 Jun 28. doi:10.1183/23120541.00773-2020